TNFAIP3 Data Analysis

HGNC Gene Name: TNF alpha induced protein 3
HGNC Gene Symbol: TNFAIP3
Identifiers: hgnc:11896 NCBIGene:7128 uniprot:P21580
Orthologs: mgi:1196377 rgd:1589275
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for TNFAIP3
Number of Papers: 1619 retrieved on 2023-02-19

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol	Name	DepMap Correlation	Evidence	CCLE Correlation	CCLE Z-score	CCLE p-value (adj)	CMAP Score	CMAP Type
TNIP1	TNFAIP3 interacting protein 1	0.353	BioGRID IntAct INDRA (22) Reactome (4)	0.16	0.80	1.59e-02
NFKBIA	NFKB inhibitor alpha	0.292	INDRA (9) Reactome (8)	-0.05	-0.38	5.63e-01	95.99	oe
CYLD	CYLD lysine 63 deubiquitinase	0.272	INDRA (10) Reactome (15)	0.14	0.66	7.05e-02
ATG101	autophagy related 101	0.228		-0.01	-0.13	9.33e-01
PPM1A	protein phosphatase, Mg2+/Mn2+ dependent 1A	0.227	Reactome (1)	-0.00	-0.10	9.78e-01
IRAK1	interleukin 1 receptor associated kinase 1	-0.218	INDRA (3) Reactome (6)	-0.00	-0.10	9.78e-01	-99.89	kd
EPG5	ectopic P-granules 5 autophagy tethering factor	0.216		0.12	0.59	1.04e-01

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with TNFAIP3using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier	GO Name	GO Type	p-value	p-value (adj.)	q-value
GO:1901222	regulation of NIK/NF-kappaB signaling	Biological Process	3.83e-08	1.09e-05	4.56e-06
GO:0035872	nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	Biological Process	2.18e-07	6.20e-05	9.94e-06
GO:0038061	NIK/NF-kappaB signaling	Biological Process	2.51e-07	7.12e-05	9.94e-06
GO:0002221	pattern recognition receptor signaling pathway	Biological Process	3.70e-07	1.05e-04	1.10e-05
GO:0002753	cytoplasmic pattern recognition receptor signaling pathway	Biological Process	1.15e-06	3.27e-04	2.50e-05
GO:0007249	I-kappaB kinase/NF-kappaB signaling	Biological Process	1.26e-06	3.58e-04	2.50e-05
GO:0002218	activation of innate immune response	Biological Process	2.51e-06	7.12e-04	4.26e-05
GO:0032088	negative regulation of NF-kappaB transcription factor activity	Biological Process	3.44e-06	9.78e-04	5.12e-05
GO:0045088	regulation of innate immune response	Biological Process	9.45e-06	2.68e-03	1.25e-04
GO:0002224	toll-like receptor signaling pathway	Biological Process	1.47e-05	4.16e-03	1.74e-04
GO:0043433	negative regulation of DNA-binding transcription factor activity	Biological Process	2.41e-05	6.84e-03	2.60e-04
GO:1901223	negative regulation of NIK/NF-kappaB signaling	Biological Process	4.71e-05	1.34e-02	4.67e-04
GO:0034142	toll-like receptor 4 signaling pathway	Biological Process	6.51e-05	1.85e-02	5.96e-04
GO:0002755	MyD88-dependent toll-like receptor signaling pathway	Biological Process	7.31e-05	2.07e-02	6.21e-04
GO:0030522	intracellular receptor signaling pathway	Biological Process	1.04e-04	2.96e-02	8.27e-04
GO:0070646	protein modification by small protein removal	Biological Process	1.29e-04	3.67e-02	9.13e-04
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB signaling	Biological Process	1.31e-04	3.71e-02	9.13e-04

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out TNFAIP3 using CRISPR-Cas9.

Knockout Differential Expression

Symbol	Name	log₂-fold-change	p-value	p-value (adj.)
CSF2	colony stimulating factor 2	1.51e+00	1.50e-22	2.08e-18
C15orf48	chromosome 15 open reading frame 48	1.15e+00	7.38e-20	5.14e-16
CXCL8	C-X-C motif chemokine ligand 8	1.64e+00	2.09e-19	9.69e-16
CXCL1	C-X-C motif chemokine ligand 1	1.46e+00	4.52e-14	1.58e-10
CXCL2	C-X-C motif chemokine ligand 2	1.33e+00	1.63e-11	4.54e-08
AKR1B1	aldo-keto reductase family 1 member B	5.51e-01	1.83e-10	4.26e-07
RPL13	ribosomal protein L13	5.46e-01	6.63e-10	1.32e-06
MMP1	matrix metallopeptidase 1	4.86e-01	1.22e-09	2.13e-06
SOD2	superoxide dismutase 2	6.83e-01	1.66e-09	2.58e-06
BIRC3	baculoviral IAP repeat containing 3	7.64e-01	4.35e-09	6.07e-06
BCL2A1	BCL2 related protein A1	1.05e+00	4.78e-08	6.06e-05
CSF3	colony stimulating factor 3	1.24e+00	1.01e-07	1.17e-04
NSA2	NSA2 ribosome biogenesis factor	7.84e-01	1.16e-07	1.24e-04
CXCL3	C-X-C motif chemokine ligand 3	1.12e+00	3.18e-07	2.96e-04
SAT1	spermidine/spermine N1-acetyltransferase 1	5.59e-01	3.15e-07	2.96e-04
GPX1	glutathione peroxidase 1	6.04e-01	5.78e-07	5.04e-04
PTX3	pentraxin 3	6.69e-01	9.08e-07	7.45e-04
RPS15	ribosomal protein S15	7.66e-01	1.52e-06	1.18e-03
NFKBIA	NFKB inhibitor alpha	6.37e-01	2.02e-06	1.49e-03
SAA1	serum amyloid A1	8.55e-01	2.15e-06	1.50e-03
RPL7	ribosomal protein L7	3.93e-01	2.92e-06	1.94e-03
SEC61G	SEC61 translocon subunit gamma	3.61e-01	3.37e-06	2.13e-03
RPS10-NUDT3	RPS10-NUDT3 readthrough	-5.78e-01	4.28e-06	2.59e-03
ICAM1	intercellular adhesion molecule 1	8.68e-01	6.10e-06	3.54e-03
ZC3H12C	zinc finger CCCH-type containing 12C	9.87e-01	9.52e-06	5.31e-03
CTSS	cathepsin S	8.41e-01	1.03e-05	5.52e-03
POU2F2	POU class 2 homeobox 2	6.84e-01	1.39e-05	7.18e-03
SAA2	serum amyloid A2	8.64e-01	2.33e-05	1.16e-02
PLAU	plasminogen activator, urokinase	4.50e-01	2.59e-05	1.25e-02
PDZK1IP1	PDZK1 interacting protein 1	9.52e-01	4.92e-05	2.28e-02
EPS8	epidermal growth factor receptor pathway substrate 8	7.72e-01	5.90e-05	2.65e-02
TFPI2	tissue factor pathway inhibitor 2	5.18e-01	7.72e-05	3.36e-02
HACD3	3-hydroxyacyl-CoA dehydratase 3	4.66e-01	8.88e-05	3.75e-02
SPRED1	sprouty related EVH1 domain containing 1	7.59e-01	9.22e-05	3.78e-02
IL6	interleukin 6	8.71e-01	9.96e-05	3.97e-02
ZMIZ2	zinc finger MIZ-type containing 2	7.55e-01	1.26e-04	4.88e-02

Gene Set Enrichment Analysis

The GSEA method was applied for all genes whose knockout resulted in at least 20 significantly differentially expressed genes.

ID	Name	p-value	p-value (adj.)	log₂ Error	ES	NES
msig:M5890	HALLMARK_TNFA_SIGNALING_VIA_NFKB	8.15e-14	3.19e-10	9.55e-01	6.01e-01	2.63e+00
go:0030545	receptor regulator activity	1.65e-11	3.22e-08	8.63e-01	6.23e-01	2.59e+00
msig:M9809	KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION	1.24e-09	1.61e-06	7.88e-01	6.85e-01	2.52e+00
go:0005126	cytokine receptor binding	6.93e-09	5.41e-06	7.61e-01	5.85e-01	2.40e+00
go:0031012	extracellular matrix	6.12e-09	5.41e-06	7.61e-01	5.30e-01	2.31e+00
go:0019221	cytokine-mediated signaling pathway	1.22e-08	7.94e-06	7.48e-01	3.79e-01	1.91e+00
go:0005125	cytokine activity	1.86e-08	1.04e-05	7.34e-01	7.45e-01	2.59e+00
go:0010469	regulation of signaling receptor activity	2.37e-08	1.16e-05	7.34e-01	5.08e-01	2.24e+00
msig:M5930	HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION	6.54e-08	2.84e-05	7.05e-01	5.41e-01	2.29e+00
go:0005102	signaling receptor binding	7.84e-08	3.06e-05	7.05e-01	3.24e-01	1.69e+00
go:0050900	leukocyte migration	1.69e-07	6.01e-05	6.90e-01	4.76e-01	2.13e+00
go:0034097	response to cytokine	1.85e-07	6.02e-05	6.90e-01	3.17e-01	1.67e+00
go:0009607	response to biotic stimulus	3.33e-07	9.31e-05	6.75e-01	3.54e-01	1.80e+00
go:0009617	response to bacterium	3.31e-07	9.31e-05	6.75e-01	4.46e-01	2.06e+00
go:0008083	growth factor activity	4.64e-07	1.21e-04	6.75e-01	6.70e-01	2.38e+00
go:0097530	granulocyte migration	5.64e-07	1.38e-04	6.59e-01	6.64e-01	2.32e+00
go:0062023	collagen-containing extracellular matrix	6.16e-07	1.42e-04	6.59e-01	5.16e-01	2.18e+00
go:0060326	cell chemotaxis	7.75e-07	1.68e-04	6.59e-01	5.37e-01	2.23e+00
go:0002237	response to molecule of bacterial origin	1.30e-06	2.68e-04	6.44e-01	4.86e-01	2.09e+00
go:0097529	myeloid leukocyte migration	1.89e-06	3.69e-04	6.44e-01	5.90e-01	2.26e+00
reactome:R-HSA-1280215	Cytokine Signaling in Immune system	2.53e-06	4.49e-04	6.27e-01	3.26e-01	1.68e+00
go:0006954	inflammatory response	2.46e-06	4.49e-04	6.27e-01	4.08e-01	1.92e+00
go:0005783	endoplasmic reticulum	4.34e-06	7.37e-04	6.11e-01	2.69e-01	1.49e+00
go:0030595	leukocyte chemotaxis	5.74e-06	9.34e-04	6.11e-01	5.52e-01	2.18e+00
go:1990266	neutrophil migration	6.30e-06	9.47e-04	6.11e-01	6.87e-01	2.30e+00
go:0001816	cytokine production	6.27e-06	9.47e-04	6.11e-01	3.54e-01	1.75e+00
go:0005201	extracellular matrix structural constituent	8.78e-06	1.27e-03	5.93e-01	7.15e-01	2.27e+00
reactome:R-HSA-449147	Signaling by Interleukins	9.91e-06	1.38e-03	5.93e-01	3.50e-01	1.73e+00
go:1990868	response to chemokine	1.41e-05	1.89e-03	5.93e-01	7.65e-01	2.26e+00
msig:M15569	KEGG_NOD_LIKE_RECEPTOR_SIGNALING_PATHWAY	1.62e-05	2.12e-03	5.76e-01	6.94e-01	2.30e+00
go:0071216	cellular response to biotic stimulus	2.29e-05	2.88e-03	5.76e-01	4.83e-01	1.99e+00
msig:M5913	HALLMARK_INTERFERON_GAMMA_RESPONSE	2.49e-05	3.01e-03	5.76e-01	4.64e-01	1.97e+00
go:0043062	extracellular structure organization	2.54e-05	3.01e-03	5.76e-01	4.27e-01	1.89e+00
msig:M5947	HALLMARK_IL2_STAT5_SIGNALING	3.12e-05	3.48e-03	5.57e-01	4.73e-01	1.98e+00
msig:M5932	HALLMARK_INFLAMMATORY_RESPONSE	3.07e-05	3.48e-03	5.57e-01	4.84e-01	1.98e+00
msig:M4844	KEGG_CHEMOKINE_SIGNALING_PATHWAY	3.71e-05	4.02e-03	5.57e-01	5.43e-01	2.09e+00
go:0071396	cellular response to lipid	4.19e-05	4.42e-03	5.57e-01	3.54e-01	1.73e+00
go:0048585	negative regulation of response to stimulus	4.44e-05	4.45e-03	5.57e-01	2.70e-01	1.46e+00
go:0006952	defense response	4.44e-05	4.45e-03	5.57e-01	2.83e-01	1.50e+00
go:0040017	positive regulation of locomotion	4.64e-05	4.54e-03	5.57e-01	3.45e-01	1.69e+00
go:1901701	cellular response to oxygen-containing compound	5.14e-05	4.78e-03	5.57e-01	2.95e-01	1.54e+00
go:0002684	positive regulation of immune system process	5.07e-05	4.78e-03	5.57e-01	3.07e-01	1.58e+00
msig:M12868	KEGG_PATHWAYS_IN_CANCER	7.14e-05	6.34e-03	5.38e-01	3.93e-01	1.78e+00
reactome:R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling	7.00e-05	6.34e-03	5.38e-01	6.02e-01	2.10e+00
msig:M5925	HALLMARK_E2F_TARGETS	7.70e-05	6.64e-03	5.38e-01	-3.75e-01	-1.75e+00
go:0051240	positive regulation of multicellular organismal process	7.81e-05	6.64e-03	5.38e-01	2.70e-01	1.45e+00
go:0002224	toll-like receptor signaling pathway	8.09e-05	6.65e-03	5.38e-01	5.48e-01	2.08e+00
go:0032103	positive regulation of response to external stimulus	8.17e-05	6.65e-03	5.38e-01	4.64e-01	1.95e+00
go:0071548	response to dexamethasone	9.42e-05	7.51e-03	5.38e-01	7.29e-01	2.11e+00
go:0042127	regulation of cell population proliferation	9.86e-05	7.71e-03	5.38e-01	2.69e-01	1.44e+00
go:0006959	humoral immune response	1.16e-04	8.91e-03	5.38e-01	6.10e-01	2.11e+00
go:0046545	development of primary female sexual characteristics	1.19e-04	8.92e-03	5.38e-01	5.76e-01	2.05e+00
go:0050918	positive chemotaxis	1.56e-04	1.15e-02	5.19e-01	7.05e-01	2.09e+00
go:0050921	positive regulation of chemotaxis	1.86e-04	1.33e-02	5.19e-01	5.34e-01	1.99e+00
go:0097190	apoptotic signaling pathway	2.04e-04	1.42e-02	5.19e-01	3.02e-01	1.53e+00
reactome:R-HSA-375276	Peptide ligand-binding receptors	2.13e-04	1.46e-02	5.19e-01	6.95e-01	2.12e+00
reactome:R-HSA-373076	Class A/1 (Rhodopsin-like receptors)	2.43e-04	1.63e-02	5.19e-01	6.40e-01	2.12e+00
go:1903900	regulation of viral life cycle	2.47e-04	1.63e-02	4.98e-01	4.43e-01	1.87e+00
go:0023057	negative regulation of signaling	2.78e-04	1.75e-02	4.98e-01	2.71e-01	1.45e+00
go:0002682	regulation of immune system process	2.75e-04	1.75e-02	4.98e-01	2.64e-01	1.40e+00
go:0042330	taxis	2.71e-04	1.75e-02	4.98e-01	3.65e-01	1.70e+00
go:0071384	cellular response to corticosteroid stimulus	3.17e-04	1.97e-02	4.98e-01	5.86e-01	2.02e+00
go:0001775	cell activation	3.45e-04	2.07e-02	4.98e-01	2.67e-01	1.41e+00
go:0001664	G protein-coupled receptor binding	3.41e-04	2.07e-02	4.98e-01	5.01e-01	1.97e+00
go:0046660	female sex differentiation	3.71e-04	2.19e-02	4.98e-01	5.43e-01	2.01e+00
go:0048514	blood vessel morphogenesis	4.28e-04	2.46e-02	4.98e-01	3.38e-01	1.61e+00
go:0002690	positive regulation of leukocyte chemotaxis	4.84e-04	2.74e-02	4.98e-01	5.79e-01	2.01e+00
go:0035150	regulation of tube size	5.03e-04	2.80e-02	4.77e-01	5.93e-01	2.03e+00
go:0003682	chromatin binding	5.10e-04	2.80e-02	4.77e-01	-3.17e-01	-1.55e+00
go:1902533	positive regulation of intracellular signal transduction	5.19e-04	2.82e-02	4.77e-01	2.78e-01	1.43e+00
go:0001541	ovarian follicle development	5.29e-04	2.82e-02	4.77e-01	6.50e-01	2.04e+00
go:0032101	regulation of response to external stimulus	5.69e-04	2.92e-02	4.77e-01	3.24e-01	1.59e+00
go:0034121	regulation of toll-like receptor signaling pathway	5.63e-04	2.92e-02	4.77e-01	7.10e-01	2.01e+00
reactome:R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	5.88e-04	2.98e-02	4.77e-01	5.08e-01	1.94e+00
go:0003018	vascular process in circulatory system	6.15e-04	3.08e-02	4.77e-01	5.43e-01	1.90e+00
go:1903035	negative regulation of response to wounding	6.49e-04	3.21e-02	4.77e-01	6.12e-01	2.03e+00
go:0034612	response to tumor necrosis factor	6.70e-04	3.27e-02	4.77e-01	3.82e-01	1.72e+00
msig:M5921	HALLMARK_COMPLEMENT	6.92e-04	3.29e-02	4.77e-01	4.24e-01	1.79e+00
reactome:R-HSA-1474244	Extracellular matrix organization	6.99e-04	3.29e-02	4.77e-01	4.09e-01	1.73e+00
go:2001243	negative regulation of intrinsic apoptotic signaling pathway	6.85e-04	3.29e-02	4.77e-01	4.79e-01	1.89e+00
go:0050819	negative regulation of coagulation	7.17e-04	3.34e-02	4.77e-01	6.81e-01	1.97e+00
go:2001234	negative regulation of apoptotic signaling pathway	7.30e-04	3.35e-02	4.77e-01	3.76e-01	1.68e+00
go:0005604	basement membrane	7.44e-04	3.38e-02	4.77e-01	6.17e-01	2.00e+00
msig:M19096	KEGG_BLADDER_CANCER	7.54e-04	3.38e-02	4.77e-01	6.17e-01	1.99e+00
go:0050778	positive regulation of immune response	7.82e-04	3.47e-02	4.77e-01	2.96e-01	1.49e+00
go:0055092	sterol homeostasis	7.91e-04	3.47e-02	4.77e-01	6.42e-01	2.01e+00
go:0035239	tube morphogenesis	8.38e-04	3.56e-02	4.77e-01	3.12e-01	1.56e+00
go:0097193	intrinsic apoptotic signaling pathway	8.26e-04	3.56e-02	4.77e-01	3.44e-01	1.60e+00
go:0043407	negative regulation of MAP kinase activity	8.39e-04	3.56e-02	4.77e-01	5.79e-01	1.98e+00
go:0060968	regulation of gene silencing	9.04e-04	3.72e-02	4.77e-01	-4.21e-01	-1.74e+00
go:0097191	extrinsic apoptotic signaling pathway	9.03e-04	3.72e-02	4.77e-01	3.83e-01	1.69e+00
go:0043408	regulation of MAPK cascade	9.35e-04	3.80e-02	4.77e-01	3.05e-01	1.52e+00
go:0040011	locomotion	9.90e-04	3.95e-02	4.55e-01	2.55e-01	1.37e+00
go:1901700	response to oxygen-containing compound	9.84e-04	3.95e-02	4.55e-01	2.48e-01	1.34e+00
go:0098780	response to mitochondrial depolarisation	1.04e-03	4.10e-02	4.55e-01	-6.87e-01	-1.92e+00
go:0006900	vesicle budding from membrane	1.08e-03	4.22e-02	4.55e-01	4.32e-01	1.76e+00
go:1901655	cellular response to ketone	1.09e-03	4.22e-02	4.55e-01	5.26e-01	1.90e+00
reactome:R-HSA-500792	GPCR ligand binding	1.11e-03	4.26e-02	4.55e-01	5.08e-01	1.88e+00
go:0002687	positive regulation of leukocyte migration	1.13e-03	4.29e-02	4.55e-01	4.98e-01	1.86e+00
go:0002685	regulation of leukocyte migration	1.18e-03	4.38e-02	4.55e-01	4.56e-01	1.80e+00
go:0002688	regulation of leukocyte chemotaxis	1.22e-03	4.50e-02	4.55e-01	5.34e-01	1.92e+00
go:0001819	positive regulation of cytokine production	1.25e-03	4.51e-02	4.55e-01	3.54e-01	1.60e+00
go:0000226	microtubule cytoskeleton organization	1.25e-03	4.51e-02	4.55e-01	-2.99e-01	-1.46e+00
go:0070373	negative regulation of ERK1 and ERK2 cascade	1.32e-03	4.75e-02	4.55e-01	5.29e-01	1.84e+00
go:0033993	response to lipid	1.34e-03	4.76e-02	4.55e-01	2.85e-01	1.45e+00
go:0044450		1.37e-03	4.83e-02	4.55e-01	-4.02e-01	-1.68e+00
go:0046903	secretion	1.41e-03	4.92e-02	4.55e-01	2.46e-01	1.33e+00
go:0050684	regulation of mRNA processing	1.42e-03	4.92e-02	4.55e-01	-3.81e-01	-1.63e+00
go:0070972	protein localization to endoplasmic reticulum	1.50e-03	5.15e-02	4.55e-01	3.67e-01	1.64e+00
go:0002526	acute inflammatory response	1.56e-03	5.20e-02	4.55e-01	5.90e-01	1.95e+00
go:1903428	positive regulation of reactive oxygen species biosynthetic process	1.54e-03	5.20e-02	4.55e-01	6.58e-01	1.90e+00
go:0045087	innate immune response	1.55e-03	5.20e-02	4.55e-01	2.79e-01	1.42e+00
go:0034451	centriolar satellite	1.61e-03	5.32e-02	4.55e-01	-6.75e-01	-1.89e+00
go:0035295	tube development	1.66e-03	5.36e-02	4.55e-01	2.81e-01	1.43e+00
go:0010876	lipid localization	1.67e-03	5.36e-02	4.55e-01	3.70e-01	1.64e+00
go:0071622	regulation of granulocyte chemotaxis	1.67e-03	5.36e-02	4.55e-01	6.47e-01	1.92e+00
go:0023056	positive regulation of signaling	1.65e-03	5.36e-02	4.55e-01	2.44e-01	1.33e+00
go:0031401	positive regulation of protein modification process	1.80e-03	5.65e-02	4.55e-01	2.53e-01	1.33e+00
go:0031226	intrinsic component of plasma membrane	1.81e-03	5.65e-02	4.55e-01	2.83e-01	1.43e+00
go:0072599	establishment of protein localization to endoplasmic reticulum	1.88e-03	5.83e-02	4.55e-01	3.80e-01	1.65e+00
go:0050663	cytokine production	1.93e-03	5.94e-02	4.55e-01	4.70e-01	1.79e+00
go:0051247	positive regulation of protein metabolic process	1.95e-03	5.94e-02	4.55e-01	2.42e-01	1.32e+00
go:0005539	glycosaminoglycan binding	2.01e-03	6.05e-02	4.32e-01	4.55e-01	1.75e+00
go:0016050	vesicle organization	2.00e-03	6.05e-02	4.32e-01	3.29e-01	1.56e+00
msig:M5669	KEGG_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY	2.06e-03	6.15e-02	4.32e-01	5.10e-01	1.78e+00
go:2001236	regulation of extrinsic apoptotic signaling pathway	2.11e-03	6.16e-02	4.32e-01	4.13e-01	1.71e+00
go:1902883	negative regulation of response to oxidative stress	2.11e-03	6.16e-02	4.32e-01	5.77e-01	1.88e+00
go:0050920	regulation of chemotaxis	2.16e-03	6.25e-02	4.32e-01	4.45e-01	1.77e+00
go:2001233	regulation of apoptotic signaling pathway	2.19e-03	6.30e-02	4.32e-01	3.04e-01	1.48e+00
go:0002221	pattern recognition receptor signaling pathway	2.29e-03	6.45e-02	4.32e-01	4.32e-01	1.76e+00
go:0022602	ovulation cycle process	2.27e-03	6.45e-02	4.32e-01	6.63e-01	1.88e+00
go:1905954	positive regulation of lipid localization	2.30e-03	6.45e-02	4.32e-01	6.38e-01	1.90e+00
go:0070555	response to interleukin-1	2.31e-03	6.45e-02	4.32e-01	3.81e-01	1.65e+00
go:0002253	activation of immune response	2.43e-03	6.72e-02	4.32e-01	3.05e-01	1.50e+00
go:1900117	regulation of execution phase of apoptosis	2.51e-03	6.91e-02	4.32e-01	-6.19e-01	-1.84e+00
go:2001242	regulation of intrinsic apoptotic signaling pathway	2.56e-03	6.98e-02	4.32e-01	3.73e-01	1.61e+00
reactome:R-HSA-1474290	Collagen formation	2.58e-03	6.99e-02	4.32e-01	5.62e-01	1.88e+00
go:0007186	G protein-coupled receptor signaling pathway	2.68e-03	7.21e-02	4.32e-01	3.32e-01	1.54e+00
msig:M5953	HALLMARK_KRAS_SIGNALING_UP	2.70e-03	7.22e-02	4.32e-01	4.40e-01	1.74e+00
go:0002274	myeloid leukocyte activation	2.86e-03	7.54e-02	4.32e-01	2.77e-01	1.40e+00
go:0002764	immune response-regulating signaling pathway	2.89e-03	7.57e-02	4.32e-01	3.00e-01	1.47e+00
go:0043409	negative regulation of MAPK cascade	3.07e-03	7.98e-02	4.32e-01	4.06e-01	1.66e+00
go:0035924	cellular response to vascular endothelial growth factor stimulus	3.14e-03	8.07e-02	4.32e-01	6.27e-01	1.86e+00
go:1903034	regulation of response to wounding	3.16e-03	8.07e-02	4.32e-01	4.67e-01	1.75e+00
go:0001764	neuron migration	3.13e-03	8.07e-02	4.32e-01	-4.58e-01	-1.72e+00
go:0061180	mammary gland epithelium development	3.27e-03	8.30e-02	4.32e-01	5.71e-01	1.85e+00
go:0032612	interleukin-1 production	3.49e-03	8.77e-02	4.32e-01	5.64e-01	1.87e+00
go:0001649	osteoblast differentiation	3.54e-03	8.77e-02	4.32e-01	3.97e-01	1.66e+00
go:0048194	Golgi vesicle budding	3.52e-03	8.77e-02	4.32e-01	4.25e-01	1.66e+00
go:0015918	sterol transport	3.54e-03	8.77e-02	4.32e-01	5.18e-01	1.79e+00
go:0050776	regulation of immune response	3.57e-03	8.77e-02	4.32e-01	2.69e-01	1.38e+00
go:0005814	centriole	3.63e-03	8.86e-02	4.32e-01	-4.08e-01	-1.64e+00
msig:M16848	KEGG_EPITHELIAL_CELL_SIGNALING_IN_HELICOBACTER_PYLORI_INFECTION	3.69e-03	8.94e-02	4.32e-01	4.87e-01	1.73e+00
go:0008201	heparin binding	3.70e-03	8.94e-02	4.32e-01	4.85e-01	1.80e+00
go:0051094	positive regulation of developmental process	3.90e-03	9.34e-02	4.32e-01	2.55e-01	1.34e+00
go:0005788	endoplasmic reticulum lumen	3.95e-03	9.40e-02	4.07e-01	3.61e-01	1.59e+00
reactome:R-HSA-204005	COPII-mediated vesicle transport	4.08e-03	9.66e-02	4.07e-01	4.72e-01	1.76e+00
msig:M5948	HALLMARK_BILE_ACID_METABOLISM	4.12e-03	9.69e-02	4.07e-01	4.80e-01	1.70e+00
go:0032611	interleukin-1 beta production	4.16e-03	9.74e-02	4.07e-01	6.01e-01	1.86e+00

Literature Mining

INDRA was used to automatically assemble known mechanisms related to TNFAIP3 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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TNFAIP3 deubiquitinates RIPK1. 5 / 5

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However, LMP1 is also known to upregulate TNFAIP3/A20 (TNFa-induced protein 3), which could deubiquitinate RIPK1 (98, 99) .

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TNFAIP3 causes inhibition of the canonical NF-kappaB pathway by deubiquitinating RIP1, thus abolishing the recruitment of the TAK1, TAK1 binding protein 2, and NEMO complex.

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However, LMP1 is also known to upregulate TNFAIP3/A20 (TNF-α-induced protein 3), which could deubiquitinate RIPK1 (98, 99).

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TNFAIP3 (A20) leads to the ubiquitination of TRAF6 and the deubiquitination of RIP to inhibit the activation of the NF-kappaB signaling pathway that is mediated by NOD1 and NOD2.

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The targets of A20-mediated deubiquitination are K63-linked ubiquitinated TRAF6 and RIP1

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TNFAIP3 deubiquitinates OCLN. 4 / 4

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To determine whether TNFAIP3 can deubiquitinate occludin, we incubated recombinant N-terminal TNFAIP3 with ubiquitinated occludin in vitro.

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We also found that TNFAIP3 deubiquitinates polyubiquitinated occludin.

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Thus TNFAIP3 associates with occludin and can deubiquitinate occludin.

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We found that TNFAIP3 was able to decrease the total ubiquitination of occludin (XREF_FIG).

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TNFAIP3 deubiquitinates RIPK1 on K377. 3 / 3

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TNFAIP3 deubiquitinates IKBKG. 2 / 2

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The overexpression of GIT2 enhanced the deubiquitination activity of TNFAIP3 toward IKBKG, and siRNA targeted at GIT2 abrogated the TNFAIP3 dependent deubiquitination of IKBKG and impaired the ability of TNFAIP3 to inhibit NF-kappaB activation (XREF_FIG).

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TNFAIP3 deubiquitinates TRAF6. 2 / 2

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The targets of A20-mediated deubiquitination are K63-linked ubiquitinated TRAF6 and RIP1

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A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6

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TNFAIP3 deubiquitinates MAP3K5. 2 / 2

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In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes.

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TNFAIP3 affects NFkappaB

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TNFAIP3 inhibits NFkappaB.

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TNFAIP3 inhibits NFkappaB. 10 / 128

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Itch was further shown to regulate the targeting of A20 to substrates, and A20 was unable to inhibit NF-κB in the absence of Itch ( xref ).

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T cell co-stimulation with a 4-1BB agonist antibody triggers K63 ubiquitination of 4-1BB-associated TRAF2, which is crucial for NF-κB activation and induction of antitumor immunity. xref Conversely, the 4-1BB signaling is negatively regulated by two DUBs, CYLD and A20, which physically associate with the 4-1BB/TRAF2 complex. xref Overexpression of either CYLD or A20 inhibits NF-κB activation by the 4-1BB agonist antibody, whereas silencing these DUBs enhances NF-κB activation mediated by 4-1BB costimulation in human CD8 T cells. xref The role of K63 ubiquitination in 4-1BB-mediated CD8 T cell costimulation is further supported by the finding that CD8 effector and memory T cells expressing a dominant-negative mutant of the E3 ligase cIAP2 (cIAP2 H570A ) have attenuated 4-1BB signaling and impaired survival, demonstrated using a viral infection model. xref

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It is likely that CYLD and A20 inhibit NF-κB at different times during an inflammatory response.

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Since TNIP1 is a negative regulator of the NF-κB pathway, so when the TNIP1-TNFAIP3 complex inhibits NF-κB, anti-apoptotic genes are not activated by NF-κB and hence apoptosis happens.

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TNFAIP3 inhibits NF-kappaB activation as well as TNFalpha-mediated apoptosis by binding to TRAF family adaptor proteins ( Heyninck et al ., 1999 ) .

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A20 expression was regulated by NF-κB. In turn, increased A20 expression inhibited TRAF6 and NF-κB to reduce the subsequent inflammatory response.

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Some NF-kappaB pathway inhibitors are targeted by biallelic deletions (FAF1) [30] or inactivating alterations (deletion, mutation or hypermethylation) of TNFAIP3 (A20) [30,64].

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Moreover , the negative feedback loop of suppressing NF-kappaB and associated inflammatory signaling by A20 is not functional in aged HSC .

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TNFAIP3 can inactivate a number of NF-kappaB signaling molecules, like receptor interacting protein 1/2 (RIP1/2), TRAFF6, and IKKgamma (NEMO).

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The results indicate that miR-98-5p interference and 3beta-hydroxycholest-5-en-7-one treatment significantly upregulated the low TNFAIP3 expression induced by LPS stimulation, thereby inhibiting TRAF6, RIP, NF-kappaB, IL-1beta, and TNF-alpha secretion.

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TNFAIP3 bound to DEPDC1 and ZNF224 inhibits NFkappaB. 1 / 1

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In the present study, it was determined that the DEPDC1 and ZNF224 complex suppresses A20 expression and thus activates the NF-kappaB signaling pathway, eventually resulting in the inhibition of apoptosis in HepG2 cells.

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Mutated TNFAIP3 inhibits NFkappaB. 1 / 1

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Also, loss of function mutations of TNFAIP3 (A20), a negative regulator of NF-kappaB, contributes to NF-kappaB pro survival signaling in ABC-DLBCL tumors [XREF_BIBR, XREF_BIBR].

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TNFAIP3 activates NFkappaB.

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TNFAIP3 activates NFkappaB. 10 / 50

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Accordingly, overexpression of a miR-29b-refractory isoform of TNFAIP3 restored NF-kappaB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b.

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Consistent with our findings in the gut derived lethal infection model, i.p. injection of the PC resulted in downregulation of IRF3 and the upregulation of NF-kB Inhibitor Alpha (NFKBIA), NF-kB Inhibitor Beta (NFKBIB), and TNF Alpha Induced Protein 3 (TNFAIP3), known NF-kappaB pathway inhibitors XREF_BIBR, XREF_BIBR, in the cecum, liver, and spleen, 20h post PC injection in AC-FMT mice.

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Up-regulation of the inhibitor of NF-kappaB activation TNFAIP3, also known as A20, in the DM samples, along with its binding partner, TNFAIP3 interacting protein 1 (TNIP1), and RELA suggests a potenti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The C-terminal region (containing the functional zinc finger structures) mediates A20 dimerization and binding to several other proteins that might be involved in the inhibition of NF-kB activation and apoptosis by A20 [ xref ].

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Accordingly, overexpression of an miR-29b-refractory isoform of TNFAIP3 restored NF-kappaB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b.

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For example, TNFAIP3 is a transcriptional target of NF-kappaB, serves as a " global " feedback regulator to attenuate NF-kappaB activity by inactivation of NEMO, TRAF6, and RIP1, thus negatively regul[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Conclusion : Down-regulated MiR-128-3p significantly suppressed the inflammation response of RA through suppressing the activity of NF-kappaB pathway, which was mediated by TNFAIP3.

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Mutations of CARD11 but not TNFAIP3 may activate the NF-kappaB pathway in primary CNS lymphoma.

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By targeting TNFAIP3, miR-125a/b directly inhibits the expression level of TNFAIP3, and induces NF-kappaB activity, which leads to increased aggressiveness in both cell line assays and in primary tumors [XREF_BIBR].

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Tnfaip3 OTU and OTU and Tnfaip3 ZF4 and ZF4 cells produced less of the NF-kappaB dependent mRNAs IL-6 and cellular inhibitor of apoptosis protein 2 (cIAP2), and exhibited less NF-kappaB signaling than Tnfaip3 -/- cells, suggesting that neither A20 's C103 motif nor its ZF4 motif are singly responsible for all of A20 's functions during TNF signaling (XREF_SUPPLEMENTARY).

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TNF activates TNFAIP3.

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TNF activates TNFAIP3. 10 / 53

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Two targets of miR-21 : Interleukin I Beta (IL1beta) and tumor necrosis factor, alpha induced protein 3 (TNFAIP3), which is rapidly induced by the TNF were assayed by RT-qPCR on mRNA in another APP infection study in pigs [XREF_BIBR].

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In addition, reduced expression was also evident for two IL17 target genes in vertebrates : tumor necrosis factor alpha induced protein 3 (tnfaip3; also known as A20), which encodes a ubiquitin editing enzyme that inhibits NF-kappaB activation, and NF-kappaB inhibitor zeta (nfkbiz), an IL17 target gene in vertebrates that also regulates NF-kappaB activity.

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We also found that A20 (also known as tumor necrosis factor alpha induced protein 3, or TNFAIP3) protected against CVB3 induced myocarditis by inhibiting inflammatory response.

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TNFalpha induced protein-3 (TNFAIP3; also known as A20) is a ubiquitin editing enzyme that acts as a negative regulator of NFkappaB.

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Expression of TNFAIP3 is increased in PBMC from rheumatoid arthritis (RA) patients, consistent with findings that TNFAIP3 is rapidly induced by TNF, the expression of which is known to be markedly elevated in active RA patients.

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It was shown that TNFAIP3 is induced by TNF and IL-1 and might therefore be involved in the regulation of NFkappaB dependent genes in diverse bacterial infections.

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On the other hand, both untreated (basal level) and TNF-induced activation of the A20 promoter were severely compromised in E1A/Ras MEFs ( xref ).

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Aberrations in TNF signaling were apparent with upregulation of both TNF and TNF receptor superfamily members but universal downregulation of IRF8 bound TNF induced TNFAIP3, a negative regulator of cytokine mediated immune and inflammatory responses.

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As expected, TNFalpha treatment rapidly induced NF-kappaB activation, reflected by robust expression of NFKBIA (encoding IkappaBalpha) and TNFAIP3 (XREF_SUPPLEMENTARY), two direct downstream targets of NF-kappaB.

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To test this hypothesis, we targeted A20 (tumor necrosis factor alpha induced protein 3 [TNFAIP3]), an anti-inflammatory molecule and primary negative regulator of NF-kappaB activity.

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TNF bound to IRF8 activates TNFAIP3. 1 / 1

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TNF increases the amount of TNFAIP3.

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TNF increases the amount of TNFAIP3. 10 / 16

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Thirty‐eight genes involved in the defense response to virus, including bone marrow stromal antigen (BST2)/tetherin and MX Dynamin Like GTPase 2/myxovirus resistance protein 2 (MX2) and tumor necrosis factor‐alpha‐induced protein 3 (TNFAIP3) were overexpressed in VKC (Table 1 and Figure 1).

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TNF induces TNFAIP3 expression in all tissues including mouse and human intestinal epithelial cells XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR.

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The expression of TNFAIP3 is induced by TNF and is involved in the signaling pathway by GPCR.

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These results suggest that TNF induces the expression of NFKBIA and TNFAIP3 independently of c-Rel in Jurkat T cells or that the induction of these genes in response to TNF is mediated by c-Rel that is not GlcNAcylated.

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To our knowledge, our study indicates for the first time the up-regulation of TNFAIP3 and A20 gene expression by TNF-alpha through NF-kappaB.

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In primary human airway smooth muscle cells, TNFAIP3 expression was induced by TNF.

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To confirm our speculation, we pre-treated the BMDMs with TNFalpha, which could increase the levels of endogenous A20 and TNFAIP3.

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As biphasic necroptosis kinetics had indicated that the RelA‐dependent survival mechanism only protected a fraction of cells from premature necroptosis, we asked whether cell‐to‐cell heterogeneity in TNF‐induced A20 expression may be responsible.

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TNFalpha increased the expression of IL6, ICAM1, and TNFAIP3 in both cell lines (XREF_FIG).

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Additionally, GFPT2 expression was not required for TNF induced BIRC3 and cIAP -2 and TNFAIP3 and A20 mRNA expression, indicating that GFPT2 was not required to potentiate NF-kappaB transcription (Additional file 1 : Figure S4B).

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TNF inhibits TNFAIP3.

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TNF inhibits TNFAIP3. 2 / 2

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Homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappa B, had already been described in ocular adnexal MZL.

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TNF stimulation of Rela +/- splenocytes resulted in significantly impaired up-regulation of Il6, Tnfaip3, and Traf1; all which depend on NF-kappaB activation (XREF_FIG).

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TNFAIP3 affects apoptotic process

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TNFAIP3 inhibits apoptotic process.

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TNFAIP3 inhibits apoptotic process. 10 / 29

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TNF alpha induced protein 3 (TNFAIP3, A20) is a tumor enhancer in glioma [ xref ] and inhibits apoptosis in glioblastoma [ xref ].

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A20 inhibits TNF-induced apoptosis in fibroblasts, blocks necroptosis in fibroblasts and T cells, and paradoxically promotes Fas-dependent death in activated B cells ( xref ; xref ; xref ).

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One critical finding from this study is that A20 not only completely blocked the transcription of other NF-kappaB target genes known to antagonize JNK signaling , but also effectively suppressed TNF-induced JNK activation and apoptotic cell death in NF-kappaB activation-deficient MEFs ( Figure 2 ) .

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Consistently, IEC specific deletion of TNFAIP3 (encoding A20), a gene mutated in Crohn 's disease that encodes an E3 ligase editing enzyme involved in dampening NF-kappaB signaling and TNF induced apoptosis, leads to massive IEC apoptosis and increased susceptibility to experimental colitis.

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In contrast, ATRA induces the expression of BIRC3 and TNFAIP3, which inhibit Fas and TNFalpha mediated apoptosis signaling pathway by the interaction with TRAF2, and thus may prevent apoptosis.

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We found that overexpression of miR-19b-3p or knockout of TNFAIP3 decreased apoptosis rates of NPC cell lines after irradiation.

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In contrast, A20 inhibits apoptosis, at least partially, by binding to TXBP151, which inhibits TNF-α-induced apoptosis.

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A20 can inhibit TNF-induced apoptosis in many cell types.

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In pancreatic islets, A20 inhibited both apoptosis and NF-κB activation induced by cytokines, suggesting that NF-κB may actually mediate apoptosis [58] .

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Additionally , the same group has reported that TNFAIP3 can endogenously suppress ASK1 and reduce apoptosis , lipid accumulation , and inflammation [ 116 ] .

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TNFAIP3 activates apoptotic process.

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However, it is unclear how the transfected TNFAIP3 triggers apoptosis in the lymphoma cells.

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The deletions or mutations of TNFAIP3 are found in about 30% of patients with diffuse large B-cell lymphoma, while reinforced TNFAIP3 induces apoptosis and cell growth arrest XREF_BIBR, suggesting TNFAIP3 is a tumor suppressor.

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Moreover, TNFAIP3 induces cell growth arrest and apoptosis, accompanied by down-regulation of nuclear factor-kappa B (NF-kB) activation [XREF_BIBR, XREF_BIBR].

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In KRAS (G12V)-transduced bronchial epithelial (BEAS-2B) cells, introduction of anti-miR-29b constructs increased the sensitivity to apoptosis by targeting TNFAIP3 and A20, a negative regulator of nuclear factor (NF)-kappaB signaling.

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Results demonstrated that TNFAIP3 knockdown contributed to the proliferation, migration, invasion, and inflammation and suppressed the apoptosis in HAND2-AS1-overexpressed MH7A cells.

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TNFAIP3 and A20 as a Gateway Gene to Drug Induced Extrinsic Apoptosis.

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miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus related hepatocellular carcinoma.

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TNFAIP3, that was found to be up-regulated by TRAIL in our study, is an inhibitor of the NFKB pathway [XREF_BIBR] and may thereby promote apoptosis but, on the other hand, it was shown to decrease TNF mediated apoptosis and necrosis [XREF_BIBR], leaving its specific influence unclear.

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In addition, exosomes generated from lipopolysaccharide (LPS)-activated microglia promote neuron apoptosis, which can reversed by the knockdown of TNF inducible protein 3 (TNFAIP3) [XREF_BIBR].

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Accordingly, overexpression of a miR-29b-refractory isoform of TNFAIP3 restored NF-kappaB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b.

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Numerous researchers have identified that A20 is a susceptibility gene for inflammatory diseases , and that A20 inhibits inflammation by regulating the NF-kappaB pathway.17-21 Interestingly , when NF-kappaB translocates into the nucleus and binds to the kappaB binding site in the A20 gene promoter structure , it can promote the expression of the A20 gene , and A20 acts as an ubiquitinating enzyme to modify the upstream molecules of the NF-kappaB pathway , leading to a negative feedback loop between A20 and the NF-kappaB .

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Similarly , deficiency in CYLD or A20 , a master regulator of NFkappaB , lead to overt pathway activation and inflammation ( 132 ) .

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Taken together, A20 inhibited FFAs-induced inflammatory response via attenuating NF-κB activation in four cell lines we generated.

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axis likely plays a role in SARS-CoV-2 infection as well, with TNFAIP3 inhibiting NF-κB-mediated antiviral responses at the site of local infection yet promoting a systemic inflammatory response in the periphery.

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TNFAIP3 is primarily responsible for attenuation of NFkappaB signaling and thereby inhibits inflammation and tumorigenesis and TNF mediated mediated apoptosis [XREF_BIBR].

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Results demonstrated that TNFAIP3 knockdown contributed to the proliferation ( Fig. 5b ) , migration ( Fig. 5d ) , invasion ( Fig. 5e ) , and inflammation ( Fig. 5f ) and suppressed the apoptosis ( Fig. 5c ) in HAND2-AS1-overexpressed MH7A cells .

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Additionally, the same group has reported that TNFAIP3 can endogenously suppress ASK1 and reduce apoptosis, lipid accumulation, and inflammation [XREF_BIBR].

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One mechanism by which A20 inhibits inflammation is through negative regulation of NLRP3 and caspase-1 activation , suppressing interleukin production and pyroptosis ( 167 , 168 ) .

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Tnfaip3 expression is necessary for prevention of chronic inflammation and autoimmune pathology according to studies on mice with full or conditional gene deletion [XREF_BIBR].

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A variant of TNFAIP 3, which encodes an ubiquitin editing enzyme inhibiting NF-kappaB-dependent signaling and prevents inflammation, and polymorphic haplotypes of the human T-lymphotropic virus-1-related endogenous sequence (HRES) 1 long terminal repeat (LTR) have been associated with SLE [XREF_BIBR, XREF_BIBR].

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XREF_BIBR TNIP1 may interact with TNFAIP3 and inhibit TNFalpha induced NFkappaB inflammation pathway.

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TNFAIP3 activates inflammatory response.

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These findings show that neutrophilic airway inflammation induced by activated TNFAIP3 and A20 deficient myeloid cells can develop in the absence of IL-17RA-signalling.

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353 [ 4 ] Hsu ACY , Dua K , Starkey MR , Haw TJ , Nair PM , Nichol K , et al. MicroRNA-125a 354 and - b inhibit A20 and MAVS to promote inflammation and impair antiviral response 355 in COPD .

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Hepatocyte specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease- and NASH related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1 dependent manner.

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3beta-Hydroxycholest-5-en-7-one alleviates inflammation by downregulating miR-98-5p and upregulating TNFAIP3 , thereby blocking NF-kappaB pathway activation .

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According with this view , we can assume that the A20 upregulation observed in sciatic nerve of 4 months old SOD1-G93A mice can be ascribed to an activation of the non-canonical pathway , fitting with the idea that A20 ( 62 ) , when aberrantly activated , in different cell types , can promote autoimmunity and inflammation .

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Cluster 2 contained IL8, IL1A, PTGS2, DTR, TNFAIP3, and CXCL3 that were up-regulated and linked primarily to inflammatory response and cell proliferation.

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Tnfaip3 -/- Myd88 -/- double-mutant mice are rescued from lethal inflammation, suggesting that TLR signals drive the spontaneous inflammation in the absence of A20 [XREF_BIBR].

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Taken together, decreased expression of TNFAIP3 and its partners contribute to inflammation and up-regulation of apoptosis inhibitors that may create microenvironment for colorectal cancer.

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NFkappaB activates TNFAIP3.

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TNFAIP3 (also known as A20) expression is up-regulated by NF-kB activation, as confirmed in our study, and it acts in a negative feedback loop to control NF-kB-dependent gene expression.

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A20 is a protein with dual enzymatic activity (DUB/E3 ligase) encoded by the NF-kB induced gene TNF alpha induced protein 3 (TNFAIP3). xref A20 stops NF-κB activation by (1) deubiquitinating RIPK-1 and (2) polyubiquitinating RIP-1 to target it for degradation (proteolysis).

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A co-occupied intronic TNFAIP3 regulatory element mediated cooperative enhancement of transcription by GR and NF-kappaB that required the presence of a functional GR binding site (GBS).

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As A20 ZF4 proteins are recruited poorly to TNFR signaling complexes, the presence of normal NF-kappaB signaling in Tnfaip3 OTU and ZF4 cells also raises the interesting possibility that A20 OTU proteins may dimerize with A20 ZF4 proteins and recruit the latter to TNFR signaling complexes in Tnfaip3 OTU and ZF4 cells.

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Overexpression of A20 resulted in suppression of cytokine-triggered NF-kappaB activation and knockdown of A20 by RNA interference significantly attenuated induction of anergy by ER stress.

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XREF_BIBR, XREF_BIBR Both miR-125b 37 and TNFAIP3 38 are induced by NF-kappaB activity.

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Thus, we suggest the ability of COUP-TFII to inhibit NFkappaB stimulated TNFAIP3 may play a role in the observed ability of COUP-TFII to resensitize LCC9 cells to 4-OHT.

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In addition , Kadiyala et al. reported that GR and NF-kappaB cooperatively bound to the enhancer of the A20 locus and induced A20 expression ( 35 ) .

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Tnfaip3 is induced by NF-kappaB signaling as an early response gene and encodes the A20 protein, a ubiquitin modifier that inhibits formation of linear and K63 linked ubiquitin chains on key proteins in the NF-kappaB signaling pathway to provide a negative feedback that terminates further activation of NF-kappaB.

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TCR specific signalling protein MALT1 (through the CARD11-BCL10-MALT1 complex) was recently reported to be required for optimal NF-κB activation through proteolysis of the NF-κB inhibitor TNFAIP3 [ xref , xref ].

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NFkappaB increases the amount of TNFAIP3.

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TNFAIP3 expression is induced by NFkappaB 31.

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NF-kappaB signaling also induces TNFAIP3 expression, thus providing a further feedback loop that modifies inflammation.

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NF-kappaB signaling induces transcription of the TNFAIP3 gene, encoding a ubiquitin modifying enzyme (also known as A20) that negatively regulates the NF-kappaB signaling pathway [XREF_BIBR - XREF_BIBR].

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TNF-induced expression of IkappaB attenuates NFkappaB , whereas A20 inhibits IKK and RIPK3 .

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Our results suggest a non-catalytic mechanism of IKK inhibition by A20 and a means by which polyubiquitin chains can specify a signaling outcome.

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These results provide direct evidence that A20 inhibits IKK by preventing the phosphorylation of IKK by TAK1.

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It has been found that A20 inhibits the IKK complex by non-catalytic functions, mediated by recruitment of A20 to the C-terminal domain of IKKα [31,32] .

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In addition to TNFAIP3 modulating ubiquitin others have found that TNFAIP3 can also inhibit IKK complex activity through a mechanism that is independent of ubiquitin.

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The model simulations ( xref ) confirmed the experimental findings that RC3H1 reduces A20 mRNA and subsequently A20 protein expression, and, due to the attenuated IKK inhibition by A20, leads to an increased IKK activity.

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Indeed, we present multiple lines of evidence that A20 inhibits IKK through a non-catalytic mechanism.

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However, direct evidence of IKK inhibition by A20 is lacking, and the inhibitory mechanism remains poorly understood.

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We found evidence that A20 can inhibit IKK through a mechanism that cannot be accounted for by reducing the interaction of polyubiquitin chains with NEMO.

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A20 inhibition of IKK was dependent on A20 binding to NEMO which was induced by K63-linked polyubiquitin chains. xref The binding of A20 with NEMO occurred rapidly upon IL-1 stimulation (2–5 min) in HeLa cells. xref Therefore, the polyubiquitin chains that serve to activate IKK also serve a dual function in its negative regulation by the recruitment of A20 to NEMO.

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Direct, Non-Catalytic Impairment of IKK Activation by A20.

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TNFAIP3 affects TNF

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TNFAIP3 inhibits TNF.

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The feedback regulator TNFAIP3 (A20) which negatively regulates TNF-alpha and IL-1beta signalling is up-regulated in two datasets and is down-regulated in one dataset.

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Thus, the heterologous expression of TNFAIP3 in IECs can prevent TNF induced decreases in barrier function in these cells.

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Recently, it has been shown by gene knock-out studies that A20, a protein interacting with IKKγ, can also specifically inhibit TNF- but not IL-1-induced NF-κB activation [34] .

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While A20 restricts TNF signaling in vitro , elimination of TNF does not prevent spontaneous disease in A20 - / - mice or A20Flox LysM-Cre mice 10 , 34 .

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We thus propose a model in which A20 inhibits TNF- and LUBAC-induced NF-κB signalling by binding to linear polyubiquitin chains via its seventh zinc finger, which prevents the TNF-induced interaction between LUBAC and NEMO.

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A20 also inhibits TNF and IL-1 induced activation of NF-κB, suggesting that it may act as a general inhibitor of NF-κB activation xref – xref .

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For example, the expression of tumor necrosis factor-alpha inducing protein (TNFAIP3) that inhibits NF-kappaB activation and negatively regulates TNF-alpha signaling exhibited individual variability among our human donors.

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TNFAIP3 also perturbs caspase activation of TNF receptor 1 (TNFR1) which is coupled to apoptotic caspases 8 and 10 [XREF_BIBR, XREF_BIBR].

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Furthermore, A20 inhibits TNF- and IL-1-induced NF-κB activation in 293 cells [ xref ], and deregulated Toll-like receptor signaling in response to commensal bacteria was shown to be responsible for the multiorgan inflammation and premature death of A20-knockout mice [ xref ].

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TNFAIP3 activates TNF.

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TNFAIP3 protein as a zinc finger protein and ubiquitin shearing enzyme can suppress activated NF-kappaB signal pathway and induce apoptosis of TNF by activating ubiquitin ligase and ubiquitinase.

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TNFAIP3, a negative regulator of inflammation that inhibits NF-kB (nuclear factor kappa-B) and TNF (tumor necrosis factor)-mediated pathways, has been linked to several immune mediated diseases like T1D, systemic lupus erythematosus, and rheumatoid arthritis [XREF_BIBR, XREF_BIBR].

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It has not been determined whether TNFAIP3 -/- mucosal immune cells cause decreased IEC barrier function, but TNFAIP3 -/- immune cells produce higher amounts of TNF XREF_BIBR.

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In addition to IFN pathway genes, the higher anti-viral activity of hub genes related to TNF signaling and NAD metabolisms such as TNFAIP3, PARP9, and DTX3L would be able to characterize patients with a high viral load, indicating a clear association of their expression to the presence of the virus and the phase of the disease.

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The negative expression of TNFAIP3 inhibits TNF, and the unspecified expression of TNFAIP3 affects the catalysis of TNF.

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TNFAIP3 increases the amount of TNF.

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Although dexamethasone mediated activation of the glucocorticoid receptor (GR) potently repressed expression of IL1beta, IL8, and several other pro inflammatory TNF targets, the expression of anti-inflammatory TNF targets such as TNFAIP3 (A20) and NFKBIA was selectively spared or augmented by dexamethasone treatment.

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TNFAIP3 knockdown enhanced TNF expression in the presence of TNF, TNF plus budesonide, and TNF plus budesonide-formoterol combination and confirms feedback inhibition.

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The finding does not preclude the observation increased TNF-α signaling in the bloodstream of severe patients [33] , as TNFAIP3 depletion has been shown to cause increased TNF-α expression [56] .

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TNFAIP3 affects cell population proliferation

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In addition, TNFAIP3 re-expression can inhibit proliferation, decrease expression of target genes in NF-kappaB signaling pathway, increase cytotoxicity and induce apoptosis in cells lacking TNFAIP3.

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However, there are no reports on whether A20 can inhibit vascular smooth muscle cell proliferation in vivo.

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A20 Like CYLD , A20 suppresses cell proliferation and promotes apoptosis as a negative regulator of the NF-kappaB pathway , and it is well known to play an important role in inflammation and immunity ( Dixit et al. 1990 ; Hoesel and Schmid 2013 ) .

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The phenotype of this patient characterized by autoinflammation might be explained by increased cell proliferation and cell death caused by reduced TNFAIP3 (A20) expression.

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With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 inhibited NPC cell proliferation, induced NPC cell apoptosis, and reduced the growth of NPC xenograft tumors.

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A20 inhibits SMC proliferation via increased expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1.

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Here, we report that miR-125b is upregulated, whereas A20 is downregulated in NPC tissues relative to normal nasopharyngeal mucosa (NNM); miR-125b promotes NPC cell proliferation and inhibits NPC cell apoptosis by targeting A20/NF-κB signaling pathway; A20 inhibits NPC cell proliferation, induces NPC cell apoptosis, and reduces the growth of NPC xenograft tumors.

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Results demonstrated that TNFAIP3 knockdown contributed to the proliferation, migration, invasion, and inflammation and suppressed the apoptosis in HAND2-AS1-overexpressed MH7A cells.

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Importantly, TNFAIP3 knockout not only inhibited the AP20187 induced proliferation and tumor growth of DCIS-iFGFR1 cells, but also further reduced baseline proliferation and tumor growth of DCIS-iFGFR1 cells without AP20187 treatment.

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A20 could also promote liver regeneration [ xref ] and inhibit HCC proliferation, metastasis and microvascular invasions [ xref , xref ].

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However, when overexpressing TNFAIP3 and PLAU or upon activation of the NFkappaB pathway, all the inhibitory effects of SFE were reversed (XREF_FIG A-D), suggesting that SFE blocked the p65 promotion of TNFAIP3 and PLAU expression to inhibit ESCC cell proliferation and metastasis.

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Both Emu- BCL10 and Emu- API2-MALT1 mice develop splenic marginal zone hyperplasia but not lymphoma [86,113], while TNFAIP3 (A20) deficiency in B-cells enhances B-cell proliferation with an excessive [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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miR-29c targets TNFAIP3, inhibits cell proliferation and induces apoptosis in hepatitis B virus related hepatocellular carcinoma.

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TNFAIP3 deficient B-cells are hyper-reactive to antigen stimulation, leading to enhanced proliferation and survival.

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Cluster 2 contained IL8, IL1A, PTGS2, DTR, TNFAIP3, and CXCL3 that were up-regulated and linked primarily to inflammatory response and cell proliferation.

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In addition, the knockdown of TNFAIP3 restores the significant decrease in invasion and proliferation in miR-605-5p-inhibitor-transfected lung cancer cells.

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Lipopolysaccharide affects TNFAIP3

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Lipopolysaccharide increases the amount of TNFAIP3.

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In the TREM2 + ScMglia population, expression of IL-1beta, CCL2, and TNFAIP3 were all significantly induced by LPS stimulation compared with untreated controls (XREF_FIG).

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We have proposed a working model based on these results (XREF_FIG) and suggest that Tnfaip3 might be expressed through transcriptional regulation of both p65 and the p38-downstream transcription factor C/EBPbeta in response to LPS.

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In this study, LJF significantly inhibited the LPS stimulated downregulation of CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9, and TNFAIP3 mRNA expression in lung tissue homogenates according to RNA-Seq and qRT-PCR, which indicates that the IL-17 signalling pathway is critical for treatment by LJF of LPS induced ALI.

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No evidence text available

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Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatics and shifted NF-kappaB signaling associated gene expression towards an anti-inflammatory state (p < 0.001).

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The LPS induced immune markers, specifically TLR4, TNF alpha induced protein 3 (TNFAIP3) and interleukin-1 receptor associated kinase like 2 (IRAK2), were identified among the strongest variables of the PC1, along with the increase in expression of genes related to mitochondrial metabolism (e.g. NADH dehydrogenase (ubiquinone) 1 beta sub-complex 5; NDUFB5).

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While LPS upregulated both IL-12p40 and TNFAIP3 and A20 production, adding DEHP to cultures dramatically reduced IL-12p40 and TNFAIP3 and A20 levels.

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We thus utilized anti-G-G antibody assisted mass spectrometry to find potential ubiquitinated IL-1beta peptides from LPS stimulated Tnfaip3 -/- BMDMs.

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To test whether Tnfaip3 -/- cells might release such ligands, we stimulated LPS primed control BMDMs with supernatants from LPS stimulated Tnfaip3 -/- cells and assayed for additional IL-1beta production by control cells.

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These results showed that TNFAIP3 induced by LPS is insufficient for persistently inflammatory stimulation, and TNFAIP3 may be important for the metabolism in nucleus pulposus cells, providing a new research idea for the treatment and prevention of degenerative diseases.

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Secondly, in parallel to what was observed in cambinol treated cells, we also observed a significant upregulation of such LPS induced genes as ADORA2A, RUNX3, TNFAIP3 and SLC1A2 in MACs treated with DAC following LPS stimulation.

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TNFAIP3 activates autophagy.

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TNFAIP3 activates autophagy. 10 / 14

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TNFAIP3 and DEPTOR together rapidly promoted autophagy after LPS treatment to prevent NLRP3 inflammasome formation.

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TNFAIP3 promotes autophagy in LPS stimulated human NPCs.

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The above results suggested that TNFAIP3 induces autophagy through inhibiting mTOR signaling.

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It has been reported that Zinc finger protein A20 and TNFAIP3 (A20) can inhibit the activity of the NF-kappaB pathway and promote autophagy.

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TNFAIP3 promotes autophagy by inhibiting mTOR signaling in inflammatory human NPCs.

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These results demonstrated that TNFAIP3 may induce autophagy in the LPS stimulated human NPCs.

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In normal monocytes, TNFAIP3 induced autophagy, which restricted inflammasome activation to the early stage of LPS stimulation.

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Moreover, autophagy triggered by TNFAIP3 can ameliorate the degeneration of inflammatory human NPCs, providing a potential and an attractive therapeutic strategy for degenerative disease.

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In summary, overexpressed TNFAIP3 can promote autophagy and reduce inflammation in LPS induced human NPCs.

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It has been reported that Zinc finger protein A20 / TNFAIP3 ( A20 ) can inhibit the activity of the NF-kappaB pathway and promote autophagy .

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Simultaneously, TNFAIP3 also decreased the secretion of inflammatory corpuscles by promoting autophagy in Ankylosing spondylitis [XREF_BIBR].

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TRAF6 K63-linked ubiquitination of Beclin 1 was shown to induce autophagy [ xref ]; suggesting a possible feedback loop, the authors also demonstrated that A20 inhibits autophagy by deubiquitinating Beclin 1, thereby inhibiting the autophagy-activating ubiquitination by TRAF6.

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XREF_BIBR In contrast, the deubiquitinase TNFAIP3 and A20 reduces TLR4 triggered autophagy by decreasing K63 ubiquitination of BECN1.

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The results of this study showed that TNFAIP3 significantly reduces inflammatory response and ameliorates the degradation of the extracellular matrix by promoting autophagy in LPS-induced-inflammatory human NPCs that mimics IVDD.

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TNFAIP3 affects HSPB3

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TNFAIP3 activates HSPB3.

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At least 36 different loci have been identified as susceptibility loci of psoriasis by GWAS [XREF_BIBR], including the TNIP1 gene, which encodes TNF-alpha-induced protein 3 interacting protein 1 (TNIP1), as well as the tumor necrosis factor alpha induced protein 3 (TNFAIP3) gene, which encodes protein A20 [XREF_BIBR, XREF_BIBR].

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When younger brother also developed recurrent oral ulcers, genetic studies were performed in the index patent and targeted panel revealed a novel variant in Tumor necrosis factor alpha induced protein 3 (TNFAIP3) gene (XREF_TABLE).

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A20, a protein encoded by the tumor necrosis factor alpha induced protein 3 gene (TNFAIP3), plays a vital role in the negative regulation of inflammation and immunity.

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The variant proximal to NFkappaB1 controls signaling responses by altering the expression of NFkappaB itself, with the GG risk genotype expressing 20-fold more p50 NFkappaB and diminished expression of the negative regulators of the NFkappaB pathway : TNFalpha induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1).

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A20 (TNFAIP3, tumor necrosis factor, alpha induced protein 3) is an endogenous negative regulator of the NF-kappaB pathway and is rapidly and transiently induced in response to bacterial and viral sti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Other potential hubs includes TRAF6 (TNF receptor associated factor 6), PIN1 (Peptidyl-prolyl cis-trans isomerase NIMA interacting 1), FOS (FBJ murine osteosarcoma viral oncogene homolog), CTNNB1 (Catenin (cadherin associated protein) beta 1), CDKN1A (Cyclin dependent kinase inhibitor 1A (P21, Cip1)-A), TNFAIP3 (Tumor necrosis factor, alpha induced protein 3), SIRT1 (Sirtuin 1), ESR1 (Estrogen receptor 1) and HDAC5 (Histone deacetylase 5).

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Two groups identified a strong association between systemic lupus erythematosus (SLE) and haplotypes that contain variants in the protein coding region of the gene tumour necrosis factor alpha induced protein 3 (TNFAIP3) XREF_BIBR, XREF_BIBR.

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TNFAIP3 codes for tumor necrosis factor alpha induced protein-3 and has been identified as a risk factor in SSc [XREF_BIBR, XREF_BIBR] particularly with dcSSc, ILD (fibrosing alveolitis) and PAH as well as in individuals with SSc and other autoimmune diseases [XREF_BIBR].

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A20 is a cytoplasmic zinc finger protein encoded by the gene TNF-alpha induced protein 3 TNFAIP3.

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A GWA study reported a new association of the tumor necrosis factor alpha induced protein 3 (TNFAIP3) gene with SLE XREF_BIBR.

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TNFAIP3 inhibits HSPB3.

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Furthermore, miR-125b target genes (histone methyltransferase Suv39h1 and the NF-kappaB negative regulator TNFAIP3 [tumor necrosis factor alpha induced protein 3]) were downregulated, which resulted in increased proinflammatory cytokine expression, aortic macrophage recruitment, MMP (matrix metalloproteinase)-2/9 activity, elastin fragmentation, and vascular smooth muscle cell loss in ATP7A mut/+ / ApoE -/- mice and reversed by locked nucleic acid-anti-miR-125b infusion.

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TNFAIP3 affects MTOR

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TNFAIP3 inhibits MTOR.

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TNFAIP3 inhibits MTOR. 9 / 9

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As mTOR is a major negative regulator of autophagy, we hypothesized that TNFAIP3 could inhibit mTOR signaling for the introduction of autophagy.

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Taken together, our findings illustrate that TNFAIP3 restricts MTOR signaling and promotes autophagy, providing new insight into the manner in which MTOR and autophagy regulate survival in CD4 T cells.

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Thus, TNFAIP3 inhibits mTOR signaling in this cell model.

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TNFAIP3 promotes autophagy by inhibiting mTOR signaling in inflammatory human NPCs.

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A recent study has identified that TNF-alpha-induced protein 3 (TNFAIP3) restricts mTOR activity and promotes macroautophagy and survival in CD4 + T-cells [XREF_BIBR].

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These findings revealed the relationship between degeneration process, inflammatory response, and autophagy in human NPCs, in which TNFAIP3 inhibits the mTOR signaling to ameliorate IVDD.

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TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy.

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TNFAIP3 inhibits mTOR signaling in the inflammatory human NPCs.

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Yu Matsuzawa et al. also found that TNFAIP3 promoted the survival of CD4 T cells by restricting mTOR and promoting autophagy [XREF_BIBR].

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TNFAIP3 decreases the amount of MTOR.

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Thus, we infer that TNFAIP3 may decrease phosphorylation level of mTOR after LPS stimulation in human NPCs.

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RELA affects TNFAIP3

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RELA increases the amount of TNFAIP3.

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RelA also enhanced Tnfaip3 expression following TNFalpha treatment, but significant differences were not detected between wild-type and Thr 435 mutants (XREF_FIG C).

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Together these data indicate that NF-kappaB p65 and C/EBPbeta were mediators of LPS induced Tnfaip3 expression in macrophages.

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This finding is consistent with the hypothesis that elevated expression of RelA enhances transcription of the TNFAIP3, PIGR and TNF genes through the classical NF-kappaB signaling pathway.

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RELA activates TNFAIP3.

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Real-time ChIP-PCR showed that the occupancy of the TNFAIP3 promoter by p65 was decreased in MDA-MB-231 cells in response to CTCF overexpression.

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TNFAIP3 affects cell death

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Therefore, A20 inhibits RIP3-dependent necroptotic cell death. xref This finding sheds new light on the importance of RIP3 ubiquitination in the process of necroptosis ( xref ).

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Although most studies have focused on the role of A20 in the inhibition of NF-κB and inflammatory signaling, little is known about how A20 inhibits cell death.

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In future studies, determining the precise role and mechanisms by which A20 inhibits cell death promises to be an exciting avenue of research.

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The phenotype of this patient characterized by autoinflammation might be explained by increased cell proliferation and cell death caused by reduced TNFAIP3 (A20) expression.

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We considered two major hypotheses, how the increased NF-κB activation of A20-deficient pathogen-specific CD8 + T cells might cause reduced numbers of T EM and T CM : (i) A20 regulates the development of SLEC and MPEC CD8 + T cells, and (ii) A20 inhibits cell death and enables persistence of CD8 + T cells.

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Given that A20 inhibits T effector cell death in CD4 + T cells, unleashing T effector cell–mediated inflammatory activity, our data complement the picture of A20 as a potent regulator of T cell–mediated inflammation, inducing T effector cell survival while reducing T reg cell generation.

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While the cell biological mechanisms by which A20 restricts cell death remain incompletely understood , some clues are provided by the observations that several death signaling proteins undergo physiological ubiquitination , and ubiquitinated death signaling complexes are dependent upon A20 .

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Upon searching the microarray for candidate genes involved in apoptosis downstream of PGC-1alpha4, we identified Birc2 (Ciap1) and Tnfaip3 (also known as A20), two anti-apoptotic proteins that prevent cell death downstream of inflammatory signaling.

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TNFAIP3 activates cell death.

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Reconstitution of wild type TNFAIP3 in the TNFAIP3 mutated lymphoma cells induces cell death.

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TNFAIP3 affects RIPK1

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TNFAIP3 inhibits RIPK1.

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Second, TNFAIP3 inactivates RIPK1, which regulates IκB kinase (IKK) [ xref ].

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Together, our results indicated that following TNF‐induced, RelA‐responsive A20 expression in a subset of cells, A20 binds to and subsequently inhibits RIPK1‐RIPK3 complexes, thereby transiently protecting these cells from necroptosis.

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Therefore, A20 inactivates RIP1 via sequential deubiquitinase and E3 ligase activities ( xref ).

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Downstream to Toll-like receptor 4 (TLR4) and tumor necrosis factor receptor 1 (TNFR1) the A20 complex inactivates TRAF6 and RIP1, repressing the NF- κ B signaling pathway [ xref , xref ].

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A20 inhibits pro-necroptotic RIPK1-RIPK3 complexes.

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TNFAIP3 activates RIPK1.

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However, molecules that negatively regulate Ripk1 and Jnk signaling, such as Tnfaip3 (A20) and GADD45beta respectively XREF_BIBR, are decreased in gammadelta T cells isolated from obese db/db mice.

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The signaling pathway also has several levels of autoregulation, one of which includes the activation and association of the RIP1 and IκB kinases by the A20 ubiquitin-editing protein complex [ xref ].

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A20 (TNFAIP3), TNF alpha inducible protein 3; IkappaBalpha, inhibitor of kappaB alpha subunit; IKK, IkappaB kinase; IKKK, IKK kinase; IRAK1 interleukin-1 receptor associated kinase 1; MEKK3, mitogen activated protein kinase kinase kinase 3; NF-kappaB, nuclear factor-kappaB; RIP, receptor interacting protein; TAK1, transforming growth factor-beta-activated kinase 1; TNFalpha, tumor necrosis factor alpha; TNFR, TNF receptor; TRAF2, tumor necrosis factor receptor associated factor 2.

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TNFAIP3 affects IL6

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TNFAIP3 activates IL6.

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At this time, very little information is available regarding the interaction of TNFAIP3 and STAT3 activation, and what is there appears disease and tissue dependent : in liver, TNFAIP3 activity results in increased STAT3 phosphorylation and IL-6 induction via inhibition of suppressor of cytokine signaling 3.

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Rather, these mice express increased quantities of splenic IL-4 mRNA (data not shown), and Tnfaip3 fl/fl CD19-Cre B cells produced more IL-6 and expressed higher amounts of co-stimulatory molecules upon stimulation.

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Thirdly, Tnfaip3 fl/fl CD19-Cre B cells produced more IL-6 than Tnfaip3 fl/+ CD19-Cre and Tnfaip3 +/+ CD19-Cre cells after treatment with LPS and CpG (XREF_FIG).

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Both Tnfaip3 OTU and OTU and Tnfaip3 ZF4 and ZF4 cells produced elevated amounts of the NF-kappaB dependent IL-6 and A20 mRNAs within one hour of TNF stimulation, consistent with increased NF-kappaB signaling in these cells (XREF_FIG).

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Moreover, TNFAIP3 has been reported to control NF-kappa B activity and promote liver regeneration by activating the inflammatory IL-6/STAT3 signaling pathway.

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TNFAIP3 inhibits IL6.

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This agrees with A20 inhibiting interleukin-6 and promoting transforming growth factor-β production by medial SMC and in SMC cultures exposed to cytokines, which favors differentiation of regulatory over pathogenic T cells.

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This agrees with A20 inhibiting IL-6 and promoting TGFβ production by medial SMC and in SMC cultures exposed to cytokines, thereby favoring differentiation of regulatory over pathogenic T cells.

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Furthermore, when compared with TNFAIP3 non knockdown and UBE2L3 knockdown in human HeLa cells, TNFAIP3 knockdown and UBE2L3 non knockdown synergistically increase three cytokines, CCL2, CXCL8 (IL8), and IL6, all regulated by NF-kappaB in the human TNFR signaling pathway.

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TNFAIP3 affects TRAF6

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Downstream to Toll-like receptor 4 (TLR4) and tumor necrosis factor receptor 1 (TNFR1) the A20 complex inactivates TRAF6 and RIP1, repressing the NF- κ B signaling pathway [ xref , xref ].

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TRAF6 are inhibited by A20 , CYLD and OTUB2 that specially remove TRAF6 K63-linked ubiquitination .

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TRAF6 are inhibited by A20, CYLD and OTUB2 that specially remove TRAF6 K63‐linked ubiquitination.

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A20 inhibits TRAF6, a molecule required for IL-17 induced NFκB and MAPK signaling ( xref ).

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A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6

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A20 expression was regulated by NF-κB. In turn, increased A20 expression inhibited TRAF6 and NF-κB to reduce the subsequent inflammatory response.

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Some of the proteins induced include SOCS3 – which inhibits JAKs, A20- which inhibits TRAF6, ABIN-3 which inhibits NFκB, and the transcriptional regulators, Hes1 and STAT3, that suppress the synthesis of inflammatory cytokines ( xref ).

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TNFAIP3 affects cytokine production

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We noted that A20 significantly inhibited poly(I:C)-induced cytokine production, and this effect was related to the inhibition of NF-κB signaling.

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Downstream of TLR activation , Quercetin supplement decreased cytokine production by regulating NF-kappaB activation and possibly modulating A20 expression , in response to oral bacteria and TLR agonist challenge .

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Downstream of TLR activation , Quercetin supplement decreased cytokine production by regulating NF-kB activation and possibly modulating A20 expression , in response to oral bacteria and TLR agonist challenge .

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Given the relationship we observed between elevated TNFAIP3 and decreased TNF-alpha, the lower levels of TNFAIP3 in AxSpA subjects may contribute to excessive cytokine production in response to PRR agonists.

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We hypothesized that lower levels of TNFAIP3 contributes to excessive cytokine production in response to inflammatory stimuli in axial spondyloarthritis (AxSpA).

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Porphyromonas gingivalis (P. gingivalis) , one of the keystone periodontal bacteria, can activate NF-κB signaling in macrophages and induce A20 expression in vivo when injected intraperitoneal cavity of mice and therefore it is included as a model oral bacteria in in vitro assays. ( xref ) Our results revealed that A20 inhibits pro-inflammatory cytokine production both in human and mouse macrophages infected with P. gingivalis through its effect on NF-κB signaling.

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TNFAIP3 activates cytokine production.

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Although multiple factors converge to regulate inflammatory cytokine production, we hypothesized that low TNFAIP3 may contribute to excessive cytokine production in spondyloarthritis.

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Compared with control siRNA, Tnfaip3 and Socs1 siRNAs increased both IL-13 and IL-5 cytokine production and mRNA expression in ILC2s (XREF_FIG).

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Benzo[a]pyrene affects TNFAIP3

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Benzo[a]pyrene decreases the amount of TNFAIP3.

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TNFAIP3 affects MAP3K5

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TNFAIP3 inhibits MAP3K5.

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The results from this study reveal a novel anti-apoptotic mechanism of A20 in TNF signaling pathway : A20 binds to apoptosis signal-regulating kinase1 ( ASK1 ) and mediates ASK1 degradation , leading to suppression of JNK activation and eventually blockage of apoptosis .

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Taken together , the results from this study reveal a novel anti-apoptotic mechanism of A20 in TNF signaling pathway : A20 binds to ASK1 and mediates ASK1 degradation , leading to suppression of JNK activation and eventually blockage of apoptosis .

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A20 signaling in APAP necrosis is through the MAPK cascade Since A20 is known to degrade ASK1 , thus abrogating JNK activation ( 26 ) , we examined JNK expression in A20HepCKO mice after APAP .

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Additionally, the same group has reported that TNFAIP3 can endogenously suppress ASK1 and reduce apoptosis, lipid accumulation, and inflammation [XREF_BIBR].

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Additionally , the same group has reported that TNFAIP3 can endogenously suppress ASK1 and reduce apoptosis , lipid accumulation , and inflammation [ 116 ] .

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A20 reduces the stability and promotes the degradation of ASK1 through the ubiquitination process A20 restricts TNF-induced NF-kappaB signaling through its ubiquitin editing activity on RIP1 ,14,15 it is thus of interest to test whether A20 would be affecting the stability of ASK1 through a similar mechanism .

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TNFAIP3 activates MAP3K5.

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The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis.

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Particulate Matter affects TNFAIP3

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Particulate Matter increases the amount of TNFAIP3.

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Particulate Matter decreases the amount of TNFAIP3.

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MALT1 affects TNFAIP3

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Although MALT1 inactivates A20 by protease activity-mediated cleavage, it seems to be dispensable for initial IKK/NF-κB activation by TCR stimulation ( Coornaert et al., 2008 ).

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Firstly, Malt1 directly cleaves and inactivates A20, a negative regulator of the antigen receptor-to-NF-kappaB pathway.

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MALT1 proteolytically cleaves and inactivates A20 as well as CYLD, two negative regulators of NF-κB signaling ( xref , xref ).

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For example , following TCR stimulation , A20 is degraded by paracaspase MALT1 [ 79 , 80 ] .

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Firstly, Malt1 directly cleaves and inactivates A20, a negative regulator of the antigen receptor-to-NF-κB pathway.

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However, MALT1 inactivates A20 by cleavage after arginine 439 to disrupt its inhibitory effect on NF-κB ( xref ) ( xref ).

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In turn, MALT1 mediates rapid proteolytic cleavage and inactivation of TNFAIP3 after TCR stimulation, thus fine tuning TCR activation 21.

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Infections affects TNFAIP3

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Infections increases the amount of TNFAIP3.

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FIG 5: Deltacoronavirus infection synchronously activates endogenous circTNFAIP3 and TNFAIP3 expression.

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Therefore, we performed experiments using cell lines A549 and THP1, and observed that IAV infection remarkably upregulated the expression of Tnfaip3 (Supplementary Figures 6C, D).

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Both OSU and NCDV NSP1 interact with β-TrCP, indicating that an association between NSP1 and target is likely necessary to induce turnover, as is true for NSP1 proteins that mediate IRF3 degradation.Recently, microarray analysis of host gene expression in HT-29 (human colorectal adenocarcinoma) cells has demonstrated that infection with SA11-4F, Wa, or bovine A5-13 RVA upregulates transcription of the tumor necrosis factor (TNF)-α-induced protein 3 (TNFAIP3) gene (Bagchi et al., 2012).

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Deltacoronavirus infection synchronously activates endogenous circTNFAIP3 and TNFAIP3 expression.

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(A) Expression of TNFAIP3 pre-mRNA, mRNA, and circRNA induced by PDCoV infection.

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Infections activates TNFAIP3.

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We speculated that NFKBIA and TNFAIP3 were significantly induced by ALV-J infection in MDM to down-regulate cytokines in macrophages, resulting in viral persistence in the host.

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EPs 7630 treatment post-SARS-CoV-2 infection resulted in a significant reduction of IL1B gene expression and strong upregulation of anti-inflammatory TNFAIP3.

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Silicon dioxide affects TNFAIP3

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U90/U89 affects TNFAIP3

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The results of similar transfection assays showed that IE1 activated the wild-type A20 promoter by 32-fold but upregulated the NF-κB mutant version by only 6-fold, whereas IE2 did not significantly affect IE1 activity (Figure xref C).

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Although A20 has been shown to be induced during HCMV entry, we also found that IE1 activates the A20 promoter through the upstream NF-κB sites.

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We also found that the viral IE1 protein activates the A20 promoter through the upstream NF-κB biding sites, suggesting a role of IE1 in the initial A20 activation.

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The direct activation of A20 promoter by IE1 is not surprising, since IE1 induces NF-κB activity and the A20 promoter contains two NF-κB binding sites.

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These results indicate that IE1 activates the A20 promoter through the NF-κB sites in reporter assays.

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We also found that IE1 activates the A20 promoter.

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IL1 affects TNFAIP3

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IL1 activates TNFAIP3. 6 / 6

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IL-1 induced six of these genes (ATF3, DUSP1, TNFAIP3, KLF6, PPP1R15A, and EGR1) indicating that HCoV-229E shares pathways with this cytokine but activates additional specific sets of genes (Fig 2A).

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It was shown that TNFAIP3 is induced by TNF and IL-1 and might therefore be involved in the regulation of NFkappaB dependent genes in diverse bacterial infections.

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This result was also substantiated by studies of the role of IKKα and IKKβ on either IL-1 or TNFα activation of the A20 gene.

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Furthermore, TAK1 siRNA reduced IL-1-induced activation of the A20 gene to 3.2-fold ().

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The relatively small effect of the individual IKKα and IKKβ siRNAs on inhibiting IL-1-induced activation of A20 was seen in three separate experiments.

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IL-8, TNFAIP3 and A20 and IL-6 (Early genes in response to TNF) were also rapidly induced by IL-1, peaking 1 h after stimulation.

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IE1 affects TNFAIP3

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IE1 activates TNFAIP3. 6 / 6

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We also found that IE1 activates the A20 promoter.

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The direct activation of A20 promoter by IE1 is not surprising, since IE1 induces NF-κB activity and the A20 promoter contains two NF-κB binding sites.

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Although A20 has been shown to be induced during HCMV entry, we also found that IE1 activates the A20 promoter through the upstream NF-κB sites.

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These results indicate that IE1 activates the A20 promoter through the NF-κB sites in reporter assays.

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We also found that the viral IE1 protein activates the A20 promoter through the upstream NF-κB biding sites, suggesting a role of IE1 in the initial A20 activation.

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Zinc atom affects TNFAIP3

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Silencing of the zinc-sensing receptor G protein-coupled receptor 39 (GPR39) was shown to abolish zinc-induced TNFAIP3 expression and the effects of zinc on high glucose-induced osteogenic marker expression.

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TNFAIP3 affects TLR

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On the other hand, TNFAIP3 can inhibit TLR induced activity of NFkappaB by de-ubiquitination of TRAF6.

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As TNFAIP3 normally restricts inflammatory TLR signals and its expression is induced in a variety of tissue types XREF_BIBR, XREF_BIBR, XREF_BIBR, the increased gut permeability in TNFAIP3 -/- mice might reflect an indirect effect of ongoing inflammation in these mice, a direct role for TNFAIP3 in IEC TJ stability, or a combination of these two effects.

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As mentioned earlier, Tnfaip3 −/− mice develop spontaneous multi-organ inflammation that leads to premature lethality. xref Tnfaip3 −/− mice on a Rag1 −/− background still developed spontaneous inflammation, indicating that adaptive lymphocytes were not essential for the uncontrolled inflammatory response, xref although hematopoietic cells were clearly involved. xref Signals from TNF were similarly dispensable for the inflammation in Tnfaip3 −/− mice, and A20 potently inhibited TLR signaling in macrophages. xref Consistent with these observations, homeostatic TLR signaling dependent on the Myd88 adaptor was dysregulated in A20-deficient mice. xref The homeostatic Myd88-dependent signals were derived from commensal intestinal bacteria since treatment of Tnfaip3 −/− mice with broad spectrum antibiotics reduced systemic inflammation and prevented cachexia. xref A20 is therefore a critical regulator of immune homeostasis and TLR signaling in vivo .

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TNFAIP3 activates TLR.

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However, polymorphisms genes encoding proteins and transcription factors downstream of TLR activation, including TNFAIP3, TNIP1 and IRF5, correlate with lupus risk [XREF_BIBR, XREF_BIBR].

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83 In ABC DLBCL, biallelic inactivation of TNFAIP3 (by mutations, deletions or both) occurs in 30% of cases and can coexist with mutations in both MYD88 and CD79B, suggesting that inactivation of TNFAIP3 can enhance both BCR and TLR signalling pathways.

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Mice adoptively transferred with TNFAIP3 -/- x Myd88 -/- hematopoietic stem cells display decreased inflammatory activation in the intestine demonstrating that the control of immune cell TLR signaling by TNFAIP3 is also required for intestinal homeostasis XREF_BIBR.

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TNFAIP3 affects RIPK3

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A20 inhibits pro-necroptotic RIPK1-RIPK3 complexes.

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In addition , A20 integrates into the downstream necrosome and restricts RIPK3 activation to limit necroptosis ( Onizawa et al , 2015 ) .

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TNF-induced expression of IkappaB attenuates NFkappaB , whereas A20 inhibits IKK and RIPK3 .

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TNFAIP3 activates RIPK3.

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TNFAIP3-upregulated RIP3 exacerbates acute pancreatitis via activating NLRP3 inflammasome.

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Collectively, overexpressed TNFAIP3 could contribute to the progression of AP by activating RIP3/NLRP3 axis, providing a potential therapeutic target for AP treatment.

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TNFAIP3 affects Neoplasm Invasiveness

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TNFAIP3 inhibits Neoplasm Invasiveness.

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Functional studies indicated that TNFAIP3 knockdown promoted migration and invasion, whereas TNFAIP3 overexpression alleviated these functions.

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Our data suggested that TNFAIP3 inhibited migration and invasion by suppressing epithelial mesenchymal transition in NPC.

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Furthermore, Huang et al reported that overexpression of TNFAIP3 inhibited migration and invasion in nasopharyngeal carcinoma XREF_BIBR.

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IL17A activates TNFAIP3. 2 / 3

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A20 ( Tnfaip3 ) , a deubiquitinase associated with susceptibility to autoimmune syndromes including psoriasis , is upregulated by IL-17A through NF-kappaB .

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IL-17 increased the abundance of TNFAIP3 mRNA and the subsequent production of A20 protein, which inhibited IL-17-mediated activation of TRAF6, NF-kappaB, and MAPKs, as well as downstream gene expression.

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TNFAIP3 affects IL17A

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A20 can block IL-17 production by interrupting the MAPK signaling pathway through abrogating K63 ubiquitination of TNF receptor associated factor 6 ( TRAF6 ) and preventing the prolonged phosphorylation of c-Jun-N-terminal-kinase ( JNK ) , which are both important for MAPK activation [ 46 ] .

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A20 can block IL-17 production and IL-17-mediated inflammatory aggravation during anti-TNF treatment by preventing the prolonged phosphorylation of JNK and inhibiting p38 MARK and PKC activity , which is dependent on the ZnF7 motif of A20 .

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Using RNA-silencing and A20 −/− cells, we showed that the expression of various IL-17 target genes was inhibited by A20 ( xref to xref ).

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MTX1 activates TNFAIP3. 4 / 4

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TNFAIP3 induction by MTX was inhibited by the simultaneous addition of FA, indicating that MTX triggered TNFAIP3 induction relies on blocking one-carbon metabolism (XREF_FIG).

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By contrast, TNFAIP3 induction by MTX was observed in all donors examined.

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XREF_BIBR Assessment of the underlying mechanism revealed that MTX triggered TNFAIP3 induction in GM-MO was significantly diminished (40%) after TS silencing with two different small interfering RNA (XREF_FIG), thus indicating that MTX triggered TNFAIP3 upregulation is partly dependent on TS expression.

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MTX induces upregulation of the TNFAIP3 gene, which encodes for the protein A20, a negative regulator of NFkappaB signaling.

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MTX1 inhibits TNFAIP3.

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MTX1 increases the amount of TNFAIP3.

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Therefore, MTX induces a tolerant state in macrophages by upregulating the expression of TNFAIP3 in a TS/p53 dependent pathway.

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Tax affects TNFAIP3

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Tax inhibits TNFAIP3. 5 / 5

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HTLV-1 Tax might also provide a bridge to the proteasome by disrupting the interaction between an E3 ubiquitin ligase and its substrate, illustrated by the inactivation by Tax of the A20-Itch E3 ligase complex, potentially leading to a permanent activation of tumor necrosis factor (TNF) receptor (TNFR) signaling [ xref ].

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CADM1 is required for Tax to inactivate the A20 complex.

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The inhibition of A20 by Tax may contribute to the constitutive activation of NF-κB in HTLV-1 infected cells.

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Tax inactivation of A20 alleviates the negative feedback control of NF-κB and facilitates persistent NF-κB signaling that drives cell transformation.

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The exact mechanism by which Tax inactivates A20 has remained elusive.

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Cyclosporin A affects TNFAIP3

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Cyclosporin A increases the amount of TNFAIP3.

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TNFAIP3 activates Ubiquitin. 3 / 3

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In addition to TNFAIP3 modulating ubiquitin others have found that TNFAIP3 can also inhibit IKK complex activity through a mechanism that is independent of ubiquitin.

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TNFAIP3 protein as a zinc finger protein and ubiquitin shearing enzyme can suppress activated NF-kappaB signal pathway and induce apoptosis of TNF by activating ubiquitin ligase and ubiquitinase.

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Therefore, it is plausible that TNFAIP3 mediated ubiquitin editing contributes to the modification of tight junction proteins.

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TNFAIP3 inhibits Ubiquitin.

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TNFAIP3 inhibits NF-kappaB activation by exerting dual ubiquitin editing functions [XREF_BIBR].

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CYLD and TNFAIP3 and A20 negatively regulate the NFkappaB pathway by removing ubiquitin chains from multiple signaling molecules including TRAFs and RIP.

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TNFAIP3 affects TRAF2

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Since TRAF2 overexpression activates these signaling events via distinct downstream components [ xref ], a simple explanation of these observations is that A20 may directly inhibit TRAF2 to terminate these signals.

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Moreover we demonstrated that A20 could inhibit RIP- and TRAF2- but not NIK-induced NF-κB–dependent reporter gene activation, suggesting that A20 interferes with NF-κB activation upstream of NIK.

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WT TNFAIP3 induces the degradation of TRAF2 in a dose dependent manner; whereas, the catalytic mutant C103A fails to do so (XREF_FIG).

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The mechanism of A20-dependent TRAF2 inhibition is still unknown.

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The ability of these TNFAIP3 mutants to induce the degradation of TRAF2 was tested to evaluate the functional consequence of nonsynonymous coding variants in TNFAIP3.

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Phorbol 13-acetate 12-myristate affects TNFAIP3

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Phorbol 13-acetate 12-myristate increases the amount of TNFAIP3.

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Carbon nanotube affects TNFAIP3

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NFKB1 affects TNFAIP3

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NFKB1 increases the amount of TNFAIP3. 4 / 4

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MTOR affects TNFAIP3

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MTOR inhibits TNFAIP3. 4 / 4

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Moreover, inhibition of mTOR signaling reversed TNFAIP3 inhibition on both IL-1beta and TNF-alpha production (XREF_FIG, XREF_FIG).

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The induction of autophagy in naive CD4 T cells following TCR stimulation is dependent on mTOR inhibition downstream of the ubiquitin editing enzyme TNFAIP3 (A20) 114.

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Further, pharmacological inhibition of mTOR signaling can significantly reverse the effects of TNFAIP3 knockdown, including inhibition of autophagy and extracellular matrix production, as well as the promotion of inflammatory response.

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The induction of autophagy in naïve CD4 T cells following TCR stimulation is dependent on mTOR inhibition downstream of the ubiquitin editing enzyme TNFAIP3 (A20) 114 .

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(+)-JQ1 compound affects TNFAIP3

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(+)-JQ1 compound decreases the amount of TNFAIP3. 4 / 4

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Cisplatin affects TNFAIP3

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Cisplatin increases the amount of TNFAIP3.

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Cisplatin decreases the amount of TNFAIP3.

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TNFAIP3 affects IL1B

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TNFAIP3 inhibits IL1B.

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The feedback regulator TNFAIP3 (A20) which negatively regulates TNF-alpha and IL-1beta signalling is up-regulated in two datasets and is down-regulated in one dataset.

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TNFAIP3 activates IL1B.

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TLR activates TNFAIP3. 3 / 3

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Consistent with these observations, treatment of A20 deficient mice with broad-spectrum antibiotics rescues the severe inflammation and lethality, indicating that a dysregulated response to commensal intestinal flora is responsible for the constitutive TLR signaling in Tnfaip3 -/- mice [XREF_BIBR].

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Interestingly, TNFAIP3 is reported to suppress SOCS3 expression to enhance STAT3 proliferative signals.

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These findings suggested that STAT3 could also be activated by increased Tnf and Tnfaip3 signals that further led to reduced Socs3 level in Vldlr -/- retinas.

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TNFAIP3 inhibits SOCS3.

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IL-6 activated the STAT3 and vascular endothelial growth factor A (VEGFA) pathway directly, and elevated TNFAIP3 suppressed SOCS3 (suppressor of cytokine signaling 3)-activated STAT3 and VEGFA indirectly.

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TNFAIP3 activates SOCS3.

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Valproic acid affects TNFAIP3

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Bis(2-chloroethyl) sulfide affects TNFAIP3

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Bis(2-chloroethyl) sulfide increases the amount of TNFAIP3. 3 / 3

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Bacterial infection affects TNFAIP3

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Bacterial infection increases the amount of TNFAIP3. 3 / 3

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TABLE 2. Genes differentially expressed in human neutrophils following 4 h of A. phagocytophilum infection # Anaplasma phagocytophilum is a gram-negative bacterial pathogen

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Understanding the response of innate immune cells to pathogens may provide insights to host defenses and the tactics used by pathogens to circumvent these defenses. We used DNA microarrays to explore the responses of human macrophages to a variety of bacteria. Macrophages responded to a broad range of bacteria with a robust, shared pattern of gene expression. The shared response includes genes encoding receptors, signal transduction molecules, and transcription factors. This shared activation program transforms the macrophage into a cell primed to interact with its environment and to mount an immune response. Further study revealed that the activation program is induced by bacterial components that are Toll-like receptor agonists, including lipopolysaccharide, lipoteichoic acid, muramyl dipeptide, and heat shock proteins. Pathogen-specific responses were also apparent in the macrophage expression profiles. Analysis of Mycobacterium tuberculosis-specific responses revealed inhibition of interleukin-12 production, suggesting one means by which this organism survives host defenses. These results improve our understanding of macrophage defenses, provide insights into mechanisms of pathogenesis, and suggest targets for therapeutic intervention.

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Early infection was characterized by an upregulation of anti-apoptotic genes and a downregulation of pro-apoptotic genes. This correlated with a necrotic, rather than apoptotic cell death.

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Aflatoxin B1 affects TNFAIP3

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Aflatoxin B1 increases the amount of TNFAIP3. 3 / 3

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TNFAIP3 affects IRF3

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TNFAIP3 inhibits IRF3. 3 / 3

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TNFAIP3 downregulates the activity of IRF-3, a key transcription factor for the induction of IFN-gamma [XREF_BIBR].

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XREF_BIBR Also, IRF3 dependent signaling is negatively regulated by TAX1BP1 and TNFAIP3.

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TNFAIP3 downregulates the activity of IRF-3 , a key transcription factor for the induction of IFN-gamma [ 36 ] .

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TNFAIP3 affects IKBKB

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TNF alpha induced protein 3 (A20, also known as TNFAIP3) is also induced upon NF-kappaB activation and negatively regulates IKKbeta activity.

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A20, a deubiquitinating enzyme, inactivates IKKβ by removing regulatory K63-linked polyubiquitin chains from IKKγ.

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Also, TNFAIP3 acts to deactivate IKK1 and IKK2.

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TNFAIP3 affects Disease

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Therefore , A20 directly preserves immune homeostasis and prevents disease .

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As inflammasomes are implicated in a number of experimental and clinical disease models , restricting inflammasome activation is another mechanism by which A20 can prevent disease .

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In this study , we have used six distinct gene-targeted lines of Tnfaip3 knock-in mice to dissect how A20 prevents disease .

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TNFAIP3 affects Death

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TNFAIP3 inhibits Death. 3 / 3

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Intestinal epithelial cell (IEC) expression of TNFAIP3 improves barrier function and tight junction integrity and prevents dextran sulfate sodium (DSS)-induced IEC death and colitis.

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As TNFAIP3 inhibits NF-kappaB activation and IEC death, expression of TNFAIP3 in IEC may provide an avenue to inhibit IEC NF-kappaB activation without inducing IEC death and inflammation.

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These results indicate that TNFAIP3 expression in IEC prevents colitis involving DSS induced IEC death, but not colitis driven by T cell mediated inflammation.

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TNFAIP3 affects Cell Survival

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TNFAIP3 , an important anti-inflammatory factor , can repress the expression of inflammatory NF-kappaB signaling and promote cell survival ( Catrysse et al ., 2014 ) .

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This signature of EGFR TKI induced NF-kappaB output consisted of 36 NF-kappaB target genes, including established regulators of NF-kappaB signaling and cell survival such as TNFAIP3, BIRC3, and IL6 (XREF_FIG and XREF_SUPPLEMENTARY).

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Activation of canonical NF-κB in response to EGFR oncogene inhibition in mutant EGFR-bearing human and mouse lung cancer cells, drives tumour cell survival and residual disease in lung cancer via several established regulators of canonical NF-κB signalling and cell survival such as TNFAIP3 (TNFα-induced protein 3), BIRC3 (c-IAP2, TNFR2-TRAF signalling complex protein) and IL-6 [16].

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TNFAIP3 affects CD4

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A20 also promotes CD4 + T cell survival via restriction of mTOR activity and increased autophagy [ 52 ] ) .

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Yu Matsuzawa et al. also found that TNFAIP3 promoted the survival of CD4 T cells by restricting mTOR and promoting autophagy [XREF_BIBR].

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TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy.

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TNFAIP3 affects Arthritis

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TNFAIP3 inhibits Arthritis. 3 / 3

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Additionally , domain-specific mutant mice can be generated by mutating OTU ( C103A ) , ZnF4 ( C609A and C612A ) , or ZnF7 ( C764A and C767A ) and other specific sites The inflammatory features of arthritis and the anti-inflammatory function of A20 suggest that A20 can suppress arthritis by restricting inflammation , which has been verified by a growing number of studies .

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A20 prevents arthritis by inhibiting macrophage necroptosis and restricting spontaneous immune activation through its ZnF7 Necroptosis is a modified form of necrosis in which dead cells break up and release intracellular components , triggering an innate immune response that includes IL-1beta release and NLRP3 inflammasome activation [ 29 , 57 ] .

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More recently , it has been shown that A20 restricts Th17 cell expansion and arthritis through its ZnF7 motif [ 28 ] .

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SPP1 affects TNFAIP3

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All-trans-retinoic acid increases the amount of TNFAIP3.

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All-trans-retinoic acid increases the amount of TNFAIP3. 2 / 2

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Sodium arsenite affects TNFAIP3

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Pirinixic acid decreases the amount of TNFAIP3.

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Ochratoxin A decreases the amount of TNFAIP3.

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Mechanistically, GABA treatment significantly induced the sustained expression of TNFAIP3.

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Gamma-aminobutyric acid activates TNFAIP3.

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Gamma-aminobutyric acid activates TNFAIP3. 1 / 1

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Gamma-Aminobutyric Acid Promotes Osteogenic Differentiation of Mesenchymal Stem Cells by Inducing TNFAIP3.

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Doxorubicin affects TNFAIP3

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Doxorubicin decreases the amount of TNFAIP3.

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Doxorubicin activates TNFAIP3.

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Unexpectedly, no differences were detected in ICAM-1 and TNFAIP3 mRNA levels between CT and p53 knocked down cells when treated with doxorubicin.

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Dexamethasone affects TNFAIP3

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Dexamethasone increases the amount of TNFAIP3.

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While stimulation with MOG antigen failed to induce TNFAIP3, dexamethasone stimulation, a potent glucocorticoid, partially rescued the expression of TNFAIP3 protein and transcriptome levels in the relapse sample thereby suggesting that the induction of TNFAIP3 by glucocorticoids can improve relapses in MOG-AAD patients.

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Dexamethasone decreases the amount of TNFAIP3.

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Benzene decreases the amount of TNFAIP3.

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In bladder carcinogenesis , ZNF224 , interacting with the transcriptional co-repressor DEPDC1 , downregulates the expression of A20 , a negative regulator of the NF-kB pathway [ 29 ] , whereas , in breast cancer , ZNF224 acts as an oncogenic transcriptional activator .

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ZNF224 activates TNFAIP3.

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In more detail , chromatin immunoprecipitation and luciferase reporter assays showed that DEPDC1 is recruited on the promoter of A20 by ZNF224 and functions as a ZNF224 transcriptional co-repressor .

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Thr-Thr affects TNFAIP3

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Thr-Thr inhibits TNFAIP3.

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TNFAIP3 gene rs10499194, rs13207033 polymorphisms decrease the risk of rheumatoid arthritis.

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TNFAIP3 activates rheumatoid arthritis.

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TNFAIP3 inhibits PCBD1. 1 / 1

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Enterocyte specific deletion of Tnfaip3 (Tnfaip3 Flox Vil1-Cre) causes hypersensitivity to dextran sodium sulfate (DSS)-induced colitis, which is associated with hypersensitivity of enterocytes to TNF induced PCD and is partially rescued by TNFR1 deficiency.

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TNFAIP3 activates PCBD1.

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These results align with prior studies suggesting that A20 can inhibit IKKgamma activity without affecting RIP1 ubiquitination 17 .

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TNFAIP3 activates IKBKG.

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Conclusions : Following stimulation of the renin angiotensin system , A20 suppresses DC activation and thereby mitigates T cell-dependent blood pressure elevation .

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TNFAIP3 activates Dendritic Cells.

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These observations suggested that the proinflammatory DC phenotype was induced by the caerin gel.Caerin gel treatment significantly upregulated the expression of Tnfaip3 in NK cells.

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TNFAIP3 affects Caspase

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TNFAIP3 inhibits Caspase.

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This was attributable at least partially to the NIK induced overexpression of some canonical pathway inhibitors like Nfkbia, Nfkbie, and Tnfaip3 (A20) (XREF_FIG).

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NFKBIA activates TNFAIP3.

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KLF6 inhibits TNFAIP3. 1 / 1

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As shown in XREF_FIG, NFKBIA knockdown completely or partially rescued KLF6-wt effect on the majority of the tested genes; furthermore, although not always statistically significant, it seemed to prevent KLF6 mediated upregulation of the other NF-kappaB-negative regulators (TNIP1, TNIP2 and TNFAIP3, XREF_SUPPLEMENTARY), suggesting that NF-kappaB could mediate a positive feedback loop by downregulating its negative regulators as previously described.

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