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
1521 retrieved on 2022-05-22

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) CCLE Significant 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

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
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
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).
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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Review
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
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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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.
TNFAIP3 deubiquitinates CALCOCO2. 1 / 1
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NDP52 itself has to be activated by the E3 ligase TRAF6 via the attachment of Lys63-linked polyubiquitin chains. A20 counteracts the function of NDP52 in order to prevent an overactivation.?
TNFAIP3 deubiquitinates BECN1. 1 / 1
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However, this TRAF6-dependent polyubiquitination of Beclin 1 is antagonized by the deubiquitinase A20
TNFAIP3 deubiquitinates NFKB1. 1 / 1
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Review
TNFAIP3 deubiquitinates TP53. 1 / 1
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TNFAIP3 deubiquitinates RIPK2. 1 / 1
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Activation of RIPK2 depends on its K63 ubiquitination by E3 ligases, whereas the deubiquitinating enzyme A20 counter regulates RIPK2 activity by cleaving K63-polyubiquitin chains from RIPK2.
TNFAIP3 deubiquitinates IRF7. 1 / 1
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Thus, A20 negatively regulates LMP1-stimulated IRF7 ubiquitination and activity in EBV latency, and its DUB activity is indispensable for this function.
TNFAIP3 deubiquitinates CASP8. 1 / 1
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Apo2L induces both K48 and K63-linked polyubiquitination of caspase 8.
TNFAIP3 deubiquitinates RIPK2 on K209. 1 / 1
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TNFAIP3 deubiquitinates TRAF2. 1 / 1
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A tight control in TNF-a led NF-kB activation is exerted byA20 as it targets both RIP1 and TRAF2 through different mechanisms.
TNFAIP3 leads to the deubiquitination of Proteasome. 1 / 1
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TNFAIP3 and TAX1BP1 inhibit the inflammatory signaling pathway by interacting with Ubc13 and UbcH5c and triggering their ubiquitination and proteasome dependent degradation [XREF_BIBR].

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
TNFAIP3 affects NFkappaB
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TNFAIP3 inhibits NFkappaB.
| 29 35 51
| 29 35 49

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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.
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.
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].
TNFAIP3 activates NFkappaB.
| 9 40
| 9 39

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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).
Mutated TNFAIP3 activates NFkappaB. 1 / 1
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TNFAIP3 mutations likely contribute to lymphomagenesis by inducing unregulated prolonged NF-kappaB responses.
TNFAIP3 increases the amount of NFkappaB.
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TNFAIP3 increases the amount of NFkappaB. 1 / 1
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For example, in C. concisus infected cells the protein coding gene TNFAIP3 (which was upregulated 25.7-fold by the infection) adjacent to regulated lncRNAs was shown to inhibit TNF- and IL1 induced NFkappaB gene expression.
TNFAIP3 decreases the amount of NFkappaB.
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TNFAIP3 decreases the amount of NFkappaB. 1 / 1
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TNFAIP3, an important anti-inflammatory factor, can repress the expression of inflammatory NF-kappaB signaling and promote cell survival.
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TNF affects TNFAIP3
| 1 6 53
TNF activates TNFAIP3.
| 1 5 41
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.
TNF bound to IRF8 activates TNFAIP3. 1 / 1
| 1

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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.
TNF increases the amount of TNFAIP3.
| 1 10
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).
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).
| 4 17 28
| 2 17 10
| 2 17 10

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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 ] .
| 2 18

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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.
| 9 5 20
| 6 5 15

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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.
| DOI

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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].
TNFAIP3 bound to TNIP1 inhibits inflammatory response. 1 / 1
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XREF_BIBR TNIP1 may interact with TNFAIP3 and inhibit TNFalpha induced NFkappaB inflammation pathway.
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| 3 5

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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.
NFkappaB affects TNFAIP3
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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 ].
NFkappaB increases the amount of TNFAIP3.
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NFkappaB increases the amount of TNFAIP3. 5 / 5
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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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In our work, we found that NF-kappaB induced the expression of CXCL1, ICAM1 and TNFAIP3 after doxorubicin treatment only in a subset of tumors, suggesting that differences in responses may exist among tumor subtypes.

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Furthermore, persistent endothelial NF-kappaB activation by vFLIP induces expression of the NF-kappaB regulator A20 and TNFAIP3, which represses vFLIP induced NF-kappaB activation and augments IKK1 protein expression [XREF_BIBR].
NFkappaB decreases the amount of TNFAIP3.
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NFkappaB decreases the amount of TNFAIP3. 2 / 3
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This inhibition led to downregulation of TNFalpha induced NFkappaB target gene expression of IL6, ICAM1, and TNFAIP3, which had reduced basal and/or TNFalpha induced expression upon COUP-TFII overexpression.

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These results suggested that SFE suppressed ESCC progression through inactivating the NFkappaB pathway which lowered TNFAIP3 and PLAU expression.
NFkappaB inhibits TNFAIP3.
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Numerous lines of evidence, from human disease linkage analyses to mouse experimental models, attest to critical roles for the NFκB inhibiting partner proteins A20 and ABIN1 in systemic and cutaneous inflammatory disease.

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Moreover, Tax requires CADM1 for its K63-linked polyubiquitination, NF-κB activation, and inactivation of the NF-κB negative regulatory A20 complex.
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TNFAIP3 inhibits IKK_complex.
| 5 25 1
| 5 25 1

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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.
TNFAIP3 activates IKK_complex.
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Direct, Non-Catalytic Impairment of IKK Activation by A20.
TNFAIP3 affects TNF
| 1 5 19
TNFAIP3 inhibits TNF.
| 1 5 10
| 1 5 10

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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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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 ].
TNFAIP3 activates TNF.
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TNFAIP3 activates TNF. 6 / 6
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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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This inhibition led to downregulation of TNFalpha induced NFkappaB target gene expression of IL6, ICAM1, and TNFAIP3, which had reduced basal and/or TNFalpha induced expression upon COUP-TFII overexpression.
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.
TNFAIP3 decreases the amount of TNF.
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TNFAIP3 decreases the amount of TNF. 2 / 2
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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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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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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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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 increases the amount of TNFAIP3.
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Lipopolysaccharide increases the amount of TNFAIP3. 10 / 13
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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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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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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).
1 | 6

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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.
Lipopolysaccharide decreases the amount of TNFAIP3.
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Lipopolysaccharide decreases the amount of TNFAIP3. 2 / 2
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TNFAIP3 affects autophagy
| 1 1 15
TNFAIP3 activates autophagy.
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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 .
TNFAIP3 inhibits 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.
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.
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.
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].
TNFAIP3 decreases the amount of MTOR.
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TNFAIP3 decreases the amount of MTOR. 1 / 1
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Thus, we infer that TNFAIP3 may decrease phosphorylation level of mTOR after LPS stimulation in human NPCs.
RELA affects TNFAIP3
2 2 | 5
RELA increases the amount of TNFAIP3.
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RELA increases the amount of TNFAIP3. 7 / 8
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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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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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Modified RELA increases the amount of TNFAIP3. 1 / 1
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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.
RELA activates TNFAIP3.
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RELA activates TNFAIP3. 1 / 1
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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 inhibits 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.
TNFAIP3 activates cell death.
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Reconstitution of wild type TNFAIP3 in the TNFAIP3 mutated lymphoma cells induces cell death.
TNFAIP3 affects RIPK1
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TNFAIP3 inhibits RIPK1.
| 5 1
| 5 1

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

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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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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.
TNFAIP3 activates RIPK1.
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TNFAIP3 activates RIPK1. 3 / 3
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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.
TNFAIP3 affects IL6
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TNFAIP3 activates IL6.
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TNFAIP3 activates IL6. 6 / 6
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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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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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