CYLD Data Analysis

HGNC Gene Name
CYLD lysine 63 deubiquitinase
HGNC Gene Symbol
CYLD
Identifiers
hgnc:2584 NCBIGene:1540 uniprot:Q9NQC7
Orthologs
mgi:1921506 rgd:1308346
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for CYLD
Number of Papers
767 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
N4BP1 NEDD4 binding protein 1 0.466 0.32 1.69 1.40e-07
TRAF3 TNF receptor associated factor 3 0.383 INDRA (3) Reactome (7) 0.11 0.53 1.36e-01 99.44 kd
NFKBIA NFKB inhibitor alpha 0.283 INDRA (7) Reactome (9) 0.14 0.66 1.22e-01 90.25 oe
TNFAIP3 TNF alpha induced protein 3 0.272 INDRA (10) Reactome (15) 0.14 0.66 7.05e-02 -94.74 oe
TRAF2 TNF receptor associated factor 2 0.242 BioGRID Pathway Commons INDRA (19) Reactome (13) 0.25 1.30 6.91e-05 99.91 oe
BCL10 BCL10 immune signaling adaptor -0.233 Reactome (4) 0.24 1.21 2.22e-04 99.95 oe
CHUK component of inhibitor of nuclear factor kappa B kinase complex -0.231 Pathway Commons INDRA (11) Reactome (10) 0.27 1.38 2.23e-05

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with CYLDusing 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:0002224 toll-like receptor signaling pathway Biological Process 4.87e-10 2.23e-07 4.52e-08
GO:0051090 regulation of DNA-binding transcription factor activity Biological Process 9.24e-10 4.23e-07 4.52e-08
GO:0033209 tumor necrosis factor-mediated signaling pathway Biological Process 1.03e-09 4.72e-07 4.52e-08
GO:0002221 pattern recognition receptor signaling pathway Biological Process 2.25e-09 1.03e-06 7.40e-08
GO:0035631 CD40 receptor complex Cellular Component 5.07e-09 2.32e-06 1.33e-07
GO:0007249 I-kappaB kinase/NF-kappaB signaling Biological Process 1.05e-08 4.81e-06 2.30e-07
GO:0032088 negative regulation of NF-kappaB transcription factor activity Biological Process 1.57e-08 7.17e-06 2.94e-07
GO:0034612 response to tumor necrosis factor Biological Process 2.30e-08 1.06e-05 3.65e-07
GO:0002218 activation of innate immune response Biological Process 2.50e-08 1.14e-05 3.65e-07
GO:0045088 regulation of innate immune response Biological Process 1.33e-07 6.07e-05 1.74e-06
GO:0043433 negative regulation of DNA-binding transcription factor activity Biological Process 2.13e-07 9.76e-05 2.55e-06
GO:0031663 lipopolysaccharide-mediated signaling pathway Biological Process 8.92e-07 4.09e-04 9.78e-06
GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway Biological Process 1.10e-06 5.02e-04 1.11e-05
GO:0070646 protein modification by small protein removal Biological Process 2.04e-06 9.33e-04 1.92e-05
GO:0044389 ubiquitin-like protein ligase binding Molecular Function 2.23e-06 1.02e-03 1.96e-05
GO:0002237 response to molecule of bacterial origin Biological Process 3.44e-06 1.57e-03 2.83e-05
GO:0031996 thioesterase binding Molecular Function 6.41e-06 2.93e-03 4.96e-05
GO:0070431 nucleotide-binding oligomerization domain containing 2 signaling pathway Biological Process 9.08e-06 4.16e-03 6.64e-05
GO:0032606 type I interferon production Biological Process 9.82e-06 4.50e-03 6.80e-05
GO:0002697 regulation of immune effector process Biological Process 1.08e-05 4.94e-03 7.10e-05
GO:0051092 positive regulation of NF-kappaB transcription factor activity Biological Process 1.69e-05 7.74e-03 1.06e-04
GO:0007252 I-kappaB phosphorylation Biological Process 1.78e-05 8.15e-03 1.06e-04
GO:2001236 regulation of extrinsic apoptotic signaling pathway Biological Process 1.86e-05 8.53e-03 1.07e-04
GO:0032495 response to muramyl dipeptide Biological Process 2.21e-05 1.01e-02 1.21e-04
GO:0034614 cellular response to reactive oxygen species Biological Process 2.33e-05 1.06e-02 1.22e-04
GO:0098562 cytoplasmic side of membrane Cellular Component 2.58e-05 1.18e-02 1.28e-04
GO:0060759 regulation of response to cytokine stimulus Biological Process 2.67e-05 1.22e-02 1.28e-04
GO:0038061 NIK/NF-kappaB signaling Biological Process 2.72e-05 1.24e-02 1.28e-04
GO:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling Biological Process 2.95e-05 1.35e-02 1.34e-04
GO:0051059 NF-kappaB binding Molecular Function 4.71e-05 2.16e-02 2.00e-04
GO:0097191 extrinsic apoptotic signaling pathway Biological Process 5.49e-05 2.51e-02 2.06e-04
GO:0005164 tumor necrosis factor receptor binding Molecular Function 5.40e-05 2.47e-02 2.06e-04
GO:0001782 B cell homeostasis Biological Process 5.05e-05 2.31e-02 2.06e-04
GO:1903320 regulation of protein modification by small protein conjugation or removal Biological Process 5.27e-05 2.41e-02 2.06e-04
GO:0002756 MyD88-independent toll-like receptor signaling pathway Biological Process 5.76e-05 2.64e-02 2.10e-04
GO:0000302 response to reactive oxygen species Biological Process 6.01e-05 2.75e-02 2.14e-04
GO:0071216 cellular response to biotic stimulus Biological Process 6.17e-05 2.83e-02 2.14e-04
GO:0034142 toll-like receptor 4 signaling pathway Biological Process 6.51e-05 2.98e-02 2.20e-04
GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway Biological Process 7.31e-05 3.35e-02 2.40e-04
GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Biological Process 7.72e-05 3.54e-02 2.48e-04
GO:0051091 positive regulation of DNA-binding transcription factor activity Biological Process 8.84e-05 4.05e-02 2.77e-04

Transcriptomics

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

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
BIRC3 baculoviral IAP repeat containing 3 1.01e+00 1.57e-18 1.99e-14
CXCL8 C-X-C motif chemokine ligand 8 1.49e+00 3.06e-17 1.94e-13
CSF2 colony stimulating factor 2 1.20e+00 5.02e-16 2.12e-12
CXCL2 C-X-C motif chemokine ligand 2 1.27e+00 5.83e-10 1.73e-06
CXCL3 C-X-C motif chemokine ligand 3 1.34e+00 7.57e-10 1.73e-06
LAMC2 laminin subunit gamma 2 9.68e-01 8.20e-10 1.73e-06
SOD2 superoxide dismutase 2 6.95e-01 1.04e-09 1.88e-06
G0S2 G0/G1 switch 2 4.73e-01 1.74e-09 2.76e-06
CXCL1 C-X-C motif chemokine ligand 1 1.10e+00 2.19e-09 3.08e-06
MMP1 matrix metallopeptidase 1 4.45e-01 4.90e-09 6.20e-06
IL1B interleukin 1 beta 1.34e+00 7.86e-09 9.04e-06
TNFSF15 TNF superfamily member 15 9.28e-01 9.39e-09 9.90e-06
C15orf48 chromosome 15 open reading frame 48 7.19e-01 1.07e-08 1.04e-05
ICAM1 intercellular adhesion molecule 1 1.00e+00 4.30e-08 3.89e-05
NAMPT nicotinamide phosphoribosyltransferase 5.70e-01 4.62e-08 3.90e-05
TFPI2 tissue factor pathway inhibitor 2 7.05e-01 6.85e-08 5.42e-05
CSF3 colony stimulating factor 3 1.29e+00 1.41e-07 1.05e-04
PTX3 pentraxin 3 6.63e-01 2.45e-07 1.73e-04
SYNGR2 synaptogyrin 2 6.75e-01 7.33e-07 4.88e-04
NFKBIA NFKB inhibitor alpha 5.70e-01 3.07e-06 1.94e-03
KYNU kynureninase 7.62e-01 1.35e-05 8.13e-03
DUSP28 dual specificity phosphatase 28 9.38e-01 2.31e-05 1.33e-02
AKR1B1 aldo-keto reductase family 1 member B 3.56e-01 2.97e-05 1.63e-02
SERPIND1 serpin family D member 1 7.78e-01 4.99e-05 2.63e-02
CD44 CD44 molecule (Indian blood group) 3.75e-01 5.72e-05 2.89e-02
IL6 interleukin 6 7.86e-01 7.26e-05 3.54e-02
SAA2 serum amyloid A2 5.76e-01 1.10e-04 4.99e-02
SQSTM1 sequestosome 1 4.96e-01 1.09e-04 4.99e-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 3.96e-17 1.55e-13 1.07e+00 6.59e-01 2.81e+00
go:0019221 cytokine-mediated signaling pathway 3.08e-10 6.02e-07 8.14e-01 4.10e-01 2.01e+00
reactome:R-HSA-1640170 Cell Cycle 2.70e-09 3.52e-06 7.75e-01 -3.60e-01 -1.83e+00
go:0030545 receptor regulator activity 8.26e-09 8.07e-06 7.48e-01 5.72e-01 2.35e+00
msig:M5932 HALLMARK_INFLAMMATORY_RESPONSE 1.68e-08 1.29e-05 7.34e-01 5.93e-01 2.38e+00
go:0006954 inflammatory response 1.98e-08 1.29e-05 7.34e-01 4.48e-01 2.10e+00
go:0050900 leukocyte migration 2.33e-08 1.30e-05 7.34e-01 5.05e-01 2.20e+00
go:0005125 cytokine activity 2.82e-08 1.38e-05 7.34e-01 7.31e-01 2.44e+00
go:0006952 defense response 4.21e-08 1.60e-05 7.20e-01 3.29e-01 1.71e+00
go:0034097 response to cytokine 4.51e-08 1.60e-05 7.20e-01 3.37e-01 1.75e+00
msig:M5925 HALLMARK_E2F_TARGETS 4.16e-08 1.60e-05 7.20e-01 -4.41e-01 -2.02e+00
msig:M9809 KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION 1.02e-07 3.34e-05 7.05e-01 6.53e-01 2.38e+00
reactome:R-HSA-69278 Cell Cycle, Mitotic 1.34e-07 4.01e-05 6.90e-01 -3.52e-01 -1.77e+00
go:0098687 chromosomal region 1.51e-06 4.22e-04 6.44e-01 -3.89e-01 -1.86e+00
go:1990266 neutrophil migration 1.89e-06 4.91e-04 6.44e-01 7.05e-01 2.31e+00
go:0005126 cytokine receptor binding 2.06e-06 5.04e-04 6.27e-01 5.40e-01 2.16e+00
go:0048285 organelle fission 3.01e-06 6.93e-04 6.27e-01 -3.72e-01 -1.79e+00
go:0001816 cytokine production 3.60e-06 7.04e-04 6.27e-01 3.69e-01 1.79e+00
go:0005102 signaling receptor binding 3.43e-06 7.04e-04 6.27e-01 3.13e-01 1.61e+00
go:0097530 granulocyte migration 3.60e-06 7.04e-04 6.27e-01 6.63e-01 2.28e+00
go:0030595 leukocyte chemotaxis 3.83e-06 7.13e-04 6.11e-01 5.63e-01 2.15e+00
go:0060326 cell chemotaxis 4.07e-06 7.23e-04 6.11e-01 5.21e-01 2.12e+00
go:0051321 meiotic cell cycle 4.94e-06 8.40e-04 6.11e-01 -4.68e-01 -1.97e+00
go:0010469 regulation of signaling receptor activity 5.68e-06 9.25e-04 6.11e-01 4.68e-01 2.00e+00
msig:M15569 KEGG_NOD_LIKE_RECEPTOR_SIGNALING_PATHWAY 6.07e-06 9.49e-04 6.11e-01 6.99e-01 2.22e+00
go:0005694 chromosome 6.69e-06 1.01e-03 6.11e-01 -2.92e-01 -1.53e+00
go:0002237 response to molecule of bacterial origin 7.20e-06 1.04e-03 6.11e-01 4.68e-01 1.99e+00
reactome:R-HSA-68877 Mitotic Prometaphase 7.65e-06 1.07e-03 5.93e-01 -4.09e-01 -1.84e+00
reactome:R-HSA-449147 Signaling by Interleukins 8.11e-06 1.09e-03 5.93e-01 3.60e-01 1.75e+00
go:0000775 chromosome, centromeric region 1.15e-05 1.49e-03 5.93e-01 -4.17e-01 -1.85e+00
go:0060089 molecular transducer activity 1.44e-05 1.82e-03 5.93e-01 3.78e-01 1.77e+00
go:0002682 regulation of immune system process 1.50e-05 1.83e-03 5.93e-01 2.95e-01 1.53e+00
go:0010939 regulation of necrotic cell death 2.35e-05 2.71e-03 5.76e-01 7.38e-01 2.12e+00
go:0097529 myeloid leukocyte migration 2.36e-05 2.71e-03 5.76e-01 5.69e-01 2.11e+00
go:0051240 positive regulation of multicellular organismal process 2.45e-05 2.73e-03 5.76e-01 2.88e-01 1.51e+00
go:0051276 chromosome organization 2.74e-05 2.98e-03 5.76e-01 -2.77e-01 -1.47e+00
go:0001775 cell activation 2.98e-05 3.14e-03 5.76e-01 2.93e-01 1.52e+00
go:0002684 positive regulation of immune system process 3.36e-05 3.46e-03 5.57e-01 3.11e-01 1.57e+00
reactome:R-HSA-5668541 TNFR2 non-canonical NF-kB pathway 4.98e-05 4.60e-03 5.57e-01 5.21e-01 2.00e+00
go:0002685 regulation of leukocyte migration 4.86e-05 4.60e-03 5.57e-01 5.24e-01 2.00e+00
go:0030968 endoplasmic reticulum unfolded protein response 5.06e-05 4.60e-03 5.57e-01 4.90e-01 1.97e+00
reactome:R-HSA-68886 M Phase 4.87e-05 4.60e-03 5.57e-01 -3.33e-01 -1.63e+00
reactome:R-HSA-2500257 Resolution of Sister Chromatid Cohesion 5.19e-05 4.61e-03 5.57e-01 -4.44e-01 -1.85e+00
go:0035967 cellular response to topologically incorrect protein 5.56e-05 4.76e-03 5.57e-01 4.52e-01 1.92e+00
go:0071396 cellular response to lipid 5.60e-05 4.76e-03 5.57e-01 3.57e-01 1.70e+00
msig:M5901 HALLMARK_G2M_CHECKPOINT 6.47e-05 5.38e-03 5.38e-01 -3.76e-01 -1.72e+00
go:0033209 tumor necrosis factor-mediated signaling pathway 6.61e-05 5.38e-03 5.38e-01 4.59e-01 1.90e+00
go:0000793 condensed chromosome 7.19e-05 5.73e-03 5.38e-01 -3.98e-01 -1.76e+00
go:0051235 maintenance of location 7.64e-05 5.97e-03 5.38e-01 4.18e-01 1.82e+00
msig:M5669 KEGG_NATURAL_KILLER_CELL_MEDIATED_CYTOTOXICITY 8.33e-05 6.26e-03 5.38e-01 6.04e-01 2.08e+00
go:0000776 kinetochore 8.32e-05 6.26e-03 5.38e-01 -4.33e-01 -1.82e+00
go:0031226 intrinsic component of plasma membrane 9.02e-05 6.53e-03 5.38e-01 3.28e-01 1.61e+00
msig:M5951 HALLMARK_SPERMATOGENESIS 9.01e-05 6.53e-03 5.38e-01 -5.62e-01 -1.97e+00
go:0042330 taxis 9.88e-05 7.02e-03 5.38e-01 3.74e-01 1.72e+00
go:0045087 innate immune response 1.04e-04 7.02e-03 5.38e-01 3.18e-01 1.59e+00
go:0031349 positive regulation of defense response 1.04e-04 7.02e-03 5.38e-01 3.66e-01 1.71e+00
go:1901701 cellular response to oxygen-containing compound 1.01e-04 7.02e-03 5.38e-01 3.00e-01 1.54e+00
reactome:R-HSA-194315 Signaling by Rho GTPases 1.11e-04 7.23e-03 5.38e-01 -3.45e-01 -1.64e+00
reactome:R-HSA-195258 RHO GTPase Effectors 1.10e-04 7.23e-03 5.38e-01 -3.57e-01 -1.65e+00
msig:M5947 HALLMARK_IL2_STAT5_SIGNALING 1.13e-04 7.27e-03 5.38e-01 4.52e-01 1.87e+00
go:1990868 response to chemokine 1.15e-04 7.27e-03 5.38e-01 7.36e-01 2.08e+00
msig:M5953 HALLMARK_KRAS_SIGNALING_UP 1.22e-04 7.27e-03 5.38e-01 5.12e-01 1.95e+00
reactome:R-HSA-373076 Class A/1 (Rhodopsin-like receptors) 1.23e-04 7.27e-03 5.19e-01 6.39e-01 2.03e+00
msig:M15913 KEGG_RIG_I_LIKE_RECEPTOR_SIGNALING_PATHWAY 1.20e-04 7.27e-03 5.38e-01 6.39e-01 2.03e+00
reactome:R-HSA-1280215 Cytokine Signaling in Immune system 1.21e-04 7.27e-03 5.38e-01 3.13e-01 1.57e+00
go:0051301 cell division 1.28e-04 7.49e-03 5.19e-01 -3.07e-01 -1.54e+00
reactome:R-HSA-1168372 Downstream signaling events of B Cell Receptor (BCR) 1.39e-04 7.96e-03 5.19e-01 5.01e-01 1.94e+00
go:0042698 ovulation cycle 1.57e-04 8.76e-03 5.19e-01 6.69e-01 2.06e+00
go:0034612 response to tumor necrosis factor 1.55e-04 8.76e-03 5.19e-01 4.00e-01 1.76e+00
go:0002274 myeloid leukocyte activation 1.67e-04 9.19e-03 5.19e-01 3.15e-01 1.55e+00
go:0009617 response to bacterium 1.81e-04 9.59e-03 5.19e-01 3.81e-01 1.73e+00
go:0050776 regulation of immune response 1.82e-04 9.59e-03 5.19e-01 3.09e-01 1.55e+00
reactome:R-HSA-69618 Mitotic Spindle Checkpoint 1.77e-04 9.59e-03 5.19e-01 -4.35e-01 -1.78e+00
msig:M16848 KEGG_EPITHELIAL_CELL_SIGNALING_IN_HELICOBACTER_PYLORI_INFECTION 1.84e-04 9.60e-03 5.19e-01 5.89e-01 2.04e+00
go:0032103 positive regulation of response to external stimulus 1.88e-04 9.61e-03 5.19e-01 4.45e-01 1.84e+00
reactome:R-HSA-1169091 Activation of NF-kappaB in B cells 1.89e-04 9.61e-03 5.19e-01 5.25e-01 1.98e+00
go:1901342 regulation of vasculature development 1.94e-04 9.73e-03 5.19e-01 4.22e-01 1.79e+00
go:0038061 NIK/NF-kappaB signaling 2.24e-04 1.11e-02 5.19e-01 4.36e-01 1.83e+00
go:0009607 response to biotic stimulus 2.33e-04 1.11e-02 5.19e-01 3.11e-01 1.55e+00
go:0002286 T cell activation involved in immune response 2.33e-04 1.11e-02 5.19e-01 6.82e-01 2.02e+00
go:0033993 response to lipid 2.32e-04 1.11e-02 5.19e-01 3.00e-01 1.50e+00
go:0030099 myeloid cell differentiation 2.49e-04 1.16e-02 4.98e-01 3.65e-01 1.68e+00
reactome:R-HSA-2980766 Nuclear Envelope Breakdown 2.50e-04 1.16e-02 4.98e-01 -5.44e-01 -1.96e+00
go:0006259 DNA metabolic process 2.59e-04 1.18e-02 4.98e-01 -2.80e-01 -1.43e+00
go:0046903 secretion 2.58e-04 1.18e-02 4.98e-01 2.67e-01 1.41e+00
go:0002250 adaptive immune response 2.67e-04 1.20e-02 4.98e-01 4.40e-01 1.82e+00
go:0070482 response to oxygen levels 2.88e-04 1.27e-02 4.98e-01 3.40e-01 1.62e+00
go:0023056 positive regulation of signaling 2.86e-04 1.27e-02 4.98e-01 2.67e-01 1.42e+00
go:0001819 positive regulation of cytokine production 2.96e-04 1.29e-02 4.98e-01 3.87e-01 1.71e+00
go:0034976 response to endoplasmic reticulum stress 3.42e-04 1.45e-02 4.98e-01 3.60e-01 1.67e+00
go:0051047 positive regulation of secretion 3.62e-04 1.50e-02 4.98e-01 3.96e-01 1.73e+00
go:0005815 microtubule organizing center 3.64e-04 1.50e-02 4.98e-01 -2.96e-01 -1.49e+00
go:0048511 rhythmic process 3.67e-04 1.50e-02 4.98e-01 4.05e-01 1.75e+00
go:0071103 DNA conformation change 3.69e-04 1.50e-02 4.98e-01 -3.57e-01 -1.62e+00
go:0032101 regulation of response to external stimulus 3.75e-04 1.51e-02 4.98e-01 3.39e-01 1.61e+00
reactome:R-HSA-68875 Mitotic Prophase 3.91e-04 1.56e-02 4.98e-01 -4.51e-01 -1.81e+00
reactome:R-HSA-375276 Peptide ligand-binding receptors 4.05e-04 1.60e-02 4.98e-01 6.65e-01 1.97e+00
go:0071216 cellular response to biotic stimulus 4.15e-04 1.62e-02 4.98e-01 4.59e-01 1.85e+00
go:0022602 ovulation cycle process 4.44e-04 1.72e-02 4.98e-01 7.29e-01 2.02e+00
reactome:R-HSA-5663220 RHO GTPases Activate Formins 4.52e-04 1.73e-02 4.98e-01 -4.16e-01 -1.75e+00
go:0010883 regulation of lipid storage 4.94e-04 1.87e-02 4.77e-01 7.02e-01 1.99e+00
go:0007249 I-kappaB kinase/NF-kappaB signaling 5.11e-04 1.87e-02 4.77e-01 3.87e-01 1.69e+00
go:2001234 negative regulation of apoptotic signaling pathway 5.13e-04 1.87e-02 4.77e-01 3.83e-01 1.68e+00
go:1903046 meiotic cell cycle process 5.08e-04 1.87e-02 4.77e-01 -4.50e-01 -1.81e+00
go:0071622 regulation of granulocyte chemotaxis 5.12e-04 1.87e-02 4.77e-01 6.64e-01 1.91e+00
reactome:R-HSA-1236975 Antigen processing-Cross presentation 5.34e-04 1.93e-02 4.77e-01 4.71e-01 1.83e+00
reactome:R-HSA-5619084 ABC transporter disorders 5.60e-04 2.01e-02 4.77e-01 5.02e-01 1.90e+00
go:0045637 regulation of myeloid cell differentiation 5.66e-04 2.01e-02 4.77e-01 4.32e-01 1.81e+00
go:0015630 microtubule cytoskeleton 5.79e-04 2.04e-02 4.77e-01 -2.61e-01 -1.37e+00
msig:M5930 HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION 5.87e-04 2.05e-02 4.77e-01 4.27e-01 1.79e+00
go:0000779 condensed chromosome, centromeric region 6.17e-04 2.13e-02 4.77e-01 -4.25e-01 -1.74e+00
msig:M5913 HALLMARK_INTERFERON_GAMMA_RESPONSE 6.72e-04 2.29e-02 4.77e-01 4.18e-01 1.75e+00
go:0002687 positive regulation of leukocyte migration 6.75e-04 2.29e-02 4.77e-01 5.08e-01 1.86e+00
go:1905954 positive regulation of lipid localization 7.43e-04 2.47e-02 4.77e-01 6.52e-01 1.88e+00
go:0045862 positive regulation of proteolysis 7.45e-04 2.47e-02 4.77e-01 3.47e-01 1.62e+00
reactome:R-HSA-500792 GPCR ligand binding 7.75e-04 2.54e-02 4.77e-01 5.15e-01 1.86e+00
go:0000819 sister chromatid segregation 7.98e-04 2.60e-02 4.77e-01 -3.70e-01 -1.63e+00
go:0040017 positive regulation of locomotion 8.16e-04 2.61e-02 4.77e-01 3.26e-01 1.55e+00
go:0006959 humoral immune response 8.13e-04 2.61e-02 4.77e-01 5.84e-01 1.93e+00
msig:M4844 KEGG_CHEMOKINE_SIGNALING_PATHWAY 8.37e-04 2.66e-02 4.77e-01 4.94e-01 1.84e+00
go:0097191 extrinsic apoptotic signaling pathway 8.87e-04 2.79e-02 4.77e-01 3.92e-01 1.68e+00
go:0010952 positive regulation of peptidase activity 9.07e-04 2.80e-02 4.77e-01 4.12e-01 1.73e+00
go:0044430 9.18e-04 2.80e-02 4.77e-01 -2.51e-01 -1.34e+00
go:0023057 negative regulation of signaling 9.04e-04 2.80e-02 4.77e-01 2.62e-01 1.36e+00
go:0002456 T cell mediated immunity 9.18e-04 2.80e-02 4.77e-01 5.90e-01 1.93e+00
go:0046887 positive regulation of hormone secretion 9.41e-04 2.85e-02 4.77e-01 5.23e-01 1.85e+00
go:0045088 regulation of innate immune response 9.63e-04 2.85e-02 4.77e-01 3.42e-01 1.60e+00
go:2001236 regulation of extrinsic apoptotic signaling pathway 9.64e-04 2.85e-02 4.77e-01 4.37e-01 1.77e+00
go:0043123 positive regulation of I-kappaB kinase/NF-kappaB signaling 9.59e-04 2.85e-02 4.77e-01 4.18e-01 1.75e+00
go:0006323 DNA packaging 1.01e-03 2.95e-02 4.55e-01 -3.97e-01 -1.67e+00
go:0035966 response to topologically incorrect protein 1.05e-03 3.06e-02 4.55e-01 3.78e-01 1.65e+00
go:0000278 mitotic cell cycle 1.10e-03 3.19e-02 4.55e-01 -2.60e-01 -1.36e+00
msig:M12294 KEGG_VIRAL_MYOCARDITIS 1.16e-03 3.33e-02 4.55e-01 6.29e-01 1.92e+00
msig:M12868 KEGG_PATHWAYS_IN_CANCER 1.20e-03 3.35e-02 4.55e-01 3.64e-01 1.61e+00
go:1903706 regulation of hemopoiesis 1.21e-03 3.35e-02 4.55e-01 3.32e-01 1.56e+00
go:0031347 regulation of defense response 1.22e-03 3.35e-02 4.55e-01 3.07e-01 1.49e+00
go:0006919 activation of cysteine-type endopeptidase activity involved in apoptotic process 1.20e-03 3.35e-02 4.55e-01 4.99e-01 1.82e+00
go:0050727 regulation of inflammatory response 1.22e-03 3.35e-02 4.55e-01 4.18e-01 1.73e+00
reactome:R-HSA-446652 Interleukin-1 family signaling 1.21e-03 3.35e-02 4.55e-01 4.28e-01 1.72e+00
go:0098813 nuclear chromosome segregation 1.30e-03 3.56e-02 4.55e-01 -3.49e-01 -1.57e+00
go:0022402 cell cycle process 1.33e-03 3.60e-02 4.55e-01 -2.45e-01 -1.32e+00
reactome:R-HSA-5218859 Regulated Necrosis 1.35e-03 3.64e-02 4.55e-01 7.00e-01 1.94e+00
go:0019915 lipid storage 1.38e-03 3.68e-02 4.55e-01 5.83e-01 1.85e+00
go:0000070 mitotic sister chromatid segregation 1.38e-03 3.68e-02 4.55e-01 -3.82e-01 -1.64e+00
go:0045185 maintenance of protein location 1.40e-03 3.68e-02 4.55e-01 4.68e-01 1.76e+00
go:0009897 external side of plasma membrane 1.40e-03 3.68e-02 4.55e-01 4.56e-01 1.79e+00
go:0140014 mitotic nuclear division 1.43e-03 3.74e-02 4.55e-01 -3.34e-01 -1.53e+00
go:1904018 positive regulation of vasculature development 1.53e-03 3.96e-02 4.55e-01 4.62e-01 1.76e+00
go:0002218 activation of innate immune response 1.66e-03 4.26e-02 4.55e-01 3.53e-01 1.58e+00
go:1903317 regulation of protein maturation 1.77e-03 4.52e-02 4.55e-01 5.87e-01 1.93e+00
go:0002790 peptide secretion 1.79e-03 4.54e-02 4.55e-01 3.27e-01 1.53e+00
go:0017056 structural constituent of nuclear pore 1.83e-03 4.62e-02 4.55e-01 -6.03e-01 -1.76e+00
go:0051094 positive regulation of developmental process 1.87e-03 4.66e-02 4.55e-01 2.73e-01 1.40e+00
go:0032612 interleukin-1 production 1.87e-03 4.66e-02 4.55e-01 5.69e-01 1.81e+00
go:0032637 interleukin-8 production 1.91e-03 4.73e-02 4.55e-01 6.34e-01 1.89e+00
go:1901655 cellular response to ketone 1.93e-03 4.74e-02 4.55e-01 5.03e-01 1.78e+00
reactome:R-HSA-5693579 Homologous DNA Pairing and Strand Exchange 1.97e-03 4.77e-02 4.32e-01 -5.83e-01 -1.82e+00
go:0008083 growth factor activity 1.96e-03 4.77e-02 4.32e-01 5.24e-01 1.83e+00
go:0002521 leukocyte differentiation 1.98e-03 4.77e-02 4.32e-01 3.46e-01 1.57e+00
go:0006310 DNA recombination 2.07e-03 4.96e-02 4.32e-01 -3.48e-01 -1.55e+00
go:0097300 programmed necrotic cell death 2.11e-03 5.02e-02 4.32e-01 6.13e-01 1.87e+00
reactome:R-HSA-69190 DNA strand elongation 2.12e-03 5.03e-02 4.32e-01 -5.74e-01 -1.82e+00
go:0002688 regulation of leukocyte chemotaxis 2.18e-03 5.13e-02 4.32e-01 5.15e-01 1.81e+00
go:0048585 negative regulation of response to stimulus 2.24e-03 5.24e-02 4.32e-01 2.53e-01 1.33e+00
reactome:R-HSA-5678895 Defective CFTR causes cystic fibrosis 2.30e-03 5.35e-02 4.32e-01 4.71e-01 1.76e+00
go:1904666 regulation of ubiquitin protein ligase activity 2.42e-03 5.46e-02 4.32e-01 -6.69e-01 -1.86e+00
reactome:R-HSA-69205 G1/S-Specific Transcription 2.43e-03 5.46e-02 4.32e-01 -6.35e-01 -1.83e+00
reactome:R-HSA-5632684 Hedgehog 'on' state 2.38e-03 5.46e-02 4.32e-01 4.48e-01 1.70e+00
reactome:R-HSA-168249 Innate Immune System 2.43e-03 5.46e-02 4.32e-01 2.61e-01 1.35e+00
reactome:R-HSA-983705 Signaling by the B Cell Receptor (BCR) 2.43e-03 5.46e-02 4.32e-01 4.33e-01 1.72e+00
go:0032611 interleukin-1 beta production 2.42e-03 5.46e-02 4.32e-01 6.26e-01 1.87e+00
go:0007010 cytoskeleton organization 2.51e-03 5.59e-02 4.32e-01 -2.54e-01 -1.32e+00
go:0001818 negative regulation of cytokine production 2.52e-03 5.59e-02 4.32e-01 3.94e-01 1.62e+00
go:0070265 necrotic cell death 2.54e-03 5.61e-02 4.32e-01 5.77e-01 1.90e+00
reactome:R-HSA-69620 Cell Cycle Checkpoints 2.56e-03 5.63e-02 4.32e-01 -3.21e-01 -1.52e+00
go:1901700 response to oxygen-containing compound 2.58e-03 5.64e-02 4.32e-01 2.50e-01 1.31e+00
go:0071453 cellular response to oxygen levels 2.65e-03 5.76e-02 4.32e-01 3.46e-01 1.55e+00
msig:M5950 HALLMARK_ALLOGRAFT_REJECTION 2.84e-03 6.07e-02 4.32e-01 4.49e-01 1.71e+00
go:0043900 regulation of multi-organism process 2.83e-03 6.07e-02 4.32e-01 3.17e-01 1.49e+00
go:0005813 centrosome 2.82e-03 6.07e-02 4.32e-01 -2.90e-01 -1.42e+00
go:0042110 T cell activation 2.87e-03 6.08e-02 4.32e-01 3.50e-01 1.55e+00
go:1903039 positive regulation of leukocyte cell-cell adhesion 2.90e-03 6.13e-02 4.32e-01 4.52e-01 1.71e+00
go:0040011 locomotion 2.92e-03 6.13e-02 4.32e-01 2.50e-01 1.31e+00
msig:M3261 KEGG_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY 2.95e-03 6.14e-02 4.32e-01 5.72e-01 1.88e+00
go:0007017 microtubule-based process 2.95e-03 6.14e-02 4.32e-01 -2.67e-01 -1.35e+00
go:0050729 positive regulation of inflammatory response 3.01e-03 6.21e-02 4.32e-01 5.22e-01 1.75e+00
reactome:R-HSA-168928 DDX58/IFIH1-mediated induction of interferon-alpha/beta 3.03e-03 6.22e-02 4.32e-01 5.08e-01 1.78e+00
go:0035690 cellular response to drug 3.07e-03 6.29e-02 4.32e-01 3.37e-01 1.52e+00
go:0045785 positive regulation of cell adhesion 3.21e-03 6.54e-02 4.32e-01 3.47e-01 1.53e+00
go:0050920 regulation of chemotaxis 3.27e-03 6.62e-02 4.32e-01 4.41e-01 1.70e+00
go:0022624 proteasome accessory complex 3.38e-03 6.82e-02 4.32e-01 5.63e-01 1.76e+00
go:0051345 positive regulation of hydrolase activity 3.44e-03 6.85e-02 4.32e-01 2.92e-01 1.43e+00
go:0002791 regulation of peptide secretion 3.44e-03 6.85e-02 4.32e-01 3.39e-01 1.52e+00
go:0007059 chromosome segregation 3.53e-03 6.99e-02 4.32e-01 -3.21e-01 -1.50e+00
msig:M5893 HALLMARK_MITOTIC_SPINDLE 3.56e-03 7.02e-02 4.32e-01 -3.38e-01 -1.51e+00
go:0009986 cell surface 3.65e-03 7.14e-02 4.32e-01 3.12e-01 1.48e+00
go:0051046 regulation of secretion 3.64e-03 7.14e-02 4.32e-01 3.06e-01 1.46e+00
go:0051149 positive regulation of muscle cell differentiation 3.71e-03 7.14e-02 4.32e-01 5.55e-01 1.81e+00
go:0050778 positive regulation of immune response 3.71e-03 7.14e-02 4.32e-01 2.89e-01 1.42e+00
go:0038095 Fc-epsilon receptor signaling pathway 3.67e-03 7.14e-02 4.32e-01 4.37e-01 1.68e+00
reactome:R-HSA-5357905 Regulation of TNFR1 signaling 3.78e-03 7.18e-02 4.32e-01 6.09e-01 1.75e+00
go:0006892 post-Golgi vesicle-mediated transport 3.79e-03 7.18e-02 4.32e-01 4.42e-01 1.68e+00
msig:M15902 KEGG_GLYCEROLIPID_METABOLISM 3.78e-03 7.18e-02 4.32e-01 6.08e-01 1.75e+00
go:0044057 regulation of system process 3.88e-03 7.25e-02 4.32e-01 3.43e-01 1.54e+00
go:0001541 ovarian follicle development 3.90e-03 7.25e-02 4.32e-01 5.96e-01 1.80e+00
reactome:R-HSA-5658442 Regulation of RAS by GAPs 3.89e-03 7.25e-02 4.32e-01 4.60e-01 1.74e+00
go:0042590 antigen processing and presentation of exogenous peptide antigen via MHC class I 3.98e-03 7.33e-02 4.07e-01 4.59e-01 1.74e+00
go:0006281 DNA repair 4.04e-03 7.41e-02 4.07e-01 -2.75e-01 -1.37e+00
go:0008608 attachment of spindle microtubules to kinetochore 4.10e-03 7.49e-02 4.07e-01 -5.46e-01 -1.76e+00
reactome:R-HSA-69273 Cyclin A/B1/B2 associated events during G2/M transition 4.15e-03 7.53e-02 4.07e-01 -5.77e-01 -1.68e+00
go:0050921 positive regulation of chemotaxis 4.19e-03 7.54e-02 4.07e-01 4.63e-01 1.70e+00
msig:M11675 KEGG_HOMOLOGOUS_RECOMBINATION 4.23e-03 7.54e-02 4.07e-01 -6.30e-01 -1.77e+00
go:0098552 side of membrane 4.24e-03 7.54e-02 4.07e-01 3.41e-01 1.53e+00
go:0050000 chromosome localization 4.24e-03 7.54e-02 4.07e-01 -4.52e-01 -1.67e+00
go:0006261 DNA-dependent DNA replication 4.22e-03 7.54e-02 4.07e-01 -3.73e-01 -1.57e+00
msig:M8492 KEGG_APOPTOSIS 4.31e-03 7.62e-02 4.07e-01 4.87e-01 1.74e+00
go:0051270 regulation of cellular component movement 4.38e-03 7.72e-02 4.07e-01 2.67e-01 1.34e+00
go:2001233 regulation of apoptotic signaling pathway 4.46e-03 7.81e-02 4.07e-01 3.03e-01 1.44e+00
go:0051310 metaphase plate congression 4.58e-03 7.96e-02 4.07e-01 -4.89e-01 -1.72e+00
reactome:R-HSA-5358351 Signaling by Hedgehog 4.57e-03 7.96e-02 4.07e-01 3.90e-01 1.61e+00
reactome:R-HSA-73886 Chromosome Maintenance 4.61e-03 7.97e-02 4.07e-01 -4.26e-01 -1.66e+00
go:0031341 regulation of cell killing 4.68e-03 8.06e-02 4.07e-01 6.37e-01 1.80e+00
go:0005506 iron ion binding 5.04e-03 8.28e-02 4.07e-01 4.78e-01 1.72e+00
go:0140272 exogenous protein binding 4.88e-03 8.28e-02 4.07e-01 5.54e-01 1.82e+00
reactome:R-HSA-382556 ABC-family proteins mediated transport 4.92e-03 8.28e-02 4.07e-01 4.33e-01 1.65e+00
go:0033044 regulation of chromosome organization 4.88e-03 8.28e-02 4.07e-01 -3.01e-01 -1.42e+00
go:0045597 positive regulation of cell differentiation 4.92e-03 8.28e-02 4.07e-01 2.78e-01 1.39e+00
go:0060548 negative regulation of cell death 4.97e-03 8.28e-02 4.07e-01 2.61e-01 1.34e+00
msig:M5915 HALLMARK_APICAL_JUNCTION 4.98e-03 8.28e-02 4.07e-01 3.81e-01 1.56e+00
go:0003779 actin binding 5.02e-03 8.28e-02 4.07e-01 -3.17e-01 -1.45e+00
reactome:R-HSA-69615 G1/S DNA Damage Checkpoints 5.03e-03 8.28e-02 4.07e-01 4.38e-01 1.65e+00
go:0006333 chromatin assembly or disassembly 5.28e-03 8.64e-02 4.07e-01 -3.80e-01 -1.56e+00
go:0034728 nucleosome organization 5.33e-03 8.65e-02 4.07e-01 -3.86e-01 -1.55e+00
go:0002764 immune response-regulating signaling pathway 5.32e-03 8.65e-02 4.07e-01 2.99e-01 1.42e+00
go:0046649 lymphocyte activation 5.43e-03 8.70e-02 4.07e-01 3.00e-01 1.42e+00
go:0042116 macrophage activation 5.43e-03 8.70e-02 4.07e-01 6.31e-01 1.79e+00
go:0002761 regulation of myeloid leukocyte differentiation 5.44e-03 8.70e-02 4.07e-01 5.10e-01 1.76e+00
reactome:R-HSA-1474244 Extracellular matrix organization 5.46e-03 8.71e-02 4.07e-01 3.85e-01 1.61e+00
go:0043044 ATP-dependent chromatin remodeling 5.67e-03 9.01e-02 4.07e-01 -4.48e-01 -1.67e+00
go:0002756 MyD88-independent toll-like receptor signaling pathway 5.70e-03 9.01e-02 4.07e-01 6.57e-01 1.82e+00
go:0006893 Golgi to plasma membrane transport 5.79e-03 9.04e-02 4.07e-01 5.01e-01 1.71e+00
reactome:R-HSA-4641258 Degradation of DVL 5.75e-03 9.04e-02 4.07e-01 4.54e-01 1.67e+00
go:0051336 regulation of hydrolase activity 5.97e-03 9.29e-02 4.07e-01 2.51e-01 1.30e+00
reactome:R-HSA-168898 Toll-like Receptor Cascades 6.08e-03 9.43e-02 4.07e-01 4.13e-01 1.63e+00
go:0046883 regulation of hormone secretion 6.16e-03 9.47e-02 4.07e-01 3.80e-01 1.57e+00
msig:M10680 KEGG_PROTEASOME 6.24e-03 9.53e-02 4.07e-01 4.73e-01 1.67e+00
go:0006997 nucleus organization 6.24e-03 9.53e-02 4.07e-01 -3.87e-01 -1.58e+00
reactome:R-HSA-5689880 Ub-specific processing proteases 6.31e-03 9.55e-02 4.07e-01 3.47e-01 1.51e+00
go:0015893 drug transport 6.37e-03 9.61e-02 4.07e-01 4.56e-01 1.67e+00
go:0051129 negative regulation of cellular component organization 6.45e-03 9.69e-02 4.07e-01 -2.72e-01 -1.35e+00
go:0006260 DNA replication 6.52e-03 9.76e-02 4.07e-01 -3.08e-01 -1.42e+00
go:0061982 meiosis I cell cycle process 6.56e-03 9.78e-02 4.07e-01 -4.64e-01 -1.63e+00
go:1902533 positive regulation of intracellular signal transduction 6.63e-03 9.81e-02 4.07e-01 2.66e-01 1.35e+00
go:0010639 negative regulation of organelle organization 6.63e-03 9.81e-02 4.07e-01 -3.04e-01 -1.42e+00
go:0070821 tertiary granule membrane 6.69e-03 9.85e-02 4.07e-01 5.34e-01 1.70e+00
reactome:R-HSA-5673000 RAF activation 6.70e-03 9.85e-02 4.07e-01 -5.59e-01 -1.63e+00
go:0019748 secondary metabolic process 6.77e-03 9.87e-02 4.07e-01 5.81e-01 1.75e+00
go:0043001 Golgi to plasma membrane protein transport 6.77e-03 9.87e-02 4.07e-01 5.80e-01 1.75e+00
reactome:R-HSA-2871837 FCERI mediated NF-kB activation 6.83e-03 9.92e-02 4.07e-01 4.23e-01 1.60e+00

Literature Mining

INDRA was used to automatically assemble known mechanisms related to CYLD 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
CYLD deubiquitinates RIPK1. 10 / 56
| 55

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Another possibility is that in cells lacking normal Optn, some other protein may act as an adaptor to facilitate CYLD dependent deubiquitination of RIP.

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Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells.

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32 Last but not least, CYLD interacts with and deubiquitinates RIP1.

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This process starts with the accelerated degradation of cIAP1/2 induced by Smac protein (or Smac mimetics), and proceeds with release of RIPK1 from the TNFRI, deubiquitination of RIPK1 by the deubiqui[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Conversely, deubiquitination of RIP1 by CYLD or the absence of cIAPs and LUBAC renders complex I unstable and facilitates other complexes assembled to initiate apoptosis or necroptosis.

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Then, a tumor suppressor cylindromatosis (CYLD) protein promotes the deubiquitination of RIP1 in either complex I or complex II.

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It does this by binding to ubiquitinated RIP (receptor interacting protein) to displace IKBKG (inhibitor of kappaB kinase gamma), and then bringing in cylindromatosis (CYLD) to deubiquitinate RIP and terminate the signaling pathway XREF_BIBR - XREF_BIBR.

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In the course of complex II formation, RIP1 deubiquitination by CYLD, a deubiquitinase that cleaves linear- and K63-ubiquitin chains, plays a crucial role.

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Thus, apoptosis and necrosis induced by death inducing cytokines share a common biochemical pathway down to the step of RIPK1 activation following receptor activation, cIAP1/2 degradation, and deubiqu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR Deubiquitination of RIPK1 by CYLD 81 stimulates the dissociation of Complex I into a secondary cytoplasmic Complex IIa where RIPK1 and/or TRADD recruit FADD via their DDs.
CYLD deubiquitinates TRAF2. 10 / 17
1 | 15

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For instance, CYLD deubiquitinates the K63-Ub chains of TRAF2 and, to some extent, TRAF6, and inhibits NF-kappaB activity.

signor
Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract)

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Using an shRNA approach, Brummelkamp et al. showed that CYLD inhibits NF-kappaB signaling by counteracting TRAF2 ubiquitination [XREF_BIBR].

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The steady state association of TRAF2 with MLKL was diminished upon TNF induced necroptosis induction, and this correlated with CYLD dependent deubiquitylation of TRAF2.

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CYLD, a protease that specifically cleaves K63-ubiquitin chains, de-ubiquitinates TRAF2, thereby inhibiting the recruitment of TAB and TAK and activation of IKK [15], and A20 deactivates RIP1 by remov[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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CYLD mediated regulation of the JNK signaling pathway appears to target TRAF2 ubiquitylation, as CYLD knockdown increases both TRAF2 ubiquitylation and JNK activation, further enhancing cell survival [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The Cylindroma tumour suppressor protein (CYLD) de-ubiquitinates NEMO and TRAF2 [XREF_BIBR - XREF_BIBR], while USP15 reverses betaTRCP mediated ubiquitination of IkappaBalpha [XREF_BIBR].

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Here we described that the adenoviral vector expressing CYLD (Ad/hTERT-CYLD) augmented the cytotoxicity of TRAIL in HCC cells by negatively regulating NF-kappaB activity since CYLD could reverse the ubiquitination of TNF receptor associated factor 2 (TRAF2) and interact with the IkappaB kinasegamma (IKKgamma).

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Contributing to the " death signal ", CYLD deubiquitylates TRAF2 and RIPK1, allowing the formation of the ripoptosome.
| PMC

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Another example is already mentioned CYLD, which is an important inflammatory mediator that deubiquitinates TRAF2 and TRAF6, resulting in negative regulation of the NF-kappaB pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].
CYLD deubiquitinates TRAF6. 10 / 16
1 | 14

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CYLD binding to one of its targets, TRAF6, requires the adaptor protein p62, which promotes the deubiquitylation of TRAF6 by CYLD 17 and probably also modulates the DUB activity of CYLD through induction of CYLD ubiquitylation 34.

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Previously it has been known that TNF receptor associated factor 6 (TRAF6) acts as an E3 ligase for Akt-K63 polyubiquitination, and CYLD deubiquitinates TRAF6.

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CYLD also decreased IFN promotor activation by deubiquitinating TRAF2 and TRAF6 in HEK293 T cells, respectively [29, 30] .

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Then we investigated the roles A20 and CYLD in CK8 mediated inhibition of TRAF6 ubiquitination.

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Conversely, the PB1 domain of p62 also interacts with CYLD, a deubiquitinase, which inhibits TRAF6 polyubiquitination and serves as a negative regulator for RANK mediated NF-kappaB activation and osteoclastogenesis 113.

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In support of this notion, in vivo poly-ubiquitination assays demonstrate that depletion of beta-TRCP impaired TRAF6 self ubiquitination likely due to enhancement of TRAF6 deubiquitination by CYLD, concomitant with a reduction in beta-TRCP-dependent ubiquitination of CYLD and impairment of auto-phosphorylation of TRAF6-downstream kinase IKKalpha.

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Moreover, additional studies showed that CYLD specifically deubiquitinates polyubiquitin chains at K63 of different substrates (e.g., TRAF2 and TRAF6), or tyrosine kinase receptors such as TrkA.

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Specifically, as suggested by Jin et al. [XREF_BIBR], deubiquitinating enzyme CYLD negatively regulated TRAF6 ubiquitination by interacting with P62 and subsequently inhibited proangiogenesis function of TRAF6.

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For instance, p62, one adaptor protein, can promote the deubiquitylation of TRAF6 (one of p62 targets) by CYLD.

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Here we demonstrated that during the RANKL dependent signaling pathway, CYLD stabilization by depletion of beta-TRCP decreased the ubiquitination of TRAF6 and impaired auto-phosphorylation of the TRAF6-downstream kinase IKKalpha.
CYLD deubiquitinates BCL3. 10 / 12
1 | 10

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In these cases, mutated CYLD is unable to deubiquitinate Bcl-3, allowing increased proliferation in cell of the skin adnexa [XREF_BIBR].

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The CYLD protein deubiquitinates Bcl-3 and inhibits its nuclear translocation, so alterations in these gene or upstream events to it present an additional layer of regulation.

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CYLD is also able to deubiquitinate Bcl-3 and prevent it from entering nucleus, where Bcl-3 can interact with NFkappaB family members (p50 and p52) to activate the transcription of NFkappaB target genes.

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In addition to its deubiquitination effects on TRAFs and IKKgamma, CYLD also deubiquitinates Bcl-3, and in so doing prevents its nuclear localization.

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CYLD deubiquitinates several NF-kappaB regulators, including TRAF2, TRAF6, and NEMO as well as BCL3, a member of the NF-kappaB family of transcription factors.

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In this issue of Cell, Massoumi et al. (2006) show that CYLD deubiquitinates the coactivator Bcl-3, thereby preventing its translocation into the nucleus, where it normally interacts with NF-kappaB and activates transcription of proliferation genes in response to growth signals.

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As for CYLD, studies have shown that CYLD binds to and deubiquitylates BCL-3 inhibiting its nuclear translocation, leading to decreased transcription of CCND, and delayed cells from entering S-phase 35.

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In our experiments, the inhibitory effect of CYLD on the nuclear accumulation of phosphorylated STAT3 resembles CYLD-Bcl3 interaction, since CYLD also deubiquitinates Bcl-3 in perinuclear regions and prevents its translocation to the nucleus, a process which significantly contributes to the development of keratinocyte hyperproliferation and development of benign tumors of the skin appendage called cylindromatosis XREF_BIBR.

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CYLD deubiquitylates BCL-3 inhibiting its nuclear translocation and so decreases the transcription of BCL-3 target genes including CCND [XREF_BIBR].

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In this region, CYLD associates with its substrate Bcl-3 and prevents the nuclear localization of Bcl3
CYLD deubiquitinates IKBKG. 10 / 10
| 9

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To confirm that Tax- or TRAF6 induced polyubiquitination of NEMO is blocked by CYLD expression, NEMO and an HA tagged ubiquitin mutant (HA-K63Ub) were co-expressed with Tax or TRAF6 in the presence or[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The Cylindroma tumour suppressor protein (CYLD) de-ubiquitinates NEMO and TRAF2 [XREF_BIBR - XREF_BIBR], while USP15 reverses betaTRCP mediated ubiquitination of IkappaBalpha [XREF_BIBR].

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CYLD also deubiquitinates IkappaB kinase gamma (IKKgamma, also known as NEMO), the regulatory subunit of IKK thus inhibiting the activation of IKK.

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When transfected into mammalian cells, CYLD deubiquitinates NEMO as well as several IKK upstream regulators, including TRAF2, TRAF6, TRAF7, RIP1, and Tak1.

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Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)

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CYLD physically interacts with and deubiquitinates NEMO, thereby negatively regulating NF-kappaB activation [XREF_BIBR].

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CYLD deubiquitinates NEMO, thus decreasing its stability and preventing the IKK complex from phosphorylating IkappaB, and NF-kappaB activation.

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Deubiquitinating enzyme CYLD inhibits NEMO linear ubiquitination, possibly by disassembling both K63 linked and linear polyubiquitin.

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CYLD can deubiquitinate NEMO, preventing it from causing phosphorylation of IkB, thereby killing the signal [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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In the absence of any robust stimulation of NF-kappaB (such as TCR engagement or cytokine signaling), CYLD deubiquitylates TRAF2, TRAF6, and NEMO, dampening NF-kappaB signaling by removing activating K63 chains formed by TRAF2/6.
CYLD deubiquitinates TP53. 9 / 9
| 8

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Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress.| Collectively, our results identify CYLD as a deubiquitinase facilitating DNA damage-induced p53 activation and suggest that regulation of p53 responses to genotoxic stress contributes to the tumour suppressor function of CYLD.

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As shown in XREF_FIG and XREF_SUPPLEMENTARY, in contrast to WT CYLD, the catalytically inactive CYLDR936X (R/X) and CYLDH871N (H/N) mutants did not diminish p53 ubiquitination although they bound p53, demonstrating that CYLD DUB activity is required to reduce p53 ubiquitination.

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To address this question, we first assessed the capacity of CYLD to reduce p53 ubiquitination in cells overexpressing HA tagged Lys-to-Arg ubiquitin mutants that can only form K48- or K63 linked chains.

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Together, these results suggested that CYLD directly interacts with and deubiquitinates p53 facilitating its optimal stabilization in response to DNA damage.

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Mechanistically, we show that CYLD interacts with and deubiquitinates p53 in response to DNA damage.

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Furthermore, recombinant His CYLD reduced ubiquitination of Flag-p53 immunoprecipitated from CpT treated HEK293T cells, showing that CYLD can directly deubiquitinate p53 in a cell-free in vitro assay (XREF_SUPPLEMENTARY).

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CYLD deubiquitinates p53 facilitating its stabilization.

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This experiment showed that CYLD diminishes p53 ubiquitination in cells expressing HA-mutant ubiquitin forming K63 only chains, but also in cells expressing HA-mutant ubiquitin forming K48 only chains (XREF_FIG).

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Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress.
CYLD deubiquitinates MAP3K7. 9 / 9
| 8

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CYLD does not inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination.

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The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation.&CYLD targets a ubiquitin-dependent kinase, transforming growth factor-beta-activated kinase 1 (Tak1), and inhibits its ubiquitination and autoactivation.

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Indeed, our data suggest that CYLD directly targets Tak1 and inhibits Tak1 ubiquitination.

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Although it is not yet clear precisely how CYLD regulates the function of the CARMA1-BCL-10-MALT1 signalosome, CYLD deubiquitylates TAK1 and thereby suppresses its catalytic activity 19.

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These results indicate that USP4 mainly inhibits inducible TAK1 polyubiquitination and activation whereas CYLD mainly inhibits basal level of TAK1 polyubiquitination and activation.

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Finally, we showed that CYLD interacts with and deubiquitinates TAK1 to negatively regulate the activation of the downstream MKK3/6-p 38alpha/beta pathway.

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In this investigation, we found that CYLD failed to inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation (XREF_FIG, XREF_SUPPLEMENTARY).

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Koga et al. had reported that CYLD interacted with and deubiquitinates TAK1 by negatively regulating the activation of the downstream MKK3/6-p 38alpha/beta pathway to resist the infection of gram positive bacterium Streptococcus pneumonia [XREF_BIBR].

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Inclusion of Cyld (WT) (XREF_FIG, lane3) but not Cyld (C601A) mutant (XREF_FIG, lane4) that lacks the DUB activity 37 resulted in diminished Tak1 ubiquitination suggesting that Cyld deubiquitinated Tak1.
CYLD deubiquitinates DDX58. 9 / 9
| 8

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CYLD can inhibit ubiquitination of the RIG1 cytoplasmic viral RNA sensor and also downregulate antiviral Interferon production by controlling IKK activation [XREF_BIBR].

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SDC4 likely promotes redistribution of RIG-I and CYLD in a perinuclear pattern post viral infection, and thus enhances the RIG-I-CYLD interaction and potentiates the K63-linked deubiquitination of RIG-I.

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XREF_BIBR, XREF_BIBR We and others have recently shown that RIG-I ubiquitination and TBK1 and IKKepsilon activation are negatively regulated by CYLD, XREF_BIBR, XREF_BIBR a deubiquitinase known to digest K63 linked ubiquitin chains.

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CYLD (cylindromatosis) deubiquitinates RIG-I and several downstream molecules to prevent premature RIG-I activation in uninfected cells [17], while USP3 deubiquitinates RIG-I specifically after viral infection, likely serving as a negative feedback regulator [18].

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ORF64, USP25, USP21, USP15, USP3, Cylindromatosis (CYLD), porcine epidemic diarrhea virus papain-like protease 2 (PEDV PLP2) and transmissible gastroenteritis virus papain-like protease1 (TGEV PL1) are the DUBs found to deubiquitinate RIG-I.

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CYLD has been shown to deubiquitinate, or prevent ubiquitination of RIG-I in cells.

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CYLD (cylindromatosis) deubiquitinates RIG-I and several downstream molecules to prevent premature RIG-I activation in uninfected cells [XREF_BIBR], while USP3 deubiquitinates RIG-I specifically after viral infection, likely serving as a negative feedback regulator [XREF_BIBR].

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Tumor suppressor protein cylindromatosis (CYLD) reduced the baseline Lys63-linked ubiquitination of RIG-I in uninfected cells [69].

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A simple explanation for this result is that the carboxyl-terminal fragment of SDC4 brings RIG-I and CYLD close together, which promotes the deubiquitination of RIG-I by CYLD.
CYLD deubiquitinates AKT. 8 / 8
| 8

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To determine whether CYLD is a direct DUB for Akt, we performed in vitro deubiquitination assays and found that deubiquitination of Akt was mediated by wild-type CYLD but not the C601A mutant (XREF_FIG).

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Because CYLD is a known deubiquitinase and Akt ubiquitination is critical for its functional activity XREF_BIBR, we next investigated whether CYLD deubiquitinates Akt.

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In this study we provided experimental evidences for direct interaction between Akt and CYLD, and also showed that CYLD does directly deubiquitinate Akt under both endogenous and exogenous conditions.

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Among the DUBs, only CYLD effectively reduced the ubiquitination of Akt (XREF_FIG and XREF_SUPPLEMENTARY).

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Both E3 ligases TRAF6 [158] and Skp2 [159] regulate Akt activity through K63 linked ubiquitination while CYLD promotes deubiquitination of Akt [160].

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Reversely, CYLD negatively regulates Akt signaling by deubiquitinating Akt in TGFbeta signaling [XREF_BIBR].

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Because CYLD suppresses ubiquitination and activation of Akt, it is possible that CYLD may also inhibit cancer cell proliferation and survival.

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CYLD repression by miR-130b restores Akt ubiquitination and activation, GSK3beta and FoxO3a phosphorylation, FoxO3a removal from Bim promoter as well as Bim downregulation during 6-OHDA administration.
CYLD deubiquitinates NFkappaB. 7 / 7
| 7

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In vivo, CYLD also reduced hepatic STAT3 K63 ubiquitination and activation, NF-kappaB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis.

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Deubiquitination of NF-kappaB members by CYLD is crucial in controlling the magnitude and nature of cell activation.

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CYLD deubiquitinates NEMO, thus decreasing its stability and preventing the IKK complex from phosphorylating IkappaB, and NF-kappaB activation.

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In this investigation, we found that CYLD failed to inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation (XREF_FIG, XREF_SUPPLEMENTARY).

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CYLD deubiquitinates several NF-kappaB regulators, including TRAF2, TRAF6, and NEMO as well as BCL3, a member of the NF-kappaB family of transcription factors.

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18 CYLD 's deubiquitination of NFkappaB inhibits NFkappaB activity without decreasing NFkappaB protein expression.

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Mechanistically, our results reveal that miR-135b directly targets the 3 '-untranslated region (UTR) of the deubiquitinase CYLD, thereby modulating ubiquitination and activation of NF-kappaB signaling.
CYLD deubiquitinates NLRP6. 5 / 5
| 5

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Cyld deubiquitinated NLRP6, suggesting that Cyld directly deubiquitinates NLRP6 (XREF_FIG).

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Coexpression of Cyld with NLRP6 and UbK63 markedly inhibited ubiquitination of NLRP6 (XREF_FIG, lane 4), suggesting that Cyld cleaves K63 linked Ub chains.

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To confirm that Cyld directly deubiquitinates NLRP6, we coexpressed Flag -- NLRP6 with Ub.

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NLRP6 ubiquitination was diminished in the presence of wild-type Cyld but not with the Cyld (C601A) deubiquitinase defective mutant, suggesting that Cyld deubiquitinates NLRP6 (XREF_FIG).

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Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation.
CYLD deubiquitinates Tax. 4 / 4
| 4

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CYLD inhibits Tax ubiquitination.

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Since CYLD deubiquitinates Tax, we examined the effect of CYLD on these Tax specific signaling events.

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Since CYLD is a K63 specific DUB, we examined whether the ubiquitination of Tax is negatively regulated by CYLD.

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As expected, the wildtype CYLD, but not its catalytically inactive mutant, efficiently inhibited Tax ubiquitination.
CYLD leads to the deubiquitination of TBK1. 4 / 4
| 3

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CYLD removes polyubiquitin chains from RIG-I as well as from TANK binding kinase 1 (TBK1), the kinase that phosphorylates IRF3, coincident with an inhibition of the IRF3 signalling pathway.

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XREF_BIBR, XREF_BIBR We and others have recently shown that RIG-I ubiquitination and TBK1 and IKKepsilon activation are negatively regulated by CYLD, XREF_BIBR, XREF_BIBR a deubiquitinase known to digest K63 linked ubiquitin chains.

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In addition, CYLD also inhibits the ubiquitination of TBK1 and IKKepsilon, which also contributes to the negative regulation of IFN responses by CYLD 79.

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CYLD also inhibits the ubiquitylation of TBK1 and IKKε, which contributes to the negative regulation of IFN responses 171 .
CYLD leads to the deubiquitination of DVL. 3 / 3
| 3

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It is also reported that a tumor suppressor CYLD deubiquitinase inhibits the ubiquitination of Dvl.

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Knockout of CYLD in tumor cells can prevent K63 linked deubiquitination of Dvl [Dishevelled], which enhances Wnt and beta-catenin signaling [XREF_BIBR].

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Based on the established role of Wnt signaling in self-renewal of the skin, associated cell lineage decisions, and skin appendage formation (Fuchs, 2007), we propose that increased or prolonged activa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
CYLD deubiquitinates ARHGEF12. 3 / 3
| 2

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In the present study, we show that CYLD deubiquitinates LARG, thus adding LARG to the growing list of CYLD substrates.

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Mechanistically, CYLD does not interact with RhoA; instead, it interacts with and deubiquitinates leukemia-associated RhoGEF (LARG).

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Taken together, our data provide the first evidence that CYLD deubiquitinates LARG and increases its ability to catalyze the GDP/GTP exchange on RhoA.
Mutated CYLD deubiquitinates Tax. 3 / 3
| 3

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Consistently, a phospho-mimetic CYLD mutant fails to inhibit Tax ubiquitination.

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A phospho-mimetic CYLD mutant failed to inhibit Tax ubiquitination.

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Importantly, a phospho-mimetic CYLD mutant harboring serine to glutamic acid substitutions at the phosphorylation sites completely failed to deubiquitinate Tax, whereas a mutant harboring serine to analine mutations at the phsphorylation sites of CYLD (CYLD7SA) remained active in Tax deubiquitination.
CYLD leads to the deubiquitination of IKBKE. 3 / 3
| 3

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We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and inhibits the ubiquitination of this IKKepsilon and TBK1 stimulator.

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In addition, CYLD also inhibits the ubiquitination of TBK1 and IKKepsilon, which also contributes to the negative regulation of IFN responses by CYLD 79.

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XREF_BIBR, XREF_BIBR We and others have recently shown that RIG-I ubiquitination and TBK1 and IKKepsilon activation are negatively regulated by CYLD, XREF_BIBR, XREF_BIBR a deubiquitinase known to digest K63 linked ubiquitin chains.
CYLD deubiquitinates IKK_complex. 3 / 3
| 3

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CYLD also deubiquitinates IkappaB kinase gamma (IKKgamma, also known as NEMO), the regulatory subunit of IKK thus inhibiting the activation of IKK.

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CYLD also inhibits the ubiquitylation of TBK1 and IKKε, which contributes to the negative regulation of IFN responses 171 .

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When transfected into mammalian cells, CYLD deubiquitinates NEMO as well as several IKK upstream regulators, including TRAF2, TRAF6, TRAF7, RIP1, and Tak1.
CYLD deubiquitinates MIB2. 3 / 3
| 2

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?To dissect CYLD function we used a proteomics approach to identify CYLD interacting proteins and identified MIB2, an ubiquitin ligase enzyme involved in Notch signalling, as a protein which interacts with CYLD. Coexpression of CYLD and MIB2 resulted in stabilisation of MIB2 protein levels and was associated with reduced levels of JAG2, a ligand implicated in Notch signalling.?

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Moreover, MIB2, an E3 ligase for the Notch ligand JAG2, is deubiquitinated and stabilized by CYLD.

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As we demonstrated that MIB2 can ubiquitylate itself as well as CYLD, we postulated that CYLD, as an ubiquitin hydrolase, might deubiquitylate MIB2, hence providing a potential mechanism of mutual regulation.
CYLD deubiquitinates NTRK1. 3 / 3
| 2

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In the internalization of the nerve growth factor receptor TrkA, siRNA mediated suppression of CYLD causes sustained TrkA ubiquitination with Lys63 chains (Geetha et al., 2005).

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Moreover, additional studies showed that CYLD specifically deubiquitinates polyubiquitin chains at K63 of different substrates (e.g., TRAF2 and TRAF6), or tyrosine kinase receptors such as TrkA.

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Geetha and collaborators saw that the polyubiquitination of TrkA increases when CYLD is depleted, but no direct evidence of TrkA deubiquitination by CYLD was provided [XREF_BIBR].
CYLD deubiquitinates CDKN2C. 3 / 3
| 3

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Knockdown of CYLD significantly increased the polyubiquitylation of p18, whereas, overexpression of CYLD reduced the levels of polyubiquitylation of p18.

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As expected, CYLD decreased p18 polyubiquitylation in vitro.

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These data indicate that CYLD directly deubiquitylates p18.
CYLD leads to the deubiquitination of DVL1. 2 / 2
| 1

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Ubiquitination of Dvl1 was diminished by overexpression of wild-type CYLD and enhanced by overexpression of a catalytically inactive CYLD (CYLD C601S).

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CYLD negatively regulates the Wnt/β-catenin signaling pathway by deubiquitinating Dvl proteins.
CYLD deubiquitinates CEP70. 2 / 2
| 1

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It has been shown previously that the cylindromatosis (CYLD) tumor suppressor deubiquitinates Cep70 and promotes its centrosomal localization, thereby contributing to ciliogenesis XREF_BIBR.

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The ciliary function of CYLD is attributed to its deconjugation of the polyubiquitin chain from centrosomal protein of 70 kDa (Cep70), a requirement for Cep70 to interact with γ -tubulin and localize at the centrosome
CYLD deubiquitinates SMAD7. 2 / 2
| 1

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CYLD deubiquitinates Smad7 and thereby inhibits the activation of TAK1 and p38, thus inhibiting the TGFbeta induced development of regulatory T cells.

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This showed that CYLD can bind to SMAD7 and deubiquitinate SMAD7 at Lysine 360 and 374 residues, which are required for the activation of TAK1 and p38 signaling
Modified CYLD leads to the deubiquitination of TRAF2. 2 / 2
| 2

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Indeed, immunoprecipitation analysis showed that overexpression of CYLD induced deubiquitination of TRAF2 in ECs.

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Of importance, overexpression of catalytically inactive CYLD did not induce deubiquitination of TRAF2.
CYLD leads to the deubiquitination of AKT1. 2 / 2
| 1

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We showed that CYLD was a DUB for Akt and suppressed growth factor-mediated ubiquitination and activation of Akt.

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Because Akt has three isoforms (Akt1, Akt2 and Akt3), we next examined whether CYLD displays differential specificity for various Akt isoforms and found that CYLD promoted deubiquitination of Akt1 and Akt2 (XREF_SUPPLEMENTARY).
CYLD deubiquitinates PLK1. 2 / 2
| 1

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It is currently unknown how deubiquitylation of PLK1 by CYLD regulates mitotic cell division.

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Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)
CYLD deubiquitinates RIPK2. 2 / 2
| 1

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The authors showed that CYLD deubiquitinated RIPK2 in macrophages infected with L. monocytogenes, leading to impaired activation of NF-kappaB, reduced production of proinflammatory cytokines and reactive oxygen and nitrogen species, which ultimately resulted in impaired infection control.

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CYLD-mediated K63 deubiquitination of RIPK2 resulted in an impaired activation of both NF-kappaB and ERK1/2 pathways, reduced production of proinflammatory cytokines interleukin-6 (IL-6), IL-12, anti-listerial reactive oxygen species (ROS) and nitric oxide (NO), and, finally, impaired pathogen control.
CYLD deubiquitinates IKBKG on K285. 2 / 2
2 |

biopax:reactome
No evidence text available

biopax:pid
No evidence text available
CYLD leads to the deubiquitination of TAB1. 1 / 1
| 1

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CYLD does not inhibit TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination.
Modified CYLD leads to the deubiquitination of TRAF6. 1 / 1
| 1

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We showed that CYLD over-expression largely inhibited TRAF-6 ubiquitination, a step that is required for its activation.
CYLD leads to the deubiquitination of FOXO3. 1 / 1
| 1

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CYLD repression by miR-130b restores Akt ubiquitination and activation, GSK3beta and FoxO3a phosphorylation, FoxO3a removal from Bim promoter as well as Bim downregulation during 6-OHDA administration.
CYLD leads to the deubiquitination of IL6. 1 / 1
| 1

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In vivo, CYLD also reduced hepatic STAT3 K63 ubiquitination and activation, NF-kappaB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis.
CYLD deubiquitinates LCK. 1 / 1
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Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)
CYLD leads to the deubiquitination of JNK. 1 / 1
| 1

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CYLD mediated regulation of the JNK signaling pathway appears to target TRAF2 ubiquitylation, as CYLD knockdown increases both TRAF2 ubiquitylation and JNK activation, further enhancing cell survival [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
CYLD leads to the deubiquitination of JUN. 1 / 1
| 1

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CYLD suppresses AP1 function by regulating c-Jun and c-Fos ubiquitination.
CYLD deubiquitinates DDX58 ubiquitinated on K172 and K154 on K164. 1 / 1
1 |

biopax:reactome
No evidence text available
CYLD deubiquitinates CNTN2. 1 / 1
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RESULTS: We show here that the deubiquitinase CYLD physically interacts with Tax and negatively regulates the ubiquitination of this viral protein.
CYLD leads to the deubiquitination of BCL2L11. 1 / 1
| 1

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CYLD repression by miR-130b restores Akt ubiquitination and activation, GSK3beta and FoxO3a phosphorylation, FoxO3a removal from Bim promoter as well as Bim downregulation during 6-OHDA administration.
CYLD deubiquitinates SMAD7 on K64. 1 / 1
| 1

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Moreover, CYLD appears to deubiquitylate SMAD7 at Lys360 and Lys374 but not at Lys64 or Lys70 [XREF_BIBR].
CYLD leads to the deubiquitination of Wnt. 1 / 1
| 1

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Based on the established role of Wnt signaling in self-renewal of the skin, associated cell lineage decisions, and skin appendage formation (Fuchs, 2007), we propose that increased or prolonged activa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
CYLD leads to the deubiquitination of MYD88. 1 / 1
| 1

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Although it is unclear whether this ubiquitination event is mediated by TRAF6 or another E3, the ubiquitination of MyD88 is negatively regulated by the DUB CYLD and is important for activating downstream proinflammatory signaling.
CYLD deubiquitinates RIPK3. 1 / 1
| 1

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CYLD deficiency leads to hyperubiquitinated RIPK1 in the necrosome and impaired phosphorylation of RIPK1 and RIPK3, thereby blocking caspase-8 activation.
CYLD leads to the deubiquitination of TNFRSF1A. 1 / 1
| 1

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CYLD, a deubiquitinating enzyme that targets both M1- and K63 linked ubiquitin chains, is recruited to TNF-RSC to negatively regulate ubiquitinations of RIPK1, TNFR1, NEMO and TRADD to attenuate the NF-kappaB pathway and promote both apoptosis and necroptosis.
CYLD deubiquitinates TGFBR1. 1 / 1
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Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma
CYLD leads to the deubiquitination of GSK3B. 1 / 1
| 1

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CYLD repression by miR-130b restores Akt ubiquitination and activation, GSK3beta and FoxO3a phosphorylation, FoxO3a removal from Bim promoter as well as Bim downregulation during 6-OHDA administration.
Mutated CYLD leads to the deubiquitination of AKT. 1 / 1
| 1

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We found that the inhibitory effect of CYLD on ubiquitination of Akt depended on its catalytic activity, because the catalytically dead mutant of CYLD (Cys 601 --> Ala 601; C601A) failed to attenuate ubiquitination of Akt (XREF_FIG).
CYLD deubiquitinates forkhead. 1 / 1
| 1

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CYLD : cylindromatosis; DUB : deubiquitylating enzyme; EBNA : Epstein-Barr nuclear antigen; FOXO : forkhead box O; HAUSP : herpesvirus associated ubiquitin specific peptidase; JAMM : Jab1 and MPN domain associated metalloisopeptidase; MJD : Machado-Joseph disease; OUT : ovarian tumor; PD : Parkinson 's disease; RIP : receptor interacting protein; TNF : tumor necrosis factor; TRAF : tumor necrosis factor receptor associated factor; UBP : ubiquitin processing peptidase; USP : ubiquitin specific peptidase; UCH : ubiquitin C-terminal hydrolase; VHL : von Hippel-Lindau.
Modified CYLD leads to the deubiquitination of ARHGEF12. 1 / 1
| 1

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Conversely, overexpression of CYLD dramatically inhibited LARG ubiquitination (XREF_FIG).
CYLD deubiquitinates DDX58 ubiquitinated on K154 and K164 on K172. 1 / 1
1 |

biopax:reactome
No evidence text available
CYLD leads to the deubiquitination of CYBB. 1 / 1
| 1

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In vivo, CYLD also reduced hepatic STAT3 K63 ubiquitination and activation, NF-kappaB activation, IL-6 and NOX2 mRNA production as well as fibrin production in murine listeriosis.
CYLD deubiquitinates TRIP12. 1 / 1
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Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)
CYLD leads to the deubiquitination of NDRG1. 1 / 1
| 1

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Given that CYLD is a deubiquitinase, we hypothesized that CYLD might inhibit NDRG1 ubiquitination and degradation via the ubiquitin-proteasome pathway.
CYLD leads to the deubiquitination of TGFB. 1 / 1
| 1

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Reversely, CYLD negatively regulates Akt signaling by deubiquitinating Akt in TGFbeta signaling [XREF_BIBR].
CYLD leads to the deubiquitination of AKT2. 1 / 1
| 1

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Because Akt has three isoforms (Akt1, Akt2 and Akt3), we next examined whether CYLD displays differential specificity for various Akt isoforms and found that CYLD promoted deubiquitination of Akt1 and Akt2 (XREF_SUPPLEMENTARY).
CYLD deubiquitinates RIPK1 on K377. 1 / 1
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No evidence text available
CYLD deubiquitinates AKT ubiquitinated on K63 on K63. 1 / 1
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CYLD deubiquitinates K63 ubiquitinated Akt to inhibit Smad3.
CYLD deubiquitinates CENPV. 1 / 1
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CENPV is deubiquitylated by CYLD and localizes in interphase to primary cilia where it increases the ciliary levels of acetylated alpha-tubulin.
CYLD deubiquitinates NOX4. 1 / 1
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Moreover, Nox4 was deubiquitinated via a direct interaction with the ubiquitin-specific protease domain of CYLD.
CYLD leads to the deubiquitination of TNF. 1 / 1
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The DUB function of CYLD was first revealed by in vitro work showing that CYLD inhibits the ubiquitination of certain TNF receptor associated factors and the regulatory subunit of IkappaB kinase.
CYLD phosphorylated on S418 deubiquitinates RIPK1 on K377. 1 / 1
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No evidence text available
CYLD deubiquitinates DDX58 ubiquitinated on K172 and K164 on K154. 1 / 1
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CYLD deubiquitinates IKBKG phosphorylated on S85 on lysine. 1 / 1
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No evidence text available
Mutated CYLD leads to the deubiquitination of TRAF2. 1 / 1
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When these serines are mutated to alanines, it generates a super-active CYLD mutant that prevents TNF-alpha-stimulated TRAF2 ubiquitination.
CYLD deubiquitinates DLG4. 1 / 1
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CYLD-mediated PSD-95 deubiquitination, mobilizing and depleting PSD-95 from synapses.
Ubiquitinated CYLD leads to the deubiquitination of AKT. 1 / 1
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We also demonstrated that PI3K activity, which is usually essential for growth factor mediated Akt activation, is dispensable for growth factor mediated ubiquitination and CYLD mediated deubiquitination of Akt.
CYLD deubiquitinates NR2C2. 1 / 1
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Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)
Modified CYLD leads to the deubiquitination of DDX58. 1 / 1
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Loss of CYLD in DCs causes accumulation of ubiquitination of RIG-I indicating that RIG-I is constantly in the cycle of ubiquitination deubiquitination with deubiquitination being a dominant event in steady state.
Modified CYLD leads to the deubiquitination of BCL3. 1 / 1
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Loss of CYLD expression in melanoma promoted ubiquitination of BCL-3, which is a transcriptional regulator of N-cadherin expression [28].
CYLD deubiquitinates FOXO. 1 / 1
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CYLD : cylindromatosis; DUB : deubiquitylating enzyme; EBNA : Epstein-Barr nuclear antigen; FOXO : forkhead box O; HAUSP : herpesvirus associated ubiquitin specific peptidase; JAMM : Jab1 and MPN domain associated metalloisopeptidase; MJD : Machado-Joseph disease; OUT : ovarian tumor; PD : Parkinson 's disease; RIP : receptor interacting protein; TNF : tumor necrosis factor; TRAF : tumor necrosis factor receptor associated factor; UBP : ubiquitin processing peptidase; USP : ubiquitin specific peptidase; UCH : ubiquitin C-terminal hydrolase; VHL : von Hippel-Lindau.
CYLD deubiquitinates SMAD7 at position 374. 1 / 1
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Under endogenous conditions, CYLD formed a complex with Smad7 that facilitated CYLD deubiquitination of Smad7 at lysine 360 and 374 residues.
Modified CYLD leads to the deubiquitination of RIPK1. 1 / 1
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As shown in XREF_FIG, CYLD overexpression caused RIP1 deubiquitination, which was exacerbated by selenite treatment.
CYLD deubiquitinates E3_Ub_ligase. 1 / 1
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As it has previously been demonstrated that CYLD deubiquitinates TRAF6 these results suggests that CYLD deubiquitinates and suppresses the activity of both the E3 ligase and its kindred substrate [184[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
CYLD deubiquitinates TRAF7. 1 / 1
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Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)
CYLD deubiquitinates NADP(+). 1 / 1
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CYLD Deubiquitinates Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Contributing to Adventitial Remodeling.
CYLD deubiquitinates USP7. 1 / 1
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CYLD : cylindromatosis; DUB : deubiquitylating enzyme; EBNA : Epstein-Barr nuclear antigen; FOXO : forkhead box O; HAUSP : herpesvirus associated ubiquitin specific peptidase; JAMM : Jab1 and MPN domain associated metalloisopeptidase; MJD : Machado-Joseph disease; OUT : ovarian tumor; PD : Parkinson 's disease; RIP : receptor interacting protein; TNF : tumor necrosis factor; TRAF : tumor necrosis factor receptor associated factor; UBP : ubiquitin processing peptidase; USP : ubiquitin specific peptidase; UCH : ubiquitin C-terminal hydrolase; VHL : von Hippel-Lindau.
CYLD leads to the deubiquitination of FOS. 1 / 1
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CYLD suppresses AP1 function by regulating c-Jun and c-Fos ubiquitination.

Other Statements

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CYLD affects NFkappaB
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CYLD inhibits NFkappaB.
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Our results show that reconsitituted expression of CYLD in miR-19a-replete cells only partially deactivates NF-kappaB, suggesting that CYLD might cooperate with other DUBs to switch off NF-kappaB signalling.

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CYLD has been shown to negatively regulate the activation of NF-kappaB XREF_BIBR.

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The results established that CYLD down-regulates NF-kappaB activation by TNF-alpha.

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For instance, CYLD negatively regulates NFkappaB activation and is involved in other immune response mechanisms.39 When TSGs such as CYLD are down-regulated, excessive inflammation occurs and tumorigenic factors can be promoted.40 Conversely, TSGs that were up-regulated were more likely to be involved in cell cycle regulation, apoptosis, and cell growth, possibly as a response to cell stress in early stages of tumorigenesis.

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Because CYLD inhibits NF-kappaB activation, it is probable that both PI3K-Akt and NF-kappaB signaling pathways are involved in CYLD regulated cell proliferation and survival.

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In TLR mediated signaling, CYLD negatively regulates NF-kappaB signaling by cleaving K63 linked polyubiquitin chains and M1 linked polyubiquitin chains from RIPK1, TRAF2, and NEMO.

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As both CYLD and OTULIN negatively regulate the NF-kappaB signalling cascade, the impact of these deubiquitinases in different LUBAC dependent signalling cascades may be context dependent.

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Interestingly, loss of CYLD causes constitutive NF-kappaB activation in developing NKT cells, which contributes to their defective IL-7 response and attenuated ICOS expression.

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When transfected in cell lines, CYLD inhibits the activation of NF-kappaB and mitogen activated protein kinases stimulated by innate immune receptors, such as the Toll like receptors and TNF receptors.

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CYLD inhibits activation of NF-kappaB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD.
Mutated CYLD inhibits NFkappaB. 2 / 2
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Furthermore, nuclear translocation of Bcl-3, a component of reported NPC associated activated NF-kappaB signal p50/p50/Bcl -3, was inhibited upon CYLD WT expression, but not by CYLD mutants (XREF_SUPPLEMENTARY).

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Surprisingly, a non cleavable CYLD mutant does not impair TCR dependent canonical NF-kappaB activation, but does block activation of JNK, a critical step in TCR induced stimulation of multiple transcription factors and production of IL-2.
CYLD-S418A inhibits NFkappaB. 1 / 1
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As observed in MCF-7 cells, however, CYLD S418A more strongly inhibited IKKepsilon induced NF-kappaB activation.
CYLD bound to Tax inhibits NFkappaB. 1 / 1
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We found that Tax interacts with CYLD, a deubiquitinase that negatively regulates NF-kappaB activity, by inactivating it.
CYLD activates NFkappaB.
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Although comparable CYLD mRNA levels were present in both tumor and normal tissue, direct binding of miR-182 to 3′UTR of CYLD activated NF-κB in tumor cells.

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However, subsequent studies have indicated that although CYLD targets NF-kappaB signaling factors, its function may depend on the cell type and stimulating receptor [XREF_BIBR].