TNFAIP3 (also known as A20) encodes a 790-amino acid ubiquitin-editing enzyme that serves as the central negative feedback regulator of NF-kB signaling. The protein has a dual enzymatic architecture: an N-terminal OTU (ovarian tumor) domain (aa 92-263) with cysteine-type deubiquitinase activity (catalytic residues Cys103, His256), and seven C-terminal A20-type zinc finger domains (ZnF1-7). The OTU domain removes K63-linked polyubiquitin chains from key signaling adaptors (RIPK1, TRAF6, NEMO/IKBKG, MALT1), while ZnF4 mediates E3 ubiquitin ligase activity that adds K48-linked chains to target substrates (notably RIPK1) for proteasomal degradation. ZnF7 binds linear (M1-linked) polyubiquitin chains non-catalytically, contributing to IKK complex inhibition. A20 is an NF-kB-inducible gene, forming a negative feedback loop that terminates inflammatory signaling downstream of TNFR1, TLR2/3/4/5, NOD1/2, and CD40 receptors. It also suppresses NLRP3 inflammasome activation and modulates RIPK1-dependent cell death checkpoints. A20 functions in the cytoplasm at receptor-proximal signaling complexes, with some localization to the nucleus and lysosomes. It forms a complex with TAX1BP1, RNF11, and ITCH for efficient NF-kB termination. Heterozygous loss-of-function variants cause A20 haploinsufficiency (HA20), an early-onset autoinflammatory disease with Behcet-like features. Common variants at the TNFAIP3 locus are associated with susceptibility to SLE, RA, and IBD.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for nuclear localization. A20 is predominantly cytoplasmic but has been detected in the nucleus by immunofluorescence (PMID:11463333). The IDA annotation from PMID:11463333 also supports this. However, the nucleus is not the primary site of A20 function. Reason: Nuclear localization is supported by direct experimental evidence (IDA from PMID:11463333) and is phylogenetically conserved per IBA. While cytoplasm is the primary functional site, nuclear localization is reproducibly observed. Supporting Evidence: PMID:11463333 The zinc finger molecule A20 is an important negative regulator of NF-kappa B |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytoplasmic localization. A20 functions at cytoplasmic receptor-proximal signaling complexes (TNFR, TLR signalosomes) where it edits ubiquitin chains on RIPK1, TRAF6, and NEMO. Well-supported by UniProt subcellular location and multiple experimental studies. Reason: Core site of A20 function. Cytoplasmic localization is the primary location where A20 carries out deubiquitination and ubiquitin ligase activities at receptor-proximal complexes. Strongly supported by multiple lines of evidence. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0004842 ubiquitin-protein transferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for E3 ubiquitin ligase activity. A20 ZnF4 domain mediates ubiquitin-protein transferase activity, catalyzing addition of K48-linked polyubiquitin chains to substrates including RIPK1, targeting them for proteasomal degradation (PMID:15258597). Reason: Core enzymatic function. The E3 ubiquitin ligase activity via ZnF4 is one of the two defining enzymatic activities of A20, experimentally demonstrated by Wertz et al. (2004). IBA is consistent with phylogenetic conservation and IDA evidence. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for negative regulation of NF-kB. This is the single most important biological process annotation for A20. A20 terminates NF-kB signaling by deubiquitinating K63-Ub chains on RIPK1/TRAF6/NEMO and adding K48-Ub chains to target them for degradation. Multiple IDA evidence lines confirm this (PMID:15258597, PMID:11463333, PMID:18223652, PMID:21127049). Reason: Core function. A20 is the prototypical negative feedback regulator of NF-kB signaling. This is the most extensively validated function of A20, supported by multiple independent experimental approaches and confirmed by phylogenetic analysis. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling PMID:8692885 The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation |
| GO:0045824 negative regulation of innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation. A20 negatively regulates innate immune signaling downstream of TLRs and NOD1/2 receptors by editing ubiquitin chains on pathway components. Supported by ISS from mouse ortholog (Q60769) and extensive mouse knockout studies showing lethal inflammation. Reason: Core function. A20 restrains innate immune activation through its deubiquitinase and E3 ligase activities targeting TLR and NLR pathway components. Mouse A20 knockouts develop severe multi-organ inflammation and die prematurely. Supporting Evidence: PMID:15142865 A20 may function as a negative regulator of TLR-mediated inflammatory responses in the airway |
| GO:0050728 negative regulation of inflammatory response | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation. A20 is a master negative regulator of inflammation. Loss of A20 leads to unchecked NF-kB activation, excessive cytokine production, and multi-organ inflammation. HA20 patients exhibit chronic inflammation. Reason: Core function. Negative regulation of inflammation is the primary biological consequence of A20 enzymatic activity. Supported by mouse knockout phenotypes and human HA20 disease. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0004843 cysteine-type deubiquitinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cysteine-type DUB activity. The OTU domain of A20 is a cysteine protease with catalytic triad Cys103/His256 that cleaves ubiquitin chains. Demonstrated by multiple crystal structures and biochemical assays (PMID:14748687, PMID:17961127, PMID:18164316, PMID:23827681). A20 can cleave K11, K48, and K63 chains in vitro. Reason: Core enzymatic function. The OTU deubiquitinase activity is one of the two defining enzymatic activities of A20, with extensive structural and biochemical characterization. Supporting Evidence: PMID:14748687 Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis |
| GO:0071947 protein deubiquitination involved in ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation. A20 deubiquitinates RIPK1 (removing K63 chains) as part of the ubiquitin editing process that subsequently leads to K48-linked ubiquitination and proteasomal degradation of RIPK1. This couples deubiquitination to protein catabolism. Reason: Accurately captures the coupling of A20 deubiquitinase activity to proteasomal degradation of signaling adaptors. The sequential removal of K63 chains followed by addition of K48 chains on RIPK1 is the canonical A20 ubiquitin-editing mechanism. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0002376 immune system process | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from ARBA. Very broad term. A20 is indeed involved in immune system processes but more specific terms are already annotated. Reason: While very broad, this IEA is not wrong. More specific immune-related annotations (negative regulation of innate immune response, negative regulation of NF-kB) are also present and represent the core function. |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | REMOVE | Summary: IEA based on InterPro A20-type zinc finger domain mapping to DNA binding. This is misleading. A20 zinc fingers bind ubiquitin, not DNA. The original A20 name "putative DNA-binding protein" was based on the zinc finger motif, but no DNA binding activity has been demonstrated. A20 functions entirely through ubiquitin editing in the cytoplasm. Reason: Incorrect annotation. A20 zinc fingers are A20-type zinc fingers specialized for ubiquitin binding, not DNA binding. No experimental evidence supports DNA binding activity for A20. The InterPro mapping is erroneous for this protein. |
| GO:0003824 catalytic activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for generic catalytic activity. A20 has well-characterized catalytic activities (deubiquitinase and ubiquitin ligase) but this term is too broad to be informative. Reason: Correct but very broad. More specific catalytic activity terms (cysteine-type deubiquitinase activity, ubiquitin-protein transferase activity) are already present. |
| GO:0004843 cysteine-type deubiquitinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: IEA from EC number mapping (EC:3.4.19.12). Consistent with experimental evidence and IBA/IDA annotations for the same term. Reason: Correct. A20 OTU domain has well-characterized cysteine-type deubiquitinase activity. Redundant with IBA and IDA annotations but correctly derived from EC mapping. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location. Consistent with IBA and IDA annotations. Reason: Correct. Nuclear localization supported by UniProt subcellular location and IDA evidence. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for cytoplasm. Consistent with IBA and multiple experimental evidence lines. Reason: Correct. Cytoplasm is the primary functional location of A20. |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location. A20 has been shown to target TRAF2 to lysosomes for degradation (PMID:18952128), and the C-terminal region (aa 697-790) is required for lysosomal localization per UniProt. Reason: Correct. Lysosomal localization is documented in UniProt based on PMID:18952128 showing A20 targets TRAF2 to lysosomes for degradation. Supporting Evidence: PMID:18952128 The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation |
| GO:0006508 proteolysis | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword mapping (KW-0645 Protease). A20 is a thiol protease (deubiquitinase) that cleaves isopeptide bonds in polyubiquitin chains. Reason: Correct but very broad. A20 performs proteolysis in the form of ubiquitin chain cleavage. More specific terms (protein deubiquitination) are also annotated. |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword (KW-0053 Apoptosis). A20 inhibits programmed cell death, particularly extrinsic apoptosis via death domain receptors. More specific terms for the anti-apoptotic role are annotated. Reason: Broadly correct. A20 is described in UniProt as an "Inhibitor of programmed cell death." More specific annotations (negative regulation of extrinsic apoptotic signaling pathway via death domain receptors) capture this more precisely. |
| GO:0006954 inflammatory response | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword (KW-0395 Inflammatory response). A20 is a key negative regulator of inflammation. More specific terms are annotated. Reason: Correct but broad. More specific negative regulation of inflammatory response terms are already present. |
| GO:0008233 peptidase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword. A20 OTU domain is indeed a peptidase (cleaves isopeptide bonds). More specific cysteine-type deubiquitinase activity is annotated. Reason: Correct but broad. Parent term of more specific annotations already present. |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword (KW-0788 Thiol protease). A20 uses Cys103 as the catalytic nucleophile. More specific cysteine-type deubiquitinase activity is annotated. Reason: Correct. A20 OTU domain is a cysteine-type peptidase. Parent of cysteine-type deubiquitinase activity which is also annotated. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from InterPro/UniProt keyword. A20 has seven A20-type zinc finger domains, each coordinating zinc ions. This is structurally confirmed. Reason: Correct. A20 has seven zinc finger domains that bind zinc ions, confirmed by crystal structures and NMR. |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword (KW-0808 Transferase). A20 has ubiquitin-protein transferase (E3 ligase) activity via its ZnF4 domain. Reason: Correct but very broad. More specific ubiquitin-protein transferase activity is annotated. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword (KW-0378 Hydrolase). The OTU deubiquitinase domain hydrolyzes isopeptide bonds. Reason: Correct but very broad. More specific terms (cysteine-type deubiquitinase activity) are annotated. |
| GO:0019899 enzyme binding | IEA GO_REF:0000117 | ACCEPT | Summary: IEA from ARBA. A20 interacts with multiple enzymes including TRAF6, TRAF2, MALT1 paracaspase, and E2 enzymes UBE2N and UBE2D3. However, 'enzyme binding' is a vague term. Reason: Broadly correct but uninformative. A20 does bind multiple enzymes. More specific binding annotations (protease binding, ubiquitin binding, kinase binding) are also present. |
| GO:0039532 negative regulation of cytoplasmic pattern recognition receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: IEA from ARBA. A20 negatively regulates NOD1 and NOD2 signaling pathways (cytoplasmic PRRs) by deubiquitinating RIPK2. This is supported by Ensembl orthology (mouse) and Reactome pathway annotation. Reason: Correct. A20 negatively regulates cytoplasmic PRR signaling, specifically NOD1/NOD2. Supported by more specific annotations for NOD1 and NOD2 pathway regulation. |
| GO:0042127 regulation of cell population proliferation | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA from ARBA. A20 affects cell proliferation indirectly through NF-kB regulation. Specific effects on smooth muscle cell proliferation and hepatocyte proliferation are annotated with better evidence. Reason: Overly broad annotation. While A20 affects proliferation indirectly through NF-kB, this is not a direct molecular function. More specific proliferation annotations (smooth muscle cell, hepatocyte) are present. |
| GO:0045732 positive regulation of protein catabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: IEA from ARBA. A20 promotes proteasomal degradation of signaling substrates (RIPK1, TRAF2, UBE2N, UBE2D3) by adding K48-linked ubiquitin chains. Supported by IDA from PMID:21127049. Reason: Correct. A20 ubiquitin-editing promotes K48-linked ubiquitination and subsequent proteasomal degradation of substrates. Consistent with IDA evidence. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword (KW-0479 Metal-binding). A20 binds zinc ions through seven zinc finger domains. Reason: Correct but very broad. More specific zinc ion binding is also annotated. |
| GO:0070536 protein K63-linked deubiquitination | IEA GO_REF:0000117 | ACCEPT | Summary: IEA from ARBA. K63-linked deubiquitination is a core function of A20 OTU domain, targeting K63-polyUb chains on RIPK1, TRAF6, NEMO, and MALT1. Supported by IDA from PMID:15258597. Reason: Correct and important. K63-linked deubiquitination is the primary in vivo deubiquitinase specificity of A20. Consistent with IDA evidence. |
| GO:1901701 cellular response to oxygen-containing compound | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA from ARBA. A20 responds to hydrogen peroxide (supported by ISS annotation). This is a very broad parent term of more specific annotations. Reason: Overly broad. More specific cellular response to hydrogen peroxide is annotated. This broad parent does not add useful information. |
| GO:0005515 protein binding | IPI PMID:11389905 Functional redundancy of the zinc fingers of A20 for inhibit... | MARK AS OVER ANNOTATED | Summary: IPI protein binding from high-throughput protein interaction study. Reason: Protein binding is too vague. A20 has well-characterized specific interactions (with TRAF2, TAX1BP1, TNIP1, IKBKG, RIPK1) that are more informative. These should be captured by more specific MF terms. |
| GO:0005515 protein binding | IPI PMID:15169888 ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p1... | MARK AS OVER ANNOTATED | Summary: IPI protein binding. Reason: Protein binding is uninformative for A20. More specific interaction-based annotations are preferred. |
| GO:0005515 protein binding | IPI PMID:15231748 Functional proteomics mapping of a human signaling pathway. | MARK AS OVER ANNOTATED | Summary: IPI protein binding from proteomics mapping study. Reason: Protein binding is uninformative. More specific binding terms are available. |
| GO:0005515 protein binding | IPI PMID:19060883 ABIN-1 is a ubiquitin sensor that restricts cell death and s... | MARK AS OVER ANNOTATED | Summary: IPI protein binding, interactor is CASP8 (Q14790). A20 interaction with CASP8 may relate to its role in modulating death receptor signaling and apoptosis. Reason: Protein binding is uninformative. The specific interaction with CASP8 is potentially relevant to A20 anti-apoptotic function but should be annotated more specifically. |
| GO:0005515 protein binding | IPI PMID:19131965 The ubiquitin-editing enzyme A20 requires RNF11 to downregul... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with RNF11 (Q9Y3C5). A20 requires RNF11 to form the ubiquitin-editing complex with TAX1BP1 and ITCH for NF-kB downregulation. Reason: Protein binding is uninformative. The A20-RNF11 interaction is functionally significant but should be captured by more specific terms. |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | MARK AS OVER ANNOTATED | Summary: IPI protein binding with YWHAG (P61981), from MAP kinase interactome study. Reason: Protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: IPI protein binding from liver protein interaction study. Multiple interactors (YWHAE, TNIP1, IKBKG). Reason: Protein binding is uninformative. Multiple protein binding annotations from this study do not add functional insight beyond what more specific terms provide. |
| GO:0005515 protein binding | IPI PMID:23032186 A20 inhibits LUBAC-mediated NF-ΞΊB activation by binding line... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with IKBKG (Q9Y6K9). A20 ZnF7 binds linear polyubiquitin on NEMO to inhibit IKK complex activation. Reason: Protein binding is uninformative. The A20-NEMO interaction is core to A20 function but should use more specific terms. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: IPI protein binding from proteome-scale interactome study. Multiple interactors. Reason: Protein binding is uninformative. High-throughput interactome data. |
| GO:0005515 protein binding | IPI PMID:30561431 A protein-protein interaction map of the TNF-induced NF-ΞΊB s... | MARK AS OVER ANNOTATED | Summary: IPI protein binding. Multiple interactors including TRAF2, TAX1BP1, TNIP1, TNIP2, IKBKG. Reason: Protein binding is uninformative. These are functionally important interactions but the generic term adds no value. |
| GO:0005515 protein binding | IPI PMID:31015422 Physical and functional interaction between A20 and ATG16L1-... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with ATG16L1 isoform 1 (Q676U5-1). Reason: Protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: IPI protein binding from study of genetic variant effects on protein interactions. Reason: Protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI protein binding from reference human binary interactome. Multiple interactors. Reason: Protein binding is uninformative. High-throughput interactome study. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with TAX1BP1 (Q86VP1) from dual proteome study. Reason: Protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with 14-3-3 proteins (YWHAG, YWHAE). A20 interacts with 14-3-3 proteins, though A20 inhibits NF-kB independently of 14-3-3 binding (PMID:9299557). Reason: Protein binding is uninformative. |
| GO:0005515 protein binding | IPI PMID:9299557 A20 inhibits NF-kappaB activation independently of binding t... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with YWHAH (14-3-3 eta). Early study showing A20 binds 14-3-3 proteins but NF-kB inhibition is independent of this interaction. Reason: Protein binding is uninformative. The 14-3-3 interaction was shown to be dispensable for A20 NF-kB inhibitory function. Supporting Evidence: PMID:9299557 A20 inhibits NF-kappaB activation independently of binding to 14-3-3 proteins |
| GO:0042802 identical protein binding | IPI PMID:11389905 Functional redundancy of the zinc fingers of A20 for inhibit... | ACCEPT | Summary: IPI for A20 homodimerization. UniProt confirms A20 is a homodimer (IntAct: 9 experiments). Reason: A20 homodimerization is well-supported. UniProt SUBUNIT states "Homodimer" and IntAct records 9 experiments confirming self-interaction. More informative than generic protein binding. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: Additional evidence for A20 homodimerization from proteome-scale interactome. Reason: Corroborates A20 self-interaction. Redundant with other identical protein binding annotations but supported by independent study. |
| GO:0042802 identical protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | ACCEPT | Summary: Additional evidence for A20 homodimerization from massively parallel cloning study. Reason: Corroborates A20 self-interaction with independent approach. |
| GO:0042802 identical protein binding | IPI PMID:30561431 A protein-protein interaction map of the TNF-induced NF-ΞΊB s... | ACCEPT | Summary: Additional evidence for A20 homodimerization. Reason: Consistent with established A20 homodimer formation. |
| GO:0042802 identical protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | ACCEPT | Summary: Additional evidence for A20 homodimerization from genetic variant study. Reason: Consistent with A20 self-interaction. |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | ACCEPT | Summary: Additional evidence for A20 homodimerization from reference interactome. Reason: Consistent with A20 self-interaction. |
| GO:0001922 B-1 B cell homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara orthology to mouse A20 (Q60769). Mouse A20 knockout shows B-1 B cell abnormalities. Also annotated with ISS evidence. Reason: This is a downstream effect of A20 function in immune regulation rather than a core molecular function. Supported by mouse data but reflects pleiotropic immune consequences. |
| GO:0002237 response to molecule of bacterial origin | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated methods. A20 responds to bacterial molecules through TLR signaling. Also annotated with IDA from PMID:19912257. Reason: Correct. A20 is induced by and functions in response to bacterial products through TLR pathways. Consistent with IDA evidence. |
| GO:0002634 regulation of germinal center formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. Mouse A20 deficiency affects germinal center formation. Also annotated with ISS evidence. Reason: Downstream effect of A20 immune regulation. Not a core molecular function but a pleiotropic consequence in the adaptive immune system. |
| GO:0002677 negative regulation of chronic inflammatory response | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. A20 prevents chronic inflammation, as demonstrated by mouse knockouts developing severe chronic inflammation and HA20 patients showing chronic autoinflammatory disease. Reason: Correct. A20 prevents chronic inflammation through its NF-kB regulatory activity. Central to A20 function. |
| GO:0016579 protein deubiquitination | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. Protein deubiquitination is a core enzymatic activity. Also annotated with TAS from PMID:20392859 and Reactome. Reason: Correct. Core enzymatic activity of A20 OTU domain. Consistent with multiple other evidence lines. |
| GO:0019900 kinase binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. A20 interacts with IKK complex (IKKbeta/IKBKG) and RIPK1. IKK phosphorylates A20. RIPK1 is a serine/threonine kinase. Reason: Correct. A20 binds RIPK1 (a kinase) and interacts with IKK complex. More specific than generic protein binding. |
| GO:0032495 response to muramyl dipeptide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. A20 negatively regulates NOD2 signaling, and muramyl dipeptide (MDP) is the NOD2 ligand. A20 likely deubiquitinates RIPK2 in the NOD2 pathway. Reason: Downstream of NOD2 signaling pathway regulation. A20 responds indirectly to MDP through its role in NOD2 pathway negative regulation. |
| GO:0032691 negative regulation of interleukin-1 beta production | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA from combined automated methods. A20 inhibits IL-1beta production by suppressing NF-kB and NLRP3 inflammasome activation. Also annotated with IMP from PMID:28094437. Reason: Downstream effect of NF-kB and inflammasome suppression. Not a direct molecular function but a well-documented pleiotropic consequence. Supported by IMP evidence. |
| GO:0032715 negative regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. A20 inhibits IL-6 production through NF-kB suppression. Also annotated with ISS. HA20 patients show elevated IL-6. Reason: Downstream effect of NF-kB regulation. IL-6 is an NF-kB target gene, so A20 indirectly suppresses its production. |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. A20 suppresses TNF production via NF-kB inhibition. Also annotated with ISS. Reason: Downstream effect. TNF is an NF-kB target gene. A20 indirectly reduces TNF production by terminating NF-kB signaling. |
| GO:0034148 negative regulation of toll-like receptor 5 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. A20 likely negatively regulates TLR5 signaling similar to its regulation of TLR2, TLR3, and TLR4 pathways. Reason: Consistent with A20 general role as negative regulator of TLR signaling. Supported by mouse ortholog data and analogous to experimentally confirmed TLR2/3/4 regulation. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated methods. Redundant with IBA and multiple IDA annotations. Reason: Correct. Core function of A20. Consistent with multiple higher-quality evidence codes. |
| GO:0045824 negative regulation of innate immune response | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. Redundant with IBA and ISS annotations. Reason: Correct. Core function. Consistent with IBA and ISS evidence. |
| GO:0050728 negative regulation of inflammatory response | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. Redundant with IBA and ISS annotations. Reason: Correct. Core function. Consistent with IBA and ISS evidence. |
| GO:0050869 negative regulation of B cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. A20 negatively regulates B cell activation through NF-kB suppression. Mouse knockouts show B cell abnormalities. Reason: Pleiotropic consequence of NF-kB regulation in B cells. Not core molecular function but documented in mouse. |
| GO:0070301 cellular response to hydrogen peroxide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. A20 expression or function may be modulated by hydrogen peroxide. Also annotated with ISS. Reason: Not a core function. Response to oxidative stress is a secondary aspect of A20 biology. |
| GO:0070429 negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. A20 negatively regulates NOD1 signaling, likely by deubiquitinating RIPK2 in the NOD1 pathway. Reason: Consistent with A20 role in negative regulation of PRR signaling. NOD1 pathway regulation is part of A20 core innate immune regulatory function. |
| GO:0070433 negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from Ensembl Compara. A20 negatively regulates NOD2 signaling. Reactome annotates A20 in the NOD1/2 signaling pathway. A20 deubiquitinates RIPK2 downstream of NOD2. Reason: Consistent with A20 core function in innate immune signaling regulation. Supported by Reactome pathway annotation. |
| GO:2000347 positive regulation of hepatocyte proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from Ensembl Compara. A20 protects hepatocytes from TNF-induced death, which may indirectly promote hepatocyte survival/proliferation. Reason: Pleiotropic downstream effect. Hepatocyte proliferation regulation is an indirect consequence of A20 anti-apoptotic/anti-inflammatory function. |
| GO:2001237 negative regulation of extrinsic apoptotic signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated methods. A20 inhibits extrinsic apoptosis by editing ubiquitin chains on RIPK1, preventing death complex formation. More specific annotation via death domain receptors is also present (IDA). Reason: Correct. A20 inhibits extrinsic apoptotic signaling through RIPK1 ubiquitin editing. Consistent with IDA annotation for the more specific via death domain receptors term. |
| GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway | TAS Reactome:R-HSA-5357905 | ACCEPT | Summary: TAS from Reactome pathway "Regulation of TNFR1 signaling". A20 is a key component of TNFR1 signaling regulation, editing ubiquitin chains on RIPK1 in the TNF receptor complex. Reason: Core function. A20 directly regulates TNFR1 signaling through ubiquitin editing of RIPK1. Well-supported by Reactome pathway analysis. |
| GO:0016579 protein deubiquitination | TAS Reactome:R-HSA-5688426 | ACCEPT | Summary: TAS from Reactome "Deubiquitination" pathway. Core enzymatic function. Reason: Correct. Core enzymatic activity of A20. |
| GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway | TAS Reactome:R-HSA-168638 | ACCEPT | Summary: TAS from Reactome "NOD1/2 Signaling Pathway". A20 participates in NLR signaling by negatively regulating NOD1/2 pathway activation. Reason: Correct. A20 is a component of NLR signaling pathway as a negative regulator. Reactome places A20 in the NOD1/2 pathway for RIPK2 deubiquitination. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IDA PMID:18223652 T cell antigen receptor stimulation induces MALT1 paracaspas... | ACCEPT | Summary: IDA from PMID:18223652. MALT1 paracaspase cleavage of A20 during TCR stimulation disrupts A20 NF-kB inhibitory function, leading to increased NF-kB activation. This demonstrates A20 is required for NF-kB suppression during T cell activation. Reason: Core function. The fact that MALT1 cleaves A20 to relieve NF-kB inhibition during T cell activation confirms A20 as an active NF-kB suppressor. Supporting Evidence: PMID:18223652 T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20 |
| GO:0061578 K63-linked deubiquitinase activity | EXP PMID:14748687 Zinc-finger protein A20, a regulator of inflammation and cel... | ACCEPT | Summary: EXP evidence for K63-linked deubiquitinase activity. Evans et al. (2004) first demonstrated A20 deubiquitinase activity using biochemical assays. Cys103 was identified as the catalytic residue. Reason: Core enzymatic function. This is the first experimental demonstration of A20 deubiquitinase activity. K63-linked chain cleavage is the primary in vivo specificity. Supporting Evidence: PMID:14748687 Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity |
| GO:0061578 K63-linked deubiquitinase activity | TAS Reactome:R-HSA-5357845 | ACCEPT | Summary: TAS from Reactome "K63polyUb-RIPK1 is deubiquitinated". A20 removes K63-linked polyubiquitin from RIPK1. Reason: Correct. Reactome pathway annotation consistent with experimental evidence for K63-linked DUB activity on RIPK1. |
| GO:0061578 K63-linked deubiquitinase activity | TAS Reactome:R-HSA-5690856 | ACCEPT | Summary: TAS from Reactome "TNFAIP3 (A20) deubiquitinates K63polyUb-RIPK1". Reason: Correct. Consistent with EXP and other TAS evidence. |
| GO:0061578 K63-linked deubiquitinase activity | TAS Reactome:R-HSA-8869506 | ACCEPT | Summary: TAS from Reactome "TNFAIP3 in OTUD7B:TNFAIP3:ZRANB1 deubiquitinates K63polyUb-TRAF6". A20 also deubiquitinates K63-linked chains on TRAF6 as part of a complex. Reason: Correct. TRAF6 is a well-characterized substrate for A20 K63-linked deubiquitination. |
| GO:0032691 negative regulation of interleukin-1 beta production | IMP PMID:28094437 The deubiquitinating enzyme, ubiquitin-specific peptidase 50... | KEEP AS NON CORE | Summary: IMP evidence. A20 mutations lead to increased IL-1beta production, demonstrating A20 negatively regulates IL-1beta. This is consistent with A20 suppression of NF-kB and NLRP3 inflammasome. Reason: Downstream consequence of NF-kB and inflammasome regulation. Supported by mutant phenotype but represents a pleiotropic effect rather than direct molecular function. |
| GO:0004843 cysteine-type deubiquitinase activity | IMP PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downre... | ACCEPT | Summary: IMP from Wertz et al. Nature 2004. Mutagenesis of Cys103 abolished deubiquitinase activity, and mutations in zinc finger cysteines abolished ubiquitin ligase activity. This landmark paper established the dual enzymatic nature of A20. Reason: Core enzymatic function. The Wertz et al. 2004 paper is the definitive study establishing A20 as a ubiquitin-editing enzyme with both DUB and E3 activities. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5357845 | ACCEPT | Summary: TAS from Reactome. A20 functions in the cytosol at receptor-proximal signaling complexes. Reason: Correct. Cytosol is the specific subcellular compartment where A20 edits ubiquitin chains on signaling adaptors. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5690827 | ACCEPT | Summary: TAS from Reactome "TNFAIP3 (A20) ubiquitinates RIPK1". Reason: Correct. Consistent with cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5690845 | ACCEPT | Summary: TAS from Reactome "TNIPs bind TNFAIP3 (A20)". Reason: Correct. A20-TNIP interaction occurs in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5690856 | ACCEPT | Summary: TAS from Reactome for K63polyUb-RIPK1 deubiquitination in cytosol. Reason: Correct. Cytosolic deubiquitination of RIPK1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5690870 | ACCEPT | Summary: TAS from Reactome for TRAF6 deubiquitination in cytosol. Reason: Correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5693055 | ACCEPT | Summary: TAS from Reactome "TAX1BP1:TNFAIP3(A20) binds RIPK1-containing complexes". Reason: Correct. TAX1BP1-A20 complex functions in cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5693108 | ACCEPT | Summary: TAS from Reactome for K48-linked ubiquitination of RIPK1 in cytosol. Reason: Correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-688136 | ACCEPT | Summary: TAS from Reactome "TNFAIP3 (A20) deubiquitinates RIP2". Reason: Correct. A20 deubiquitinates RIPK2 in the cytosol during NOD signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8869506 | ACCEPT | Summary: TAS from Reactome for TRAF6 deubiquitination complex in cytosol. Reason: Correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-937337 | ACCEPT | Summary: TAS from Reactome "TAX1BP1:A20 inhibit TBK1/IKKi K63-polyubiquitination". Reason: Correct. A20-TAX1BP1 complex inhibits TBK1/IKKi ubiquitination in cytosol, relevant to antiviral innate immune signaling regulation. |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity... | ACCEPT | Summary: IDA from Mevissen et al. Cell 2013. Comprehensive characterization of OTU family DUB specificity showing A20 can cleave K11, K48, and K63 chains. This study used ubiquitin chain restriction analysis to demonstrate linkage specificity. Reason: Core enzymatic function. Detailed biochemical characterization of A20 DUB specificity using purified enzyme and defined ubiquitin chain substrates. Supporting Evidence: PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis |
| GO:0035871 protein K11-linked deubiquitination | IDA PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity... | ACCEPT | Summary: IDA from Mevissen et al. 2013. A20 can cleave K11-linked ubiquitin chains in vitro. However, the in vivo relevance of K11 chain cleavage is less clear than K63 chain cleavage. Reason: Experimentally demonstrated. While K63 cleavage is the primary in vivo activity, K11 chain cleavage is a validated biochemical activity of A20 OTU domain. Supporting Evidence: PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis |
| GO:0071108 protein K48-linked deubiquitination | IDA PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity... | ACCEPT | Summary: IDA from Mevissen et al. 2013. A20 can cleave K48-linked chains in vitro. UniProt confirms A20 can deubiquitinate K48 chains in vitro. Reason: Experimentally demonstrated biochemical activity, though K63 cleavage is the primary in vivo specificity. K48 chain cleavage may contribute to ubiquitin editing function. Supporting Evidence: PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: HDA (high-throughput direct assay) detection of A20 in B-cell exosomes by mass spectrometry. This is from a proteomic analysis of exosome contents. Reason: Detection in exosomes by mass spectrometry may reflect passive incorporation rather than functional localization. Not a core functional location. |
| GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors | IDA PMID:12167698 A20 inhibits tumor necrosis factor (TNF) alpha-induced apopt... | ACCEPT | Summary: IDA from PMID:12167698. A20 protects cells from death receptor-mediated apoptosis. A20 edits ubiquitin chains on RIPK1 in the TNFR1 complex, preventing formation of the death-inducing signaling complex (DISC). Reason: Important function. A20 prevents TNFR1-mediated apoptosis by ubiquitin editing of RIPK1, which is part of its core NF-kB/cell death regulatory function. |
| GO:0045824 negative regulation of innate immune response | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse A20 (Q60769). Core function confirmed in mouse. Reason: Core function. Mouse A20 knockout has severe innate immune dysregulation. |
| GO:0070301 cellular response to hydrogen peroxide | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse A20. A20 responds to oxidative stress signals. Reason: Not core. Response to H2O2 is a secondary/stress-related function. |
| GO:0072573 tolerance induction to lipopolysaccharide | IMP PMID:21220427 Endotoxin tolerance impairs IL-1 receptor-associated kinase ... | ACCEPT | Summary: IMP evidence. A20 is required for LPS tolerance induction -- the phenomenon where prior LPS exposure renders cells refractory to subsequent LPS stimulation. A20 is required for LPS-induced cytokine and IFN-beta production in LPS-tolerized macrophages. Reason: Important specific function. LPS tolerance is a key innate immune regulatory mechanism, and A20 has a specific required role in this process. |
| GO:2000349 negative regulation of CD40 signaling pathway | IMP PMID:12885753 A20 protects from CD40-CD40 ligand-mediated endothelial cell... | ACCEPT | Summary: IMP from PMID:12885753. A20 protects endothelial cells from CD40-CD40L-mediated activation. A20 overexpression inhibited CD40-mediated NF-kB activation. Reason: Consistent with A20 core function of NF-kB suppression. CD40 signals through TRAF2/TRAF6 to NF-kB, and A20 targets these adaptors. Supporting Evidence: PMID:12885753 A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis |
| GO:2000352 negative regulation of endothelial cell apoptotic process | IDA PMID:12885753 A20 protects from CD40-CD40 ligand-mediated endothelial cell... | KEEP AS NON CORE | Summary: IDA from PMID:12885753. A20 protects endothelial cells from CD40-mediated apoptosis. Reason: Cell-type specific effect. A20 anti-apoptotic function in endothelial cells is a downstream consequence of NF-kB regulation rather than a core molecular function. Supporting Evidence: PMID:12885753 A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis |
| GO:0002237 response to molecule of bacterial origin | IDA PMID:19912257 A20 is an early responding negative regulator of Toll-like r... | ACCEPT | Summary: IDA evidence. A20 is induced by and responds to bacterial molecules through TLR signaling. Reason: A20 is an NF-kB-inducible gene that is directly induced by bacterial products via TLR signaling and functions to terminate the resulting inflammatory response. |
| GO:0071222 cellular response to lipopolysaccharide | IDA PMID:19912257 A20 is an early responding negative regulator of Toll-like r... | ACCEPT | Summary: IDA evidence for cellular response to LPS. A20 is rapidly induced by LPS stimulation and functions to terminate TLR4-NF-kB signaling. Reason: Core pathway involvement. A20 is a canonical LPS-responsive gene induced as negative feedback to terminate TLR4-NF-kB signaling. |
| GO:0002020 protease binding | IPI PMID:18223652 T cell antigen receptor stimulation induces MALT1 paracaspas... | ACCEPT | Summary: IPI for binding to MALT1 paracaspase (Q9UDY8). A20 is a substrate of MALT1 paracaspase, which cleaves A20 upon TCR stimulation to relieve NF-kB inhibition. Reason: Functionally significant interaction. A20 binding to MALT1 is important for TCR signaling regulation. More informative than generic protein binding. Supporting Evidence: PMID:18223652 T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20 |
| GO:0004843 cysteine-type deubiquitinase activity | TAS PMID:20392859 The A20 deubiquitinase activity negatively regulates LMP1 ac... | ACCEPT | Summary: TAS from review article PMID:20392859 documenting A20 DUB activity. Reason: Correct. Core enzymatic function. Consistent with IDA and IBA evidence. |
| GO:0005515 protein binding | IPI PMID:15142865 A20 inhibits toll-like receptor 2- and 4-mediated interleuki... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with ITCH (Q8IUC6). A20 interacts with ITCH E3 ligase as part of the ubiquitin-editing complex (A20-TAX1BP1-RNF11-ITCH). Reason: Protein binding is uninformative. The A20-ITCH interaction is functionally significant but should use more specific terms. |
| GO:0005515 protein binding | IPI PMID:15474016 A20 is a potent inhibitor of TLR3- and Sendai virus-induced ... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with TNIP1, TNIP2, TAX1BP1, IKBKG. These are key functional partners of A20 in the NF-kB regulatory complex. Reason: Protein binding is uninformative. These interactions are core to A20 function but generic protein binding adds no value. |
| GO:0005515 protein binding | IPI PMID:20392859 The A20 deubiquitinase activity negatively regulates LMP1 ac... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with IRF7 (Q92985). A20 may modulate interferon regulatory factor signaling. Reason: Protein binding is uninformative. |
| GO:0016579 protein deubiquitination | TAS PMID:20392859 The A20 deubiquitinase activity negatively regulates LMP1 ac... | ACCEPT | Summary: TAS from review. Protein deubiquitination is a core function. Reason: Correct. Core enzymatic function. |
| GO:0031397 negative regulation of protein ubiquitination | IDA PMID:20392859 The A20 deubiquitinase activity negatively regulates LMP1 ac... | ACCEPT | Summary: IDA evidence. A20 promotes disassembly of E2-E3 ubiquitin ligase complexes, negatively regulating ubiquitination of signaling proteins in the TNFR1 and IL-1R pathways. Reason: Important aspect of A20 function. A20 not only deubiquitinates substrates but also disrupts E2-E3 complexes (TRAF6, TRAF2, BIRC2 with UBE2N and UBE2D3), preventing further ubiquitination. |
| GO:0032703 negative regulation of interleukin-2 production | IMP PMID:18223652 T cell antigen receptor stimulation induces MALT1 paracaspas... | KEEP AS NON CORE | Summary: IMP evidence. MALT1 cleavage of A20 during TCR signaling leads to increased IL-2 production, demonstrating A20 normally suppresses IL-2 production. Reason: Downstream consequence of NF-kB regulation during T cell activation. IL-2 is an NF-kB target gene, so A20 indirectly suppresses its production. Supporting Evidence: PMID:18223652 T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20 |
| GO:0034136 negative regulation of toll-like receptor 2 signaling pathway | NAS PMID:15142865 A20 inhibits toll-like receptor 2- and 4-mediated interleuki... | ACCEPT | Summary: NAS from PMID:15142865. A20 negatively regulates TLR2 signaling as part of its broad role in TLR pathway regulation. Reason: Consistent with A20 core function as negative regulator of TLR signaling. TLR2 signals through TRAF6, a known A20 substrate. |
| GO:0034140 negative regulation of toll-like receptor 3 signaling pathway | IDA PMID:15474016 A20 is a potent inhibitor of TLR3- and Sendai virus-induced ... | ACCEPT | Summary: IDA evidence for A20 negative regulation of TLR3 signaling. Reason: Core function. TLR3 pathway regulation is part of A20 broad innate immune regulatory function. |
| GO:0034144 negative regulation of toll-like receptor 4 signaling pathway | NAS PMID:15142865 A20 inhibits toll-like receptor 2- and 4-mediated interleuki... | ACCEPT | Summary: NAS from PMID:15142865. A20 negatively regulates TLR4 signaling. LPS (TLR4 ligand) is one of the most studied A20 activating stimuli. Reason: Core function. TLR4-LPS signaling is one of the best-characterized pathways regulated by A20. |
| GO:0043130 ubiquitin binding | IPI PMID:19285159 Identification of polyubiquitin binding proteins involved in... | ACCEPT | Summary: IPI for ubiquitin binding with ubiquitin (P0CG48). A20 ZnF4 and ZnF7 bind polyubiquitin chains. ZnF4 recognizes K63-linked chains; ZnF7 binds linear (M1-linked) chains. This non-catalytic ubiquitin binding is essential for A20 function. Reason: Core function. Ubiquitin binding via zinc fingers is essential for A20 regulatory activity, both for substrate recognition and for non-catalytic IKK inhibition. Supporting Evidence: PMID:19285159 known NF-kappaB regulators including NEMO, A20, ABIN-1, ABIN-2, optineurin and p62 were also identified |
| GO:0050691 regulation of defense response to virus by host | NAS PMID:15142865 A20 inhibits toll-like receptor 2- and 4-mediated interleuki... | KEEP AS NON CORE | Summary: NAS evidence. A20 modulates antiviral signaling by regulating TLR3 and RIG-I/MDA5 pathways that sense viral nucleic acids. Reason: Pleiotropic consequence of A20 innate immune regulation. Antiviral defense regulation is an indirect effect of TLR/RLR pathway modulation. |
| GO:0071222 cellular response to lipopolysaccharide | IDA PMID:21220427 Endotoxin tolerance impairs IL-1 receptor-associated kinase ... | ACCEPT | Summary: IDA evidence for LPS response, specifically in the context of LPS tolerance. A20 is required for LPS tolerance. Reason: Correct. A20 mediates LPS tolerance response. Important and specific function. |
| GO:0001922 B-1 B cell homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse A20 (Q60769). Mouse A20 deficiency causes B-1 B cell abnormalities. Reason: Pleiotropic immune consequence of A20 deficiency. Not core molecular function. |
| GO:0002634 regulation of germinal center formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse. A20 regulates germinal center formation through immune cell regulation. Reason: Pleiotropic downstream effect in adaptive immunity. |
| GO:0032715 negative regulation of interleukin-6 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse. A20 deficiency leads to elevated IL-6. Reason: Downstream effect of NF-kB regulation. IL-6 is an NF-kB target gene. |
| GO:0032720 negative regulation of tumor necrosis factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse. A20 deficiency leads to elevated TNF production. Reason: Downstream effect. TNF is an NF-kB target gene. A20 suppresses TNF production indirectly through NF-kB inhibition. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IDA PMID:21127049 Role of the A20-TRAF6 axis in lipopolysaccharide-mediated os... | ACCEPT | Summary: IDA evidence for negative regulation of NF-kB. A20 inhibits RANKL-induced NF-kB activation in osteoclasts. Reason: Core function. Additional experimental evidence confirming A20 NF-kB suppression in a different cell type context. |
| GO:0045732 positive regulation of protein catabolic process | IDA PMID:21127049 Role of the A20-TRAF6 axis in lipopolysaccharide-mediated os... | ACCEPT | Summary: IDA evidence. A20 promotes proteasomal degradation of signaling substrates through K48-linked ubiquitination. Reason: Correct. A20 E3 ligase activity adds K48 chains to promote proteasomal degradation. |
| GO:0045779 negative regulation of bone resorption | NAS PMID:21127049 Role of the A20-TRAF6 axis in lipopolysaccharide-mediated os... | KEEP AS NON CORE | Summary: NAS evidence. A20 inhibits RANKL-induced osteoclast formation, which would reduce bone resorption. Reason: Pleiotropic tissue-specific effect. Bone resorption regulation is an indirect consequence of NF-kB suppression in osteoclasts. |
| GO:0048662 negative regulation of smooth muscle cell proliferation | IDA PMID:16816117 A20, a modulator of smooth muscle cell proliferation and apo... | KEEP AS NON CORE | Summary: IDA evidence. A20 inhibits smooth muscle cell proliferation, relevant to vascular biology and neointima formation. Reason: Pleiotropic tissue-specific effect. SMC proliferation regulation is an indirect consequence of NF-kB suppression in vascular cells. |
| GO:0050728 negative regulation of inflammatory response | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse A20. Core anti-inflammatory function. Reason: Core function. Consistent with IBA evidence. |
| GO:0050869 negative regulation of B cell activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse. A20 regulates B cell activation. Reason: Pleiotropic immune consequence. B cell regulation is downstream of NF-kB suppression. |
| GO:0061043 regulation of vascular wound healing | NAS PMID:16816117 A20, a modulator of smooth muscle cell proliferation and apo... | KEEP AS NON CORE | Summary: NAS evidence. A20 regulates vascular wound healing by inhibiting smooth muscle cell proliferation and NF-kB-driven inflammatory responses in vascular cells. Reason: Pleiotropic tissue-specific effect. Vascular wound healing regulation is an indirect consequence of A20 anti-inflammatory function. |
| GO:0071222 cellular response to lipopolysaccharide | IDA PMID:21127049 Role of the A20-TRAF6 axis in lipopolysaccharide-mediated os... | ACCEPT | Summary: IDA evidence for LPS response in context of osteoclast biology. Reason: Correct. A20 is induced by and responds to LPS. |
| GO:0090291 negative regulation of osteoclast proliferation | NAS PMID:21127049 Role of the A20-TRAF6 axis in lipopolysaccharide-mediated os... | KEEP AS NON CORE | Summary: NAS evidence. A20 inhibits osteoclast proliferation/formation. Reason: Pleiotropic tissue-specific effect. Osteoclast regulation is downstream of NF-kB suppression by A20. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downre... | ACCEPT | Summary: IDA from Wertz et al. Nature 2004. ZnF4 domain mediates E3 ubiquitin ligase activity, adding K48-linked polyubiquitin chains to RIPK1. Mutations in ZnF4 cysteines (C624, C627) abolished this activity. Reason: Core enzymatic function. The E3 ligase activity of ZnF4 is one of the two defining enzymatic activities of A20, experimentally demonstrated by mutagenesis. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downre... | ACCEPT | Summary: IDA from Wertz et al. 2004. Cys103 mutation abolished DUB activity. Reason: Core enzymatic function. Definitive experimental demonstration. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IDA PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downre... | ACCEPT | Summary: IDA from Wertz et al. 2004. Both DUB and E3 domains contribute to NF-kB suppression. Reason: Core function. The landmark paper establishing the mechanism of A20 NF-kB regulation. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0070536 protein K63-linked deubiquitination | IDA PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downre... | ACCEPT | Summary: IDA from Wertz et al. 2004. A20 OTU domain removes K63-linked polyubiquitin from RIPK1. Reason: Core enzymatic function. K63-linked deubiquitination of RIPK1 is the primary in vivo DUB activity of A20. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downre... | ACCEPT | Summary: IDA from Wertz et al. 2004. A20 ZnF4 adds K48-linked polyubiquitin to RIPK1, targeting it for proteasomal degradation. This is the ubiquitin ligase arm of the ubiquitin-editing mechanism. Reason: Core enzymatic function. K48-linked ubiquitination by ZnF4 is the E3 ligase arm of A20 ubiquitin-editing, complementing the OTU deubiquitinase activity. Supporting Evidence: PMID:15258597 De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling |
| GO:0005515 protein binding | IPI PMID:11463333 Isolation and characterization of two novel A20-like protein... | MARK AS OVER ANNOTATED | Summary: IPI protein binding with TRAF4 (Q9Y4K3). From the study that also established A20 nuclear/cytoplasmic localization. Reason: Protein binding is uninformative. |
| GO:0005634 nucleus | IDA PMID:11463333 Isolation and characterization of two novel A20-like protein... | ACCEPT | Summary: IDA for nuclear localization. Evans et al. (2001) showed A20 localizes to both cytoplasm and nucleus using immunofluorescence. Reason: Primary experimental evidence for nuclear localization. While cytoplasm is the main functional location, nuclear localization is directly demonstrated. Supporting Evidence: PMID:11463333 The zinc finger molecule A20 is an important negative regulator of NF-kappa B |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IDA PMID:11463333 Isolation and characterization of two novel A20-like protein... | ACCEPT | Summary: IDA for NF-kB negative regulation from Evans et al. 2001. Reason: Core function. Additional experimental support for A20 NF-kB suppression. |
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)