Protein: Tumor necrosis factor alpha-induced protein 3 (TNF alpha-induced protein 3) (EC 2.3.2.-) (EC 3.4.19.12) (Putative DNA-binding protein A20) (Zinc finger protein A20) (Q60769)
Organism: Mus musculus (Mouse)
Function: Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate 'Lys-11'-, 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Required for LPS-induced production of pro-inflammatory cytokines and IFN beta in LPS-tolerized macrophages.
Subcellular location: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. Lysosome {ECO:0000250}.
Sequence: MAEQLLPQALYLSNMRKAVKIRERTPEDIFKPTNGIIYHFKTMHRYTLEMFRTCQFCPQFREIIHKALIDRSVQASLESQKKLNWCREVRKLVALKTNGDGNCLMHAACQYMWGVQDTDLVLRKALCSTLKETDTRNFKFRWQLESLKSQEFVETGLCYDTRNWNDEWDNLVKMASADTPAARSGLQYNSLEEIHIFVLSNILRRPIIVISDKMLRSLESGSNFAPLKVGGIYLPLHWPAQECYRYPIVLGYDSQHFVPLVTLKDSGPELRAVPLVNRDRGRFEDLKVHFLTDPENEMKEKLLKEYLIVMEIPVQGWDHGTTHLINAAKLDEANLPKEINLVDDYFELVQHEYKKWQENSDQARRAAHAQNPLEPSTPQLSLMDIKCETPNCPFFMSVNTQPLCHECSERRQKNQSKLPKLNSKLGPEGLPGVGLGSSNWSPEETAGGPHSAPPTAPSLFLFSETTAMKCRSPGCPFTLNVQHNGFCERCHARQINASHTADPGKCQACLQDVTRTFNGICSTCFKRTTAEPSSSLTSSIPASCHQRSKSDPSQLIQSLTPHSCHRTGNVSPSGCLSQAARTPGDRAGTSKCRKAGCMYFGTPENKGFCTLCFIEYRENKQSVTASEKAGSPAPRFQNNVPCLGRECGTLGSTMFEGYCQKCFIEAQNQRFHEARRTEEQLRSSQHRDMPRTTQVASRLKCARASCKNILACRSEELCMECQHLSQRVGSVAHRGEPTPEEPPKQRCRAPACDHFGNAKCNGYCNECYQFKQMYG
InterPro domains: - IPR003323: OTU domain (domain) [92-263]
- IPR002653: Zinc finger, A20-type (domain) [381-775]
- IPR051346: OTU Domain-Containing Deubiquitinase (family) [33-622]
Interaction partners: - TNFAIP3-interacting protein 1
- TNF receptor-associated factor 6
- Tumor necrosis factor
- Tumor necrosis factor receptor superfamily member 1A
- TNFAIP3-interacting protein 2
- Receptor-interacting serine/threonine-protein kinase 1
- Tax1-binding protein 1 homolog
- RING finger protein 11
- Receptor-interacting serine/threonine-protein kinase 2
- TNF receptor-associated factor 2
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0016787 (hydrolase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0032182 (ubiquitin-like protein binding), GO:0008233 (peptidase activity), GO:0019787 (ubiquitin-like protein transferase activity), GO:0042802 (identical protein binding), GO:0043621 (protein self-association), GO:0019899 (enzyme binding), GO:0004842 (ubiquitin-protein transferase activity), GO:0008234 (cysteine-type peptidase activity), GO:0019783 (ubiquitin-like protein peptidase activity), GO:0002020 (protease binding), GO:0043130 (ubiquitin binding), GO:0101005 (deubiquitinase activity), GO:0004843 (cysteine-type deubiquitinase activity), GO:0061578 (K63-linked deubiquitinase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0023052 (signaling), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0044419 (biological process involved in interspecies interaction between organisms), GO:0002376 (immune system process), GO:0048519 (negative regulation of biological process), GO:0009605 (response to external stimulus), GO:0048856 (anatomical structure development), GO:0023057 (negative regulation of signaling), GO:0042221 (response to chemical), GO:0002684 (positive regulation of immune system process), GO:0006807 (nitrogen compound metabolic process), GO:0002507 (tolerance induction), GO:0051241 (negative regulation of multicellular organismal process), GO:0051239 (regulation of multicellular organismal process), GO:0009892 (negative regulation of metabolic process), GO:0002683 (negative regulation of immune system process), GO:0009607 (response to biotic stimulus), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0002253 (activation of immune response), GO:0048523 (negative regulation of cellular process), GO:0051707 (response to other organism), GO:0007165 (signal transduction), GO:0007275 (multicellular organism development), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0002682 (regulation of immune system process), GO:0071704 (organic substance metabolic process), GO:0002520 (immune system development), GO:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0048585 (negative regulation of response to stimulus), GO:0007154 (cell communication), GO:0044238 (primary metabolic process), GO:0060759 (regulation of response to cytokine stimulus), GO:0009968 (negative regulation of signal transduction), GO:0032103 (positive regulation of response to external stimulus), GO:0043207 (response to external biotic stimulus), GO:0060548 (negative regulation of cell death), GO:0080134 (regulation of response to stress), GO:0048731 (system development), GO:0009966 (regulation of signal transduction), GO:0060255 (regulation of macromolecule metabolic process), GO:0032101 (regulation of response to external stimulus), GO:0001817 (regulation of cytokine production), GO:0002218 (activation of innate immune response), GO:0031348 (negative regulation of defense response), GO:0009894 (regulation of catabolic process), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0050778 (positive regulation of immune response), GO:0031349 (positive regulation of defense response), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0002764 (immune response-regulating signaling pathway), GO:0010648 (negative regulation of cell communication), GO:0051172 (negative regulation of nitrogen compound metabolic process), GO:1901564 (organonitrogen compound metabolic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0044092 (negative regulation of molecular function), GO:0008285 (negative regulation of cell population proliferation), GO:0019538 (protein metabolic process), GO:1901700 (response to oxygen-containing compound), GO:0030522 (intracellular receptor signaling pathway), GO:0043170 (macromolecule metabolic process), GO:0071216 (cellular response to biotic stimulus), GO:0010033 (response to organic substance), GO:0002831 (regulation of response to biotic stimulus), GO:0050776 (regulation of immune response), GO:0042127 (regulation of cell population proliferation), GO:0002757 (immune response-activating signaling pathway), GO:0010941 (regulation of cell death), GO:0010646 (regulation of cell communication), GO:0002833 (positive regulation of response to biotic stimulus), GO:0070887 (cellular response to chemical stimulus), GO:0009617 (response to bacterium), GO:0051090 (regulation of DNA-binding transcription factor activity), GO:0009889 (regulation of biosynthetic process), GO:0039532 (negative regulation of viral-induced cytoplasmic pattern recognition receptor signaling pathway), GO:0001818 (negative regulation of cytokine production), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:0002832 (negative regulation of response to biotic stimulus), GO:0009896 (positive regulation of catabolic process), GO:0032102 (negative regulation of response to external stimulus), GO:0031347 (regulation of defense response), GO:0050687 (negative regulation of defense response to virus), GO:0045089 (positive regulation of innate immune response), GO:0002758 (innate immune response-activating signaling pathway), GO:0001959 (regulation of cytokine-mediated signaling pathway), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0032663 (regulation of interleukin-2 production), GO:0043069 (negative regulation of programmed cell death), GO:0051246 (regulation of protein metabolic process), GO:0043067 (regulation of programmed cell death), GO:0002237 (response to molecule of bacterial origin), GO:0048662 (negative regulation of smooth muscle cell proliferation), GO:0010468 (regulation of gene expression), GO:0048660 (regulation of smooth muscle cell proliferation), GO:0043412 (macromolecule modification), GO:0002753 (cytosolic pattern recognition receptor signaling pathway), GO:0051252 (regulation of RNA metabolic process), GO:1901701 (cellular response to oxygen-containing compound), GO:0010629 (negative regulation of gene expression), GO:0032703 (negative regulation of interleukin-2 production), GO:0071219 (cellular response to molecule of bacterial origin), GO:0032496 (response to lipopolysaccharide), GO:0045088 (regulation of innate immune response), GO:0006508 (proteolysis), GO:0042176 (regulation of protein catabolic process), GO:0071310 (cellular response to organic substance), GO:0051248 (negative regulation of protein metabolic process), GO:0062207 (regulation of pattern recognition receptor signaling pathway), GO:2001234 (negative regulation of apoptotic signaling pathway), GO:1902532 (negative regulation of intracellular signal transduction), GO:0032652 (regulation of interleukin-1 production), GO:2001233 (regulation of apoptotic signaling pathway), GO:0043433 (negative regulation of DNA-binding transcription factor activity), GO:0036211 (protein modification process), GO:0033993 (response to lipid), GO:0050688 (regulation of defense response to virus), GO:0031326 (regulation of cellular biosynthetic process), GO:0032692 (negative regulation of interleukin-1 production), GO:0051247 (positive regulation of protein metabolic process), GO:0031664 (regulation of lipopolysaccharide-mediated signaling pathway), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0045732 (positive regulation of protein catabolic process), GO:1902531 (regulation of intracellular signal transduction), GO:0071222 (cellular response to lipopolysaccharide), GO:0042981 (regulation of apoptotic process), GO:0039531 (regulation of viral-induced cytoplasmic pattern recognition receptor signaling pathway), GO:0002221 (pattern recognition receptor signaling pathway), GO:0031400 (negative regulation of protein modification process), GO:0032691 (negative regulation of interleukin-1 beta production), GO:2001141 (regulation of RNA biosynthetic process), GO:0032651 (regulation of interleukin-1 beta production), GO:0070646 (protein modification by small protein removal), GO:0031399 (regulation of protein modification process), GO:0043066 (negative regulation of apoptotic process), GO:0070647 (protein modification by small protein conjugation or removal), GO:0006355 (regulation of DNA-templated transcription), GO:0071396 (cellular response to lipid), GO:2001237 (negative regulation of extrinsic apoptotic signaling pathway), GO:0032088 (negative regulation of NF-kappaB transcription factor activity), GO:0043124 (negative regulation of I-kappaB kinase/NF-kappaB signaling), GO:0043122 (regulation of I-kappaB kinase/NF-kappaB signaling), GO:0010803 (regulation of tumor necrosis factor-mediated signaling pathway), GO:2001236 (regulation of extrinsic apoptotic signaling pathway), GO:1904036 (negative regulation of epithelial cell apoptotic process), GO:1902041 (regulation of extrinsic apoptotic signaling pathway via death domain receptors), GO:1902042 (negative regulation of extrinsic apoptotic signaling pathway via death domain receptors), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0032446 (protein modification by small protein conjugation), GO:1904035 (regulation of epithelial cell apoptotic process), GO:1903320 (regulation of protein modification by small protein conjugation or removal), GO:1903321 (negative regulation of protein modification by small protein conjugation or removal), GO:0016579 (protein deubiquitination), GO:2000351 (regulation of endothelial cell apoptotic process), GO:0071108 (protein K48-linked deubiquitination), GO:0031397 (negative regulation of protein ubiquitination), GO:0070536 (protein K63-linked deubiquitination), GO:0031396 (regulation of protein ubiquitination), GO:0016567 (protein ubiquitination), GO:2000352 (negative regulation of endothelial cell apoptotic process), GO:0000209 (protein polyubiquitination), GO:0070936 (protein K48-linked ubiquitination)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0005634 (nucleus)