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. Deubiquinates 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. Deubiquinates 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 both 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these interaction are transient and they are lost after 1 hour of stimulation with TNF. Interacts with YWHAZ and YWHAH. Interacts with IKBKG; the interaction is induced by TNF stimulation and by polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the interaction requires TAX1BP1. Interacts with TRAF6; the interaction is inhibited by HTLV-1 protein Tax. By TNF. Belongs to the peptidase C64 family. Note: This description may include information from UniProtKB.
Molecular Function: ubiquitin thiolesterase activity; protein binding; ubiquitin binding; protein self-association; protease binding; DNA binding; zinc ion binding; ubiquitin-specific protease activity; ubiquitin-protein ligase activity; kinase binding; ligase activity
Biological Process: negative regulation of toll-like receptor 5 signaling pathway; negative regulation of smooth muscle cell proliferation; apoptosis; proteolysis; negative regulation of toll-like receptor 3 signaling pathway; negative regulation of interleukin-2 production; negative regulation of innate immune response; response to molecule of bacterial origin; negative regulation of interleukin-6 production; inflammatory response; negative regulation of bone resorption; negative regulation of chronic inflammatory response; protein deubiquitination; negative regulation of toll-like receptor 2 signaling pathway; B-1 B cell homeostasis; negative regulation of cyclin-dependent protein kinase activity; negative regulation of B cell activation; negative regulation of interleukin-1 beta production; negative regulation of I-kappaB kinase/NF-kappaB cascade; negative regulation of tumor necrosis factor production; protein oligomerization; regulation of germinal center formation; inhibition of NF-kappaB transcription factor; response to muramyl dipeptide; negative regulation of inflammatory response; negative regulation of toll-like receptor 4 signaling pathway; positive regulation of protein catabolic process; innate immune response; negative regulation of protein ubiquitination; regulation of defense response to virus by host; negative regulation of interferon type I production
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.