Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:
14602072, PubMed:
17028573, PubMed:
16387660, PubMed:
18718448, PubMed:
18718449, PubMed:
11046148, PubMed:
19592251, PubMed:
19116316, PubMed:
19881509, PubMed:
20491914, PubMed:
20392206, PubMed:
20068034, PubMed:
23146885, PubMed:
24790097, PubMed:
25631046). Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:
17028573, PubMed:
18718448, PubMed:
19131965, PubMed:
19881509). Involved in the control of inflammatory signaling pathways (PubMed:
19131965). Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:
19131965). Promotes the association of the complex after TNF stimulation (PubMed:
19131965). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:
19131965). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:
19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2- dependent signal transduction pathways (PubMed:
19592251). Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:
18718448, PubMed:
20491914). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:
18718448). Mediates JUN ubiquitination and degradation (By similarity). Mediates JUNB ubiquitination and degradation (PubMed:
16387660). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:
19881509). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:
19881509). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:
23146885). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:
23146885). Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:
14602072, PubMed:
23146885). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:
17028573, PubMed:
18628966, PubMed:
23886940). Ubiquitinates SNX9 (PubMed:
20491914). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:
20068034). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:
20392206). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:
25631046). Inhibits the replication of influenza A virus (IAV) via ubiquitination of IAV matrix protein 1 (M1) through 'Lys-48'-linked conjugation resulting in M1 proteasomal degradation (PubMed:
30328013).
