E3 ubiquitin-protein ligase that catalyzes the ‘Lys-48’- and/or ‘Lys-63’-linked polyubiquitination of various substrates and thereby plays a role in a number of signaling pathways including autophagy, innate immunity, cell proliferation and cell death (PubMed:20019814, PubMed:30689267). Plays a role in the endosomal trafficking and degradation of membrane receptors including EGFR, FLT3, MET and CXCR4 through their polyubiquitination. Participates together with BST2 in antiviral immunity by facilitating the internalization of HIV-1 virions into intracellular vesicles leading to their lysosomal degradation (PubMed:20019814). Possesses also an antiviral activity independently of BST2 by promoting retroviral GAG proteins ubiquitination, redistribution to endo-lysosomal compartments and, ultimately, lysosomal degradation (PubMed:24852021). Catalyzes distinct types of ubiquitination on MAVS and STING1 at different phases of viral infection to promote innate antiviral response (PubMed:33139700). Mediates the ‘Lys-48’-linked ubiquitination of MAVS leading to its proteasomal degradation and ubiquitinates STING1 via ‘Lys-63’-linked polyubiquitination, critical for its oligomerization and the subsequent recruitment of TBK1 (PubMed:33139700). Plays a positive role in the autophagosome-lysosome fusion by interacting with STX17 and enhancing its stability without affecting ‘Lys-48’- or ‘Lys-63’-linked polyubiquitination levels, which in turn promotes autophagosome maturation (PubMed:32980859). Negatively regulates TLR-induced expression of proinflammatory cytokines by catalyzing ‘Lys-11’-linked ubiquitination of RAB1A and RAB13 to inhibit post-ER trafficking of TLRs to the Golgi by RAB1A and subsequently from the Golgi apparatus to the cell surface by RAB13 (PubMed:35343654).
