E3 ubiquitin-protein ligase that may mediate ubiquitination of TFRC and CD86, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates (PubMed:14722266, PubMed:16428329). Together with GOPC/CAL mediates the ubiquitination and lysosomal degradation of CFTR (PubMed:23818989). Ubiquitinates and therefore mediates the degradation of DLG1 (PubMed:17980554). Regulates the intracellular trafficking and secretion of alpha1-antitrypsin/SERPINA1 and HP/haptoglobin via ubiquitination and degradation of the cargo receptor ERGIC3 (PubMed:31142615). Negatively regulates the antiviral and antibacterial immune response by repression of the NF-kB and type 1 IFN signaling pathways, via MARCHF2-mediated K48-linked polyubiquitination of IKBKG/NEMO, resulting in its proteosomal degradation (PubMed:32935379). May be involved in endosomal trafficking through interaction with STX6 (PubMed:15689499). (Microbial infection) Positively regulates the degradation of Vesicular stomatitis virus (VSV) G protein via the lysosomal degradation pathway (PubMed:29573664). Represses HIV-1 viral production and may inhibit the translocation of HIV-1 env to the cell surface, resulting in decreased viral cell-cell transmission (PubMed:29573664). S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. Protein modification; protein ubiquitination. Interacts with STX6; the interaction promotes MARCHF2-mediated ubiquitination and degradation of CFTR (PubMed:23818989). Interacts with MARCHF3 (PubMed:16428329). Interacts with GOPC/CAL; the interaction leads to CFTR ubiquitination and degradation (PubMed:23818989). Interacts with CFTR; the interaction leads to CFTR ubiqtuitination and degradation (PubMed:23818989). Interacts (via PDZ domain) with DLG1 (via PDZ domains); the interaction leads to DLG1 ubiqtuitination and degradation (PubMed:17980554). Interacts with ERGIC3 (PubMed:31142615). Interacts with ADRB2 (PubMed:23166351). Interacts with IKBKG/NEMO; during the late stages of macrophage viral and bacterial infection; the interaction leads to ubiquitination and degradation of IKBKG/NEMO (PubMed:32935379). Broadly expressed. (Microbial infection) Induced by HIV-1 infection. The RING-CH-type zinc finger domain is required for E3 ligase activity.