E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation (PubMed:10456327, PubMed:11724934, PubMed:12670940, PubMed:19103148, PubMed:24424410, PubMed:28604676). Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD) (PubMed:10456327, PubMed:11724934, PubMed:19103148, PubMed:24424410). The VCP/p97-AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG1 complex at the ER membrane (PubMed:16168377, PubMed:22143767). In addition, interaction of AMFR with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced HMGCR ubiquitination (PubMed:23223569). The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction (PubMed:16168377, PubMed:22143767, PubMed:23223569). In addition to ubiquitination on lysine residues, catalyzes ubiquitination on cysteine residues: together with INSIG1, mediates polyubiquitination of SOAT2/ACAT2 at 'Cys-277', leading to its degradation when the lipid levels are low (PubMed:28604676). Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols (PubMed:17043353). Mediates polyubiquitination of INSIG2 at 'Cys-215' in some tissues, leading to its degradation (PubMed:31953408). Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex (PubMed:21636303). Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation (PubMed:21636303). Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor (PubMed:10456327). In association with LMBR1L and UBAC2, negatively regulates the canonical Wnt signaling pathway in the lymphocytes by promoting the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6 (PubMed:31073040). [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-cysteine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-S-ubiquitinyl-L-cysteine. Protein modification; protein ubiquitination. Interacts with RNF5 (By similarity). Also forms an ERAD complex containing VCP/p97, NGLY1; PSMC1; SAKS1 AND RAD23B required for coupling retrotranslocation, ubiquitination and deglycosylation (By similarity). Interacts with DERL1 (PubMed:16186510). Interacts (through a region distinct from the RING finger) with UBE2G2/UBC7 (PubMed:11724934). Component of the VCP/p97-AMFR/gp78 complex that enhances VCP/p97 binding to polyubiquitinated proteins for their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway (By similarity). Interacts (via the VIM) with VCP/p97 (PubMed:16168377, PubMed:16186510). Interacts (via its membrane domain) with INSIG1; the interaction initiates the sterol-mediated ubiquitination and degradation of HMGCR by the ERAD pathway (PubMed:16168377, PubMed:22143767). Interacts with AUP1, UBE2G2 and RNF139/TRC8; interaction with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation (PubMed:23223569). Interacts with BAG6 (PubMed:21636303). Interacts with USP13 (via UBA 2 domain); the interaction is direct (PubMed:24424410). Interacts with LMBR1L (PubMed:31073040). Interacts with UBAC2 and CTNNB1 (By similarity). Interacts with C18orf32 (PubMed:29275994). Palmitoylation promotes localization to the peripheral endoplasmic reticulum. The CUE domain is required for recognition of misfolded proteins such as mutant CFTR. The VCP/p97-interacting motif (VIM) is sufficient for binding VCP/p97 to form a complex capable of transferring VCP/p97 from the cytosol to microsomes. Palmitoylation of the RING-type zing finger by ZDHHC6 promotes localization to the peripheral endoplasmic reticulum. Several sequencing errors.