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:16987818, PubMed:18216283). Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD) (PubMed:16987818, PubMed:18216283). 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:22863805). 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 (By similarity). The ubiquitinated HMGCR is then released from the ER by the complex into the cytosol for subsequent destruction (By similarity). 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 (By similarity). Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols (By similarity). Mediates polyubiquitination of INSIG2 at 'Cys-215' in some tissues, leading to its degradation (By similarity). Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex (By similarity). Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation (By similarity). Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor (PubMed:12650607). 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. Also forms an ERAD complex containing VCP/p97, NGLY1; PSMC1; SAKS1 AND RAD23B required for coupling retrotranslocation, ubiquitination and deglycosylation. Interacts with DERL1. Interacts (through a region distinct from the RING finger) with UBE2G2/UBC7. 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. Interacts (via the VIM) with VCP/p97. Interacts (via its membrane domain) with INSIG1; the interaction initiates the sterol-mediated ubiquitination and degradation of HMGCR by the ERAD pathway. 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 HNGCR and its subsequent proteasomal degradation (By similarity). Interacts with BAG6. Interacts with USP13 (via UBA 2 domain); the interaction is direct (By similarity). Interacts with LMBR1L, UBAC2 and CTNNB1 (PubMed:31073040). Interacts with C18orf32 (By similarity). Palmitoylation promotes localization to the peripheral endoplasmic reticulum. Expressed in heart, brain, liver, lung, skeletal muscle, kidney and testis. Not detected in spleen. 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. Mice with a conditional deletion in the liver display improved hyperlipidemia and insulin resistance: mice show elevated energy expenditure and are resistant to diet-induced obesity and glucose intolerance (PubMed:22863805). Increased stability of Hmgcr, Insig1 and Insig2 and suppression of the SREBP pathway and novo lipid biosynthesis (PubMed:22863805).