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 (  , ). Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD) ( , ). 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 (, ). 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 . The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction ( ). 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 . Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols . Mediates polyubiquitination of INSIG2 at 'Cys-215' in some tissues, leading to its degradation . Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex . Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation . Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor . 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 . Regulates NF-kappa-B and MAPK signaling pathways by mediating 'Lys-27'-linked polyubiquitination of TAB3 and promoting subsequent TAK1/MAP3K7 activation .
Subcellular locations: Endoplasmic reticulum membrane
Palmitoylation promotes localization to the peripheral endoplasmic reticulum.