E3 ubiquitin-protein ligase AMFR

Definition:

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.

References:

[1]. Jun-Shan Liang, et al. Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells. J Biol Chem. 2003 Jun 27;278(26):23984-8. [Content Brief]

[2]. Jin Huk Choi, et al. LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling. Science. 2019 May 10;364(6440):eaau0812. [Content Brief]

[3]. Yanfen Liu, et al. USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation. Elife. 2014;3:e01369. [Content Brief]

[4]. K Shimizu, et al. The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein. FEBS Lett. 1999 Aug 6;456(2):295-300. [Content Brief]

[5]. Joon No Lee, et al. Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. J Biol Chem. 2006 Dec 22;281(51):39308-15. [Content Brief]

[6]. Yong-Jian Wang, et al. Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. Nat Cell Biol. 2017 Jul;19(7):808-819. [Content Brief]

[7]. Qiuyan Wang, et al. A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation. Mol Cell. 2011 Jun 24;42(6):758-70. [Content Brief]

[8]. Michael K Pabarcus, et al. CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2009 Mar 1;483(1):66-74. [Content Brief]

[9]. Zhang-Sen Zhou, et al. Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2. Nat Commun. 2020 Jan 17;11(1):379. [Content Brief]

[10]. Youngah Jo, et al. Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8. Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20503-8. [Content Brief]

[11]. Bao-Liang Song, et al. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell. 2005 Sep 16;19(6):829-40. [Content Brief]

[12]. S Fang, et al. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14422-7. [Content Brief]

[13]. Youngah Jo, et al. Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl CoA reductase in lipid droplet-associated endoplasmic reticulum membranes. Mol Biol Cell. 2013 Feb;24(3):169-83. [Content Brief]

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