E3 ubiquitin-protein ligase RNF139

Definition:

E3-ubiquitin ligase; acts as a negative regulator of cell proliferation through mechanisms involving G2/M arrest and cell death. Required for MHC class I ubiquitination in cells expressing the cytomegalovirus protein US2 before dislocation from the endoplasmic reticulum (ER). Affects SREBP processing by hindering the SREBP-SCAP complex translocation from the ER to the Golgi, thereby reducing SREBF2 target gene expression. Involved in the sterol-accelerated degradation of HMGCR. This is achieved through binding of RNF139 to INSIG1 and/or INSIG2 at the ER membrane. In addition, interaction of RNF139 with AUP1 facilitates interaction of RNF139 with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase AMFR, leading to ubiquitination of HMGCR. The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction. Required for INSIG1 ubiquitination. May be required for EIF3 complex ubiquitination.

References:

[1]. Masato Irisawa, et al. The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8 hampers ER to Golgi transport of sterol regulatory element-binding protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2 cleavage. J Biol Chem. 2009 Oct 16;284(42):28995-9004. [Content Brief]

[2]. Helen R Stagg, et al. The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER. J Cell Biol. 2009 Sep 7;186(5):685-92. [Content Brief]

[3]. K L Lorick, et al. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11364-9. [Content Brief]

[4]. A Brauweiler, et al. RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene. Oncogene. 2007 Apr 5;26(16):2263-71. [Content Brief]

[5]. Jason P Lee, et al. The TRC8 ubiquitin ligase is sterol regulated and interacts with lipid and protein biosynthetic pathways. Mol Cancer Res. 2010 Jan;8(1):93-106. [Content Brief]

[6]. Robert M Gemmill, et al. The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. Oncogene. 2002 May 16;21(22):3507-16. [Content Brief]

[7]. 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]

[8]. 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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