Insulin-induced gene 1 protein

Definition:

Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR. Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2. Binds oxysterol, including 25-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum. In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi. Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG1 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2. Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligases AMFR/gp78 and/or RNF139. Also regulates degradation of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78.

References:

[1]. Daqian Xu, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature. 2020 Apr;580(7804):530-535. [Content Brief]

[2]. Li-Ping Sun, et al. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J Biol Chem. 2005 Jul 15;280(28):26483-90. [Content Brief]

[3]. Navdar Sever, et al. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol Cell. 2003 Jan;11(1):25-33. [Content Brief]

[4]. 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]

[5]. Yi Gong, et al. Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis. Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6154-9. [Content Brief]

[6]. Yi Gong, et al. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab. 2006 Jan;3(1):15-24. [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]. Tong Yang, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell. 2002 Aug 23;110(4):489-500. [Content Brief]

[9]. 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]

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