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View Proteins belonging to: The Insulin-induced Gene 1 & 2 Protein (INSIG) Family

9.B.418.  The Insulin-induced Gene 1 & 2 Protein (INSIG) Family

INSIG 1 and 2 are oxysterol-binding proteins that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR (Yabe et al. 2002). It 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 (Xu et al. 2020). It binds oxysterols, including 22-hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (Radhakrishnan et al. 2007). In the presence of oxysterol, it 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 (PubMed:32322062). Sterol deprivation or phosphorylation by PCK1 reduces oxysterol-binding, disrupting the interaction between INSIG2 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (Xu et al. 2020). It also regulates cholesterol synthesis by regulating the degradation of HMGCR: it initiates the sterol-mediated ubiquitin-mediated ER-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligase RNF139 (Gong et al. 2006, Jo et al. 2011).

The cryo-EM structure of human SCAP bound to Insig-2 suggests how their interaction is regulated by sterols (Yan et al. 2021). The sterol regulatory element-binding protein (SREBP) pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1 and -2, are membrane-embedded sterol sensors. The 25-hydroxycholesterol (25HC)-dependent association of Scap and Insig acts as the master switch for the SREBP pathway. Yan et al. 2021 presented cryo-EM analyses of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 Å. The sterol-sensing domain in Scap and all six TMSs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMSs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. Unwinding of the middle of the Scap-S4 segment is crucial for 25HC binding and Insig association (Yan et al. 2021).

View Proteins belonging to: The Insulin-induced Gene 1 & 2 Protein (INSIG) Family

References associated with 9.B.418 family:

Gong, Y., J.N. Lee, M.S. Brown, J.L. Goldstein, and J. Ye. (2006). Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis. Proc. Natl. Acad. Sci. USA 103: 6154-6159. 16606821
Jo, Y., P.C. Lee, P.V. Sguigna, and R.A. DeBose-Boyd. (2011). Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8. Proc. Natl. Acad. Sci. USA 108: 20503-20508. 22143767
Radhakrishnan, A., Y. Ikeda, H.J. Kwon, M.S. Brown, and J.L. Goldstein. (2007). Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to Insig. Proc. Natl. Acad. Sci. USA 104: 6511-6518. 17428920
Wang, Y.J., Y. Bian, J. Luo, M. Lu, Y. Xiong, S.Y. Guo, H.Y. Yin, X. Lin, Q. Li, C.C.Y. Chang, T.Y. Chang, B.L. Li, and B.L. Song. (2017). Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. Nat. Cell Biol. 19: 808-819. 28604676
Xu, D., Z. Wang, Y. Xia, F. Shao, W. Xia, Y. Wei, X. Li, X. Qian, J.H. Lee, L. Du, Y. Zheng, G. Lv, J.S. Leu, H. Wang, D. Xing, T. Liang, M.C. Hung, and Z. Lu. (2020). The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 580: 530-535. 32322062
Yabe, D., M.S. Brown, and J.L. Goldstein. (2002). Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc. Natl. Acad. Sci. USA 99: 12753-12758. 12242332
Yan, R., P. Cao, W. Song, H. Qian, X. Du, H.W. Coates, X. Zhao, Y. Li, S. Gao, X. Gong, X. Liu, J. Sui, J. Lei, H. Yang, A.J. Brown, Q. Zhou, C. Yan, and N. Yan. (2021). A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols. Science 371:. 33446483