Insulin-induced gene 1 protein
(Redirected from INSIG1)
Insulin induced gene 1, also known as INSIG1, is a protein which in humans is encoded by the INSIG1 gene.[5][6]
INSIG1 is short for insulin-induced gene 1; it is located on chromosome 7 (7q36). This human gene encodes for a transmembrane protein of 277 amino acids with probably 6 transmembrane domains. It is localized in the endoplasmic reticulum (ER) and seems to be expressed in all tissues, especially in liver. This gene is called an insulin-induced gene because the molecule insulin can regulate it. Importantly, the protein encoded by this gene plays a critical role in regulating cholesterol concentrations in cells.
Function
[edit]- INSIG1 plays an important role in the SREBP-mediated regulation of cholesterol biosynthesis: by binding to the sterol-sensing domain of SCAP (SREBP cleavage activating protein) it makes the SCAP/SREBP complex stay longer in the ER, thus prohibiting SCAP from carrying activated SREBP to the golgi complex. This ultimately blocks SREBP from acting as a transcription factor for the SRE in the promoter region of the HMG-CoA-reductase gene and results in a decreased expression of HMG-CoA-reductase.
- INSIG1 also binds to the sterol-sensing domain of HMG-CoA-reductase, resulting in the enzyme's increased degradation.
Both functions require the binding of INSIG1 protein via the same site.
There are two other proteins whose sterol-binding sites show a great similarity to the ones of SCAP and HMG-CoA-reductase and who might thus be regulated by INSIG1 as well:
- Niemann-Pick disease type C1 protein, which participates in the intracellular movement of cholesterol
- Patched, the receptor for Hedgehog, a protein that contains covalently bound cholesterol
Oxysterols regulate cholesterol homeostasis through liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP) mediated signaling pathway. This protein binds to the sterol-sensing domains of SREBP cleavage-activating protein (SCAP) and HMG CoA reductase, and is essential for the sterol-mediated trafficking of the two proteins. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[6]
Regulation
[edit]INSIG1 is regulated by insulin and highly expressed in liver.
Sequence (277 AA)
[edit]MPRLHDHFWS CSCAHSARRR GPPRASTAGL PPKVGEMINV SVSGPSLLAA HGAPDADPAP RGRSAAMSGP EPGSPYPNTW HHRLLQRSLV LFSVGVVLAL VLNLLQIQRN VTLFPEEVIA TIFSSAWWVP PCCGTAAAVV GLLYPCIDSH LGEPHKFKRE WASVMRCIAV FVGINHASAK LDFANNVQLS LTLAALSLGL WWTFDRSRSG LGLGITIAFL ATLITQFLVY NGVYQYTSPD FLYIRSWLPC IFFSGGVTVG NIGRQLAMGV PEKPHSD
Synonyms
[edit]CL-6, INSIG-1, Insulin-induced gene 1 protein, MGC1405 (source: iHOP)
Interactions
[edit]INSIG1 has been shown to interact with SREBF2.[7][8]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000186480 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045294 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Peng Y, Schwarz EJ, Lazar MA, Genin A, Spinner NB, Taub R (Aug 1997). "Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene". Genomics. 43 (3): 278–84. doi:10.1006/geno.1997.4821. PMID 9268630.
- ^ a b "Entrez Gene: INSIG1 insulin induced gene 1".
- ^ Dobrosotskaya IY, Goldstein JL, Brown MS, Rawson RB (Sep 2003). "Reconstitution of sterol-regulated endoplasmic reticulum-to-Golgi transport of SREBP-2 in insect cells by co-expression of mammalian SCAP and Insigs". The Journal of Biological Chemistry. 278 (37): 35837–43. doi:10.1074/jbc.M306476200. PMID 12842885.
- ^ Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS (Aug 2002). "Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER". Cell. 110 (4): 489–500. doi:10.1016/S0092-8674(02)00872-3. PMID 12202038. S2CID 15052132.
Further reading
[edit]- Peng Y, Schwarz EJ, Lazar MA, Genin A, Spinner NB, Taub R (Aug 1997). "Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene". Genomics. 43 (3): 278–84. doi:10.1006/geno.1997.4821. PMID 9268630.
- Kaneda A, Kaminishi M, Nakanishi Y, Sugimura T, Ushijima T (Jul 2002). "Reduced expression of the insulin-induced protein 1 and p41 Arp2/3 complex genes in human gastric cancers". International Journal of Cancer. 100 (1): 57–62. doi:10.1002/ijc.10464. PMID 12115587. S2CID 13737339.
- Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS (Aug 2002). "Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER". Cell. 110 (4): 489–500. doi:10.1016/S0092-8674(02)00872-3. PMID 12202038. S2CID 15052132.
- Yabe D, Brown MS, Goldstein JL (Oct 2002). "Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins". Proceedings of the National Academy of Sciences of the United States of America. 99 (20): 12753–8. Bibcode:2002PNAS...9912753Y. doi:10.1073/pnas.162488899. PMC 130532. PMID 12242332.
- Janowski BA (Oct 2002). "The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP". Proceedings of the National Academy of Sciences of the United States of America. 99 (20): 12675–80. Bibcode:2002PNAS...9912675J. doi:10.1073/pnas.202471599. PMC 130519. PMID 12242342.
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- Yabe D, Xia ZP, Adams CM, Rawson RB (Dec 2002). "Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16672–7. Bibcode:2002PNAS...9916672Y. doi:10.1073/pnas.262669399. PMC 139202. PMID 12482938.
- Sever N, Yang T, Brown MS, Goldstein JL, DeBose-Boyd RA (Jan 2003). "Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain". Molecular Cell. 11 (1): 25–33. doi:10.1016/S1097-2765(02)00822-5. PMID 12535518.
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- Dobrosotskaya IY, Goldstein JL, Brown MS, Rawson RB (Sep 2003). "Reconstitution of sterol-regulated endoplasmic reticulum-to-Golgi transport of SREBP-2 in insect cells by co-expression of mammalian SCAP and Insigs". The Journal of Biological Chemistry. 278 (37): 35837–43. doi:10.1074/jbc.M306476200. PMID 12842885.
- Li J, Takaishi K, Cook W, McCorkle SK, Unger RH (Aug 2003). "Insig-1 "brakes" lipogenesis in adipocytes and inhibits differentiation of preadipocytes". Proceedings of the National Academy of Sciences of the United States of America. 100 (16): 9476–81. Bibcode:2003PNAS..100.9476L. doi:10.1073/pnas.1133426100. PMC 170943. PMID 12869692.
- Adams CM, Goldstein JL, Brown MS (Sep 2003). "Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles". Proceedings of the National Academy of Sciences of the United States of America. 100 (19): 10647–52. Bibcode:2003PNAS..10010647A. doi:10.1073/pnas.1534833100. PMC 196858. PMID 12963821.
- Feramisco JD, Goldstein JL, Brown MS (Feb 2004). "Membrane topology of human insig-1, a protein regulator of lipid synthesis". The Journal of Biological Chemistry. 279 (9): 8487–96. doi:10.1074/jbc.M312623200. PMID 14660863.
- Engelking LJ, Kuriyama H, Hammer RE, Horton JD, Brown MS, Goldstein JL, Liang G (Apr 2004). "Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis". The Journal of Clinical Investigation. 113 (8): 1168–75. doi:10.1172/JCI20978. PMC 385408. PMID 15085196.
- Sever N, Lee PC, Song BL, Rawson RB, Debose-Boyd RA (Oct 2004). "Isolation of mutant cells lacking Insig-1 through selection with SR-12813, an agent that stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase". The Journal of Biological Chemistry. 279 (41): 43136–47. doi:10.1074/jbc.M406406200. PMID 15247248.
- Lee JN, Ye J (Oct 2004). "Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1". The Journal of Biological Chemistry. 279 (43): 45257–65. doi:10.1074/jbc.M408235200. PMID 15304479.
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- Sun LP, Li L, Goldstein JL, Brown MS (Jul 2005). "Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro". The Journal of Biological Chemistry. 280 (28): 26483–90. doi:10.1074/jbc.M504041200. PMID 15899885.