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Research Paper

Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway

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Pages 1592-1613 | Received 17 Oct 2019, Accepted 12 Apr 2020, Published online: 20 May 2020

References

  • Hua X, Yokoyama C, Wu J, et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci USA. 1993;90:11603–11607.
  • Yokoyama C, Wang X, Briggs MR, et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 1993;75:187–197.
  • Rawson RB, Zelenski NG, Nijhawan D, et al. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol Cell. 1997;1:47–57.
  • Sakai J, Rawson RB, Espenshade PJ, et al. Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell. 1998;2:505–514.
  • Briggs MR, Yokoyama C, Wang X, et al. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence. J Biol Chem. 1993;268:14490–14496.
  • Moon YA, Liang G, Xie X, et al. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Cell Metab. 2012;15:240–246.
  • Tang JJ, Li JG, Qi W, et al. Inhibition of SREBP by a small molecule, betulin, improves hyperlipidemia and insulin resistance and reduces atherosclerotic plaques. Cell Metab. 2011;13:44–56.
  • Kamisuki S, Mao Q, Abu-Elheiga L, et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol. 2009;16:882–892.
  • Radhakrishnan A, Ikeda Y, Kwon HJ, et al. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: oxysterols block transport by binding to INSIG. Proc Natl Acad Sci USA. 2007;104:6511–6518.
  • Adams CM, Reitz J, De Brabander JK, et al. Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and INSIGS. J Biol Chem. 2004;279:52772–52780.
  • Watanabea M, Uesugi M. Small-molecule inhibitors of SREBP activation – potential for new treatment of metabolic disorders. Med Chem Commun. 2013;4:12.
  • Devries-Seimon T, Li Y, Yao PM, et al. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J Cell Biol. 2005;171:61–73.
  • Hager L, Li L, Pun H, et al. Lecithin:cholesterolacyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice. J Biol Chem. 2012;287:20755–20768.
  • Sozen E, Ozer NK. Impact of high cholesterol and endoplasmic reticulum stress on metabolic diseases: an updated mini-review. Redox Biol. 2017;12:456–461.
  • Feng B, Yao PM, Li Y, et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol. 2003;5:781–792.
  • Sekiya M, Yamamuro D, Ohshiro T, et al. Absence of nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages. J Lipid Res. 2014;55:2082–2092.
  • Okada K, Minamino T, Tsukamoto Y, et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation. 2004;110:705–712.
  • Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306:457–461.
  • Bozaykut P, Sahin A, Karademir B, et al. Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis. Mech Ageing Dev. 2016;157:17–29.
  • Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000;16:459–481.
  • Joseph SB, McKilligin E, Pei L, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci USA. 2002;99:7604–7609.
  • Repa JJ, Berge KE, Pomajzl C, et al. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem. 2002;277:18793–18800.
  • Venkateswaran A, Laffitte BA, Joseph SB, et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA. 2000;97:12097–12102.
  • Terasaka N, Hiroshima A, Koieyama T, et al. T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-de¢cient mice. FEBS Lett. 2003;536:6.
  • Song C, Hiipakka RA, Liao S. Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. Steroids. 2001;66:473–479.
  • Jafari R, Almqvist H, Axelsson H, et al. The cellular thermal shift assay for evaluating drug target interactions in cells. Nat Protoc. 2014;9:2100–2122.
  • Martinez Molina D, Jafari R, Ignatushchenko M, et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science. 2013;341:84–87.
  • Martinez Molina D, Nordlund P. The cellular thermal shift assay: a novel biophysical assay for in situ drug target engagement and mechanistic biomarker studies. Annu Rev Pharmacol Toxicol. 2016;56:141–161.
  • Wang J, Shi ZQ, Xu X, et al. Triptolide inhibits amyloid-beta production and protects neural cells by inhibiting CXCR2 activity. J Alzheimers Dis. 2013;33:217–229.
  • Jerabek-Willemsen M, Wienken CJ, Braun D, et al. Molecular interaction studies using microscale thermophoresis. Assay Drug Dev Technol. 2011;9:342–353.
  • Wienken CJ, Baaske P, Rothbauer U, et al. Protein-binding assays in biological liquids using microscale thermophoresis. Nat Commun. 2010;1:100.
  • Gong X, Li J, Shao W, et al. Structure of the WD40 domain of SCAP from fission yeast reveals the molecular basis for SREBP recognition. Cell Res. 2015;25:401–411.
  • Radhakrishnan A, Sun LP, Kwon HJ, et al. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol Cell. 2004;15:259–268.
  • Zheng ZG, Zhou YP, Zhang X, et al. Anhydroicaritin improves diet-induced obesity and hyperlipidemia and alleviates insulin resistance by suppressing SREBPs activation. Biochem Pharmacol. 2016;122:42–61.
  • Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6:1355–1364.
  • Zheng ZG, Zhang X, Liu XX, et al. Inhibition of HSP90β improves lipid disorders by promoting mature SREBPs degradation via the ubiquitin-proteasome system. Theranostics. 2019;9:5769–5783.
  • Dasari B, Prasanthi JR, Marwarha G, et al. The oxysterol 27-hydroxycholesterol increases beta-amyloid and oxidative stress in retinal pigment epithelial cells. BMC Ophthalmol. 2010;10:22.
  • Krycer JR, Sharpe LJ, Luu W, et al. The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab. 2010;21:268–276.
  • Salvado L, Palomer X, Barroso E, et al. Targeting endoplasmic reticulum stress in insulin resistance. Trends Endocrinol Metab. 2015;26:438–448.
  • Asano L, Watanabe M, Ryoden Y, et al. Vitamin D metabolite, 25-hydroxyvitamin D, regulates lipid metabolism by inducing degradation of SREBP/SCAP. Cell Chem Biol. 2017;24:207–217.
  • Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–326.
  • Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004;306:990–995.
  • Mauvezin C, Neufeld TP. Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy. 2015;11:1437–1438.
  • Pfister MF, Ruf I, Stange G, et al. Parathyroid hormone leads to the lysosomal degradation of the renal type II Na/Pi cotransporter. Proce Proc Natl Acad Sci USA. 1998;95:1909–1914.
  • Kimura S, Noda T, Yoshimori T. Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy. 2007;3:452–460.
  • Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2016;12:1–222.
  • Roy M, Liang L, Xiao X, et al. Lycorine downregulates HMGB1 to inhibit autophagy and enhances bortezomib activity in multiple myeloma. Theranostics. 2016;6:2209–2224.
  • Kornfeld S. Trafficking of lysosomal enzymes. Faseb J. 1987;1:462–468.
  • Shao W, Espenshade PJ. Sterol regulatory element-binding protein (SREBP) cleavage regulates Golgi-to-endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP). J Biol Chem. 2014;289:7547–7557.
  • Sahu R, Kaushik S, Clement CC, et al. Microautophagy of cytosolic proteins by late endosomes. Dev Cell. 2011;20:131–139.
  • Morozova K, Clement CC, Kaushik S, et al. Structural and biological interaction of hsc-70 protein with phosphatidylserine in endosomal microautophagy. J Biol Chem. 2016;291:18096–18106.
  • Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy: joint by a chaperone. J Biol Chem. 2018;293:5414–5424.
  • Fregno I, Fasana E, Bergmann TJ, et al. ER-to-lysosome-associated degradation of proteasome-resistant ATZ polymers occurs via receptor-mediated vesicular transport. Embo J. 2018;37(17):e99259.
  • Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy: jointed by a chaperone. J Biol Chem. 2018;293:5414–5424.
  • Sun LP, Li L, Goldstein JL, et al. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J Biol Chem. 2005;280:26483–26490.
  • Shao W, Machamer CE, Espenshade PJ. Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J Lipid Res. 2016;57:1564–1573.
  • Su L, Zhou L, Chen FJ, et al. Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites. Embo J. 2019;38(8):e100156.
  • Stephens DJ, Lin-Marq N, Pagano A, et al. COPI-coated ER-to-Golgi transport complexes segregate from COPII in close proximity to ER exit sites. J Cell Sci. 2000;113:2177–2185.
  • Xiao C, Srinivasan R, Drenan RM, et al. Characterizing functional α6β2 nicotinic acetylcholine receptors in vitro: mutant β2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells. Biochem Pharmacol. 2011;82:852–861.
  • Birgisdottir ÅB, Lamark T, Johansen T. The LIR motif–crucial for selective autophagy. J Cell Sci. 2013;126:3237–3247.
  • Otto J, Ordovas JM, Smith D, et al. Lovastatin inhibits diet-induced atherosclerosis in F1b Golden Syrian-Hamsters. Atherosclerosis. 1995;114:19–28.
  • Lebeau P, Al-Hashimi A, Sood S, et al. Endoplasmic reticulum stress and Ca2+ depletion differentially modulate the sterol regulatory protein PCSK9 to control lipid metabolism. J Biol Chem. 2017;292:1510–1523.
  • Yoshida H. ER stress and diseases. Febs J. 2007;274:630–658.
  • Brovkovych V, Izhar Y, Danes JM, et al. Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer. Oncogenesis. 2018;7:66.
  • Kuan YC, Hashidume T, Shibata T, et al. Heat shock protein 90 modulates lipid homeostasis by regulating the stability and function of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein. J Biol Chem. 2017;292:3016–3028.
  • Birgisdottir AB, Lamark T, Johansen T. The LIR motif-crucial for selective autophagy. J Cell Sci. 2013;126:3237–3247.
  • Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282:24131–24145.
  • Puvirajesinghe TM, Bertucci F, Jain A, et al. Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer. Nat Commun. 2016;7:10318.
  • Mrschtik M, Ryan KM. Lysosomal proteins in cell death and autophagy. Febs J. 2015;282:1858–1870.
  • Komatsu M, Waguri S, Koike M, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131:1149–1163.
  • Liu WJ, Ye L, Huang WF, et al. p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation. Cell Mol Biol Lett. 2016;21:29.
  • Jadhav T, Geetha T, Jiang J, et al. Identification of a consensus site for TRAF6/p62 polyubiquitination. Biochem Biophys Res Commun. 2008;371:521–524.
  • An S, Fu L. Small-molecule PROTACs: an emerging and promising approach for the development of targeted therapy drugs. EBioMedicine. 2018;36:553–562.
  • Chi KR. Drug developers delve into the cell’s trash-disposal machinery. Nat Rev Drug Discov. 2016;15:295–297.
  • Banik S, Pedram K, Wisnovsky S, et al. Lysosome targeting chimeras (LYTACs) for the degradation of secreted and membrane proteins. ChemRxiv. 2019. DOI:https://doi.org/10.26434/CHEMRXIV.7927061.V2.
  • Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–438.
  • Kita T, Brown MS, Goldstein JL. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in livers of mice treated with mevinolin, a competitive inhibitor of the reductase. J Clin Invest. 1980;66:1094–1100.
  • Singer II, Kawka DW, Kazazis DM, et al. Hydroxymethylglutaryl-coenzyme A reductase-containing hepatocytes are distributed periportally in normal and mevinolin-treated rat livers. Proce Proc Natl Acad Sci USA. 1984;81:5556–5560.
  • Chen K, Zeng J, Xiao H, et al. Regulation of glucose metabolism by p62/SQSTM1 through HIF1α. J Cell Sci. 2016;129:817–830.
  • Niu MM, Qin JY, Tian CP, et al. Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking. Acta Pharmacol Sin. 2014;35:967–979.

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