YEN-CHOU KUANHashidume TShibata TUchida KShimizu MInoue JSato R.2021-07-262021-07-262017219258https://www.scopus.com/inward/record.uri?eid=2-s2.0-85013173241&doi=10.1074%2fjbc.M116.767277&partnerID=40&md5=044fd00d508b1aeeb140ac757414390chttps://scholars.lib.ntu.edu.tw/handle/123456789/572810Sterol regulatory element-binding proteins (SREBPs) are the key transcription factors that modulate lipid biosynthesis. SREBPs are synthesized as endoplasmic reticulum-bound precursors that require proteolytic activation in the Golgi apparatus. The stability and maturation of precursor SREBPs depend on their binding to SREBP cleavage-activating protein (SCAP), which escorts the SCAP-SREBP complex to the Golgi apparatus. In this study, we identified heat shock protein (HSP) 90 as a novel SREBP regulator that binds to and stabilizes SCAP-SREBP. In HepG2 cells, HSP90 inhibition led to proteasome-dependent degradation of SCAP-SREBP, which resulted in the down-regulation of SREBP target genes and the reduction in intracellular triglyceride and cholesterol levels. We also demonstrated in vivo that HSP90 inhibition decreased SCAP-SREBP protein, down-regulated SREBP target genes, and reduced lipids levels in mouse livers. We propose that HSP90 plays an indispensable role in SREBP regulation by stabilizing the SCAP-SREBP complex, facilitating the activation of SREBP to maintain lipids homeostasis. ? 2017, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.Alcohols; Biochemistry; Cell membranes; Chemical activation; Lipids; Physiology; Transcription; Cholesterol levels; Endoplasmic reticulum; Heat shock protein; Heat-shock protein 90; Lipid biosynthesis; Lipid homeostasis; Proteolytic activation; Sterol regulatory element-binding proteins; Proteins; carrier proteins and binding proteins; cholesterol; heat shock protein 90; messenger RNA; multiprotein complex; proteasome; sterol regulatory element binding protein cleavage activating protein; triacylglycerol; unclassified drug; heat shock protein 90; membrane protein; signal peptide; SREBP cleavage-activating protein; sterol regulatory element binding protein; animal cell; animal tissue; Article; carboxy terminal sequence; controlled study; down regulation; endoplasmic reticulum; enzyme degradation; gene targeting; Golgi complex; Hep-G2 cell line; in vivo study; lipid homeostasis; mouse; nonhuman; protein analysis; protein binding; protein function; protein localization; protein protein interaction; protein stability; cell line; homeostasis; human; lipid metabolism; metabolism; physiology; protein stability; Cell Line; Homeostasis; HSP90 Heat-Shock Proteins; Humans; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Membrane Proteins; Protein Stability; Sterol Regulatory Element Binding Proteinsjournal article10.1074/jbc.M116.767277280033582-s2.0-85013173241