title: Cholesterol transport through lysosome-peroxisome membrane contacts.
abstract: Cholesterol is dynamically transported among organelles, which is essential for multiple cellular functions. However, the mechanism underlying intracellular cholesterol transport has remained largely unknown. We established an amphotericin B-based assay enabling a genome-wide shRNA screen for delayed LDL-cholesterol transport and identified 341 hits with particular enrichment of peroxisome genes, suggesting a previously unappreciated pathway for cholesterol transport. We show dynamic membrane contacts between peroxisome and lysosome, which are mediated by lysosomal Synaptotagmin VII binding to the lipid PI(4,5)P2 on peroxisomal membrane. LDL-cholesterol enhances such contacts, and cholesterol is transported from lysosome to peroxisome. Disruption of critical peroxisome genes leads to cholesterol accumulation in lysosome. Together, these findings reveal an unexpected role of peroxisome in intracellular cholesterol transport. We further demonstrate massive cholesterol accumulation in human patient cells and mouse model of peroxisomal disorders, suggesting a contribution of abnormal cholesterol accumulation to these diseases.
authors: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China; College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, Henan Province, China.
authors: Bei-Bei
authors: BB
authors: Chu
authors: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Ya-Cheng
authors: YC
authors: Liao
authors: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Wei
authors: W
authors: Qi
authors: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Chang
authors: C
authors: Xie
authors: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors: Ximing
authors: X
authors: Du
authors: College of Animal Sciences and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, Henan Province, China.
authors: Jiang
authors: J
authors: Wang
authors: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors: Hongyuan
authors: H
authors: Yang
authors: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Hong-Hua
authors: HH
authors: Miao
authors: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Bo-Liang
authors: BL
authors: Li
authors: College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China. Electronic address: blsong@whu.edu.cn.
authors: Bao-Liang
authors: BL
authors: Song
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000378:metabolism; D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D055106:Genome-Wide Association Study; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018901:Peroxisomal Disorders / Q000378:metabolism / Q000473:pathology; D020675:Peroxisomes / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D050857:Synaptotagmins / Q000378:metabolism; D015027:Zebrafish
chemical_list: D018528:ATP-Binding Cassette Transporters; D019269:Phosphatidylinositol 4,5-Diphosphate; D034741:RNA, Small Interfering; D050857:Synaptotagmins; D000666:Amphotericin B; D002784:Cholesterol