Cholesterol transport through the peroxisome-ER membrane contacts tethered by PI（4,5）P2 and extended synaptotagmins  

作　　者：Jian Xiao Jie Luo Ao Hu Ting Xiao Meixin Li Zekai Kong Luyi Jiang Zimu Zhou Yacheng Liao Chang Xie Beibei Chu Honghua Miao Boliang Li Xiongjie Shi Bao-Liang Song 

机构地区：[1]College of Life Sciences,the Institute for Advanced Studies,Wuhan University,Wuhan 430072,China [2]State Key Laboratory of Molecular Biology,Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai 200031,China [3]Shenzhen Institute of Wuhan University,Shenzhen 518057,China

出　　处：《Science China(Life Sciences)》2019年第9期1117-1135,共19页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China (91754102, 31771568, 31690102, 31600651, 31701030);National Key Research and Development Project of the Ministry of Science and Technology of China (2016YFA0500100);Shenzhen City Technology Basic Research Program (JCYJ20170818144026198);Science and Technology Department of Hubei Province (2017CFB617);the 111 Project of Ministry of Education of China (B16036)

摘　　要：Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.Most mammalian cells take up cholesterol from low-density lipoproteins（LDLs） via receptor-mediated endocytosis. After reaching lysosomes, LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs. Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts. However, whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown. Here, by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes, we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI（4,5）P2 and ER-resident extended synaptotagmin-1, 2 and 3（E-Syts）. Depletion of peroxisomal PI（4,5）P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes. Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI（4,5）P2-containing liposomes to the ER in vitro, and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER. Together, our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.

关 键 词：PEROXISOME ER MEMBRANE CONTACTS E-Syts PI(4 5)P2 

分 类 号：Q[生物学]