Cholesterol transport through the peroxisome-ER membrane contacts tethered by PI(4,5)P-2 and extended synaptotagmins
Cholesterol transport through the peroxisome-ER membrane contacts tethered by PI(4,5)P-2 and extended synaptotagmins
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胆固醇通过由 PI(4,5)P-2 和延伸突触结合蛋白束缚的过氧化物酶体-ER 膜接触进行转运
DOI：
10.1007/s11427-019-9569-9
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Song Bao-Liang
中科院分区：
文献类型：
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作者：
Xiao Jian;Luo Jie;Hu Ao;Xiao Ting;Li Meixin;Kong Zekai;Jiang Luyi;Zhou Zimu;Liao Yacheng;Xie Chang;Chu Beibei;Miao Honghua;Li Boliang;Shi Xiongjie;Song Bao-Liang
大多数哺乳动物细胞通过受体介导的内吞作用从低密度脂蛋白（LDL）中摄取胆固醇。到达溶酶体后，LDL衍生的胆固醇继续转运到下游细胞器，包括ER，以满足特定的结构和功能需求。最近发现过氧化物酶体通过溶酶体-过氧化物酶体膜接触从溶酶体接收胆固醇。然而，胆固醇是否以及如何从过氧化物酶体传递到ER仍然未知。在这里，通过结合高分辨率显微镜分析和高度纯化的细胞器或人工脂质体的体外重构，我们证明过氧化物酶体通过过氧化物酶体PI（4，5）P2和ER驻留的扩展突触结合蛋白-1，2和3（E-Syts）之间的相互作用与ER形成膜接触。过氧化物酶体PI（4，5）P2或E-Syts的耗竭显著减少过氧化物酶体-ER膜接触并诱导溶酶体中胆固醇积聚。此外，我们表明，胆固醇从3 H-标记的过氧化物酶体或PI（4，5）P2-含有脂质体的ER在体外，和过氧化物酶体的存在增强胆固醇从溶酶体转移到ER。总之，我们的研究揭示了一个新的胆固醇转运途径沿着溶酶体过氧化物酶体ER膜接触的细胞。
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 lysosome-peroxisome membrane contacts. However, whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown. Here, by combining high-resolution microscopic analyses andin vitroreconstitution 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)P2and ER-resident extended synaptotagmin-1, 2 and 3 (E-Syts). Depletion of peroxisomal PI(4,5)P2or E-Syts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes. Furthermore, we show that cholesterol is delivered from3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ERin 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.