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 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 E-Syts 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.

中文翻译：

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胆固醇通过过氧化物酶体-ER膜的运输接触由PI（4,5）P2和扩展的突触结合蛋白束缚

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）中吸收胆固醇。到达溶酶体后，LDL衍生的胆固醇继续转运至下游细胞器，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受胆固醇。然而，胆固醇是否以及如何从过氧​​化物酶体传递到ER仍是未知的。在这里，通过结合高分辨率的显微镜分析和高纯度细胞器或人工脂质体的体外重构，我们证明了过氧化物酶体通过过氧化物酶体PI（4,5）P2与ER驻留的扩展突触素-之间的相互作用而与ER形成膜接触。 1、2和3（E-Syts）。过氧化物酶体PI（4，5）P2或E-Syts显着降低过氧化物酶体-ER膜的接触并诱导溶酶体中的胆固醇蓄积。此外，我们表明胆固醇是从3H标记的过氧化物酶体或含PI（4,5）P2的脂质体在体外传递到ER的，过氧化物酶体的存在会增加胆固醇从溶酶体到ER的转移。在一起，我们的研究揭示了沿细胞中的溶酶体-过氧化物酶体-ER膜接触的新胆固醇转运途径。