Xu Zizhen, Meng Ying, St-Germain Jonathan, Afshari Arezoo, Dixon Charneal L, Heybrock Saskia, Zhao Qiang, Weng Xialian, Chen Jishun, Collins Richard, Hu Hu, Zhou Quan, Sun Qiming, Xu Pinglong, Liu Wei, Saftig Paul, Raught Brian, Fairn Gregory D, Neculai Dante
Department of Respiratory and Critical Care Medicine, Center for Metabolism Research, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
Nat Cell Biol. 2025 May 28. doi: 10.1038/s41556-025-01665-2.
Cholesterol derived from high-density lipoprotein (HDL) is rapidly redistributed to intracellular compartments in steroidogenic and bile-producing cells, but the molecular mechanisms governing this essential transport process remain poorly understood. Here we uncover a signalling cascade coordinating HDL-derived cholesterol transport through membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM). We find that HDL-resident sphingosine-1-phosphate (S1P) activates S1P receptor 3 and its associated G protein αq, leading to phospholipase-C-β3-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate and an elevation in cytosolic calcium. This calcium signal triggers the rapid recruitment of Extended-Synaptotagmin 1 to ER-PM membrane contact sites. Genetic or pharmacological disruption of this pathway impairs the non-vesicular transfer of HDL-derived cholesterol to intracellular compartments. Our findings reveal how HDL binding to the cell surface alters ER-PM membrane contact site dynamics through S1P signalling. This ensures efficient offloading and redistribution of HDL cholesterol to support steroid and bile acid synthesis.
源自高密度脂蛋白（HDL）的胆固醇会迅速重新分布到类固醇生成细胞和胆汁生成细胞的细胞内区室中，但对于这一重要转运过程的分子机制仍知之甚少。在此，我们揭示了一个信号级联反应，该反应通过内质网（ER）与质膜（PM）之间的膜接触位点来协调源自HDL的胆固醇转运。我们发现，HDL驻留的鞘氨醇-1-磷酸（S1P）激活S1P受体3及其相关的G蛋白αq，导致磷脂酶-C-β3介导的磷脂酰肌醇4,5-二磷酸水解以及胞质钙升高。这种钙信号触发扩展型突触结合蛋白1迅速募集到内质网-质膜膜接触位点。该通路的遗传或药理学破坏会损害源自HDL的胆固醇向细胞内区室的非囊泡转运。我们的研究结果揭示了HDL与细胞表面的结合如何通过S1P信号改变内质网-质膜膜接触位点的动力学。这确保了HDL胆固醇的有效卸载和重新分布，以支持类固醇和胆汁酸的合成。
