2. Academic Validation
  3. Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport

Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport

  • Nat Cell Biol. 2025 Jun;27(6):918-930. doi: 10.1038/s41556-025-01665-2.
Zizhen Xu # 1 2,  Ying Meng # 3 4,  Jonathan St-Germain # 5,  Arezoo Afshari 6,  Charneal L Dixon 6,  Saskia Heybrock 7,  Qiang Zhao 2,  Xialian Weng 2,  Jishun Chen 2,  Richard Collins 8,  Hu Hu 9,  Quan Zhou 10,  Qiming Sun 1,  Pinglong Xu 11,  Wei Liu 1,  Paul Saftig 7,  Brian Raught 12,  Gregory D Fairn 13,  Dante Neculai 14 15
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. ymeng@zju.edu.cn.
  • 4 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. ymeng@zju.edu.cn.
  • 5 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 6 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
  • 7 Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
  • 8 Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 9 Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 10 Institute of Immunology, Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 11 Life Science Institute, Zhejiang University, Hangzhou, China.
  • 12 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. brian.raught@uhnresearch.ca.
  • 13 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. gfairn@dal.ca.
  • 14 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. dneculai@zju.edu.cn.
  • 15 Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. dneculai@zju.edu.cn.
  • # Contributed equally.
PMID: 40437229 DOI: 10.1038/s41556-025-01665-2
Abstract

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.

Figures
Products