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ORP9 and ORP10 form a heterocomplex to transfer phosphatidylinositol 4-phosphate at ER-TGN contact sites

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Abstract

Oxysterol-binding protein (OSBP) and its related proteins (ORPs) are a family of lipid transfer proteins (LTPs) that mediate non-vesicular lipid transport. ORP9 and ORP10, members of the OSBP/ORPs family, are located at the endoplasmic reticulum (ER)-trans-Golgi network (TGN) membrane contact sites (MCSs). It remained unclear how they mediate lipid transport. In this work, we discovered that ORP9 and ORP10 form a binary complex through intermolecular coiled-coil (CC) domain-CC domain interaction. The PH domains of ORP9 and ORP10 specially interact with phosphatidylinositol 4-phosphate (PI4P), mediating the TGN targeting. The ORP9-ORP10 complex plays a critical role in regulating PI4P levels at the TGN. Using in vitro reconstitution assays, we observed that while full-length ORP9 efficiently transferred PI4P between two apposed membranes, the lipid transfer kinetics was further accelerated by ORP10. Interestingly, our data showed that the PH domains of ORP9 and ORP10 participate in membrane tethering simultaneously, whereas ORDs of both ORP9 and ORP10 are required for lipid transport. Furthermore, our data showed that the depletion of ORP9 and ORP10 led to increased vesicle transport to the plasma membrane (PM). These findings demonstrate that ORP9 and ORP10 form a binary complex through the CC domains, maintaining PI4P homeostasis at ER-TGN MCSs and regulating vesicle trafficking.

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Acknowledgements

The authors are grateful to Dr. Jingshi Shen and Dr. Chun Wan for helpful discussions and advice. We thank Dr. Zonghong Li for providing the pmCherry-Sec61b plasmid. We thank Dr. Xiaojun Wang for technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) Grants (nos. 32270735, 91854117, 31871425, and 32100546), Natural Science Foundation of Jiangsu Province (BK20200036), Jiangsu Province’s Innovation Program (JSSCTD202142), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China

    Ruyue He, Furong Liu, Hui Wang, Shuai Huang, Yinghui Liu & Haijia Yu

  2. Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, China

    Kai Xu

  3. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China

    Conggang Zhang

  4. Tsinghua-Peking Center for Life Sciences, Beijing, China

    Conggang Zhang

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  1. Ruyue He
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Contributions

HY, CZ, and YL conceived the project. RH, FL, HW, and SH performed the experiments. RH, FL, KX, and YL analyzed the data. RH, KX, YL, CZ, and HY wrote the manuscript with input from all authors.

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Correspondence to Yinghui Liu or Haijia Yu.

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He, R., Liu, F., Wang, H. et al. ORP9 and ORP10 form a heterocomplex to transfer phosphatidylinositol 4-phosphate at ER-TGN contact sites. Cell. Mol. Life Sci. 80, 77 (2023). https://doi.org/10.1007/s00018-023-04728-5

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