2. Academic Validation
  3. A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion

A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion

  • Nat Commun. 2023 Oct 28;14(1):6883. doi: 10.1038/s41467-023-42661-0.
Di-Ao Liu 1,  Kai Tao 2,  Bin Wu 1,  Ziyan Yu 1,  Malwina Szczepaniak 2,  Matthew Rames 3,  Changsong Yang 1,  Tatyana Svitkina 1,  Yueyao Zhu 1 4,  Fengyuan Xu 5,  Xiaolin Nan 2 3,  Wei Guo 6
Affiliations

Affiliations

  • 1 Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 2 Program in Quantitative and Systems Biology, Department of Biomedical Engineering, Oregon Health and Science University, 2730 S. Moody Ave, Portland, OR, 97201, USA.
  • 3 Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health and Science University, 2720 S. Moody Ave., Portland, OR, 97201, USA.
  • 4 Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA.
  • 5 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 6 Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
PMID: 37898620 DOI: 10.1038/s41467-023-42661-0
Abstract

Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) DOCK and fuse with the plasma membrane. However, MVEs are also known to fuse with lysosomes for degradation. How MVEs are directed to the plasma membrane for exosome secretion rather than to lysosomes is unclear. Here we report that a conversion of phosphatidylinositol-3-phosphate (PI(3)P) to phosphatidylinositol-4-phosphate (PI(4)P) catalyzed sequentially by Myotubularin 1 (MTM1) and phosphatidylinositol 4-kinase type IIα (PI4KIIα) on the surface of MVEs mediates the recruitment of the exocyst complex. The exocyst then targets the MVEs to the plasma membrane for exosome secretion. We further demonstrate that disrupting PI(4)P generation or exocyst function blocked exosomal secretion of Programmed death-ligand 1 (PD-L1), a key immune checkpoint protein in tumor cells, and led to its accumulation in lysosomes. Together, our study suggests that the PI(3)P to PI(4)P conversion on MVEs and the recruitment of the exocyst direct the exocytic trafficking of MVEs for exosome secretion.

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    Product Name
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  • HY-103489
    ≥98.0%, PI4KIIα Inhibitor