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

Di-Ao Liu, Kai Tao, Bin Wu, Ziyan Yu, Malwina Szczepaniak, Matthew Rames, Changsong Yang, Tatyana Svitkina, Yueyao Zhu, Fengyuan Xu, Xiaolin Nan and Wei Guo ()
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Di-Ao Liu: University of Pennsylvania
Kai Tao: Oregon Health and Science University
Bin Wu: University of Pennsylvania
Ziyan Yu: University of Pennsylvania
Malwina Szczepaniak: Oregon Health and Science University
Matthew Rames: Oregon Health and Science University
Changsong Yang: University of Pennsylvania
Tatyana Svitkina: University of Pennsylvania
Yueyao Zhu: University of Pennsylvania
Fengyuan Xu: University of Pennsylvania
Xiaolin Nan: Oregon Health and Science University
Wei Guo: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42661-0

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