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Fluorescence-Based Measurements of Phosphatidylserine/Phosphatidylinositol 4-Phosphate Exchange Between Membranes
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A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion

Di-Ao Liu1, Kai Tao2, Bin Wu1

  • 1Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Nature Communications
|October 29, 2023
PubMed

Insights

This study reveals how multivesicular endosomes (MVEs) are directed for exosome secretion. A lipid conversion on MVEs recruits the exocyst complex, guiding them to the plasma membrane instead of lysosomes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Exosomes are released from cells via multivesicular endosomes (MVEs) fusing with the plasma membrane.
  • MVEs can also fuse with lysosomes for degradation, creating uncertainty about their trafficking pathways.
  • Understanding MVE trafficking is crucial for controlling exosome secretion, particularly for proteins like PD-L1.

Purpose of the Study:

  • To elucidate the molecular mechanisms directing MVEs to the plasma membrane for exosome secretion.
  • To identify the key regulators involved in MVE trafficking decisions.
  • To investigate the role of specific lipid conversions and protein complexes in exosome biogenesis and release.

Main Methods:

  • Investigated the role of phosphatidylinositol-3-phosphate (PI(3)P) to phosphatidylinositol-4-phosphate (PI(4)P) conversion on MVEs.
  • Utilized Myotubularin 1 (MTM1) and phosphatidylinositol 4-kinase type IIα (PI4KIIα) in lipid conversion studies.
  • Examined the recruitment of the exocyst complex to MVEs.
  • Assessed the impact of disrupted PI(4)P generation and exocyst function on exosome secretion, including Programmed death-ligand 1 (PD-L1).

Main Results:

  • Demonstrated that PI(3)P to PI(4)P conversion on MVEs is essential for exosome secretion.
  • Showed that Myotubularin 1 (MTM1) and PI4KIIα catalyze this lipid conversion.
  • Confirmed that the exocyst complex is recruited to MVEs via PI(4)P, directing them to the plasma membrane.
  • Found that blocking PI(4)P generation or exocyst function inhibits PD-L1 exosomal secretion and causes lysosomal accumulation.

Conclusions:

  • The conversion of PI(3)P to PI(4)P on MVEs is a critical step for exosome secretion.
  • The exocyst complex, recruited by PI(4)P, mediates the targeting of MVEs to the plasma membrane.
  • This pathway regulates the secretion of cargo proteins like PD-L1, impacting cellular processes and immune responses.

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