Mast cell secretory granule fusion with amphisomes coordinates their homotypic fusion and release of exosomes

Sewar Omari, Amit Roded, Maggie Eisenberg, Hydar Ali, Mitsunori Fukuda, Stephen J. Galli, Ronit Sagi-Eisenberg

Research output: Contribution to journalArticlepeer-review

Abstract

Secretory granule (SG) fusion is an intermediate step in SG biogenesis. However, the precise mechanism of this process is not completely understood. We show that Golgi-derived mast cell (MC) SGs enlarge through a mechanism that is dependent on phosphoinositide (PI) remodeling and fusion with LC3+ late endosomes (amphisomes), which serve as hubs for the fusion of multiple individual SGs. Amphisome formation is regulated by the tyrosine phosphatase PTPN9, while the subsequent SG fusion event is additionally regulated by the tetraspanin protein CD63 and by PI4K. We also demonstrate that fusion with amphisomes imparts to SGs their capacity of regulated release of exosomes. Finally, we show that conversion of PI(3,4,5)P3 to PI(4,5)P2 and the subsequent recruitment of dynamin stimulate SG fission. Our data unveil a key role for lipid-regulated interactions with the endocytic and autophagic systems in controlling the size and number of SGs and their capacity to release exosomes.

Original languageEnglish
Article number114482
JournalCell Reports
Volume43
Issue number7
DOIs
StatePublished - 23 Jul 2024

Keywords

  • amphisomes
  • CP: Cell biology
  • CP: Immunology
  • exosomes
  • lysosome related organelles
  • mast cells
  • phosphoinositide conversion
  • secretory granules

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology

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