Unraveling the role of amphisomes in mast cell secretory granule fusion and exosome release

Abstract

Mast cells (MCs) play a crucial role in immune responses by storing and releasing inflammatory mediators from secretory granules (SGs). The biogenesis, maturation, and fusion of these granules with the plasma membrane regulate inflammation, immune cell recruitment, and tissue homeostasis. However, the exact mechanism underlying this process remains unclear. Recent studies have identified a novel mechanism of SG fusion involving amphisomes, hybrid organelles formed by the fusion of late endosomes and autophagosomes. This process not only facilitates SG enlargement but also promotes the release of exosomes, small vesicles crucial for intercellular communication and immune modulation. In particular, Omari et al. delve into the molecular machinery governing amphisome formation and SG fusion, focusing on key players such as Rab5, PTPN9, CD63, and phosphoinositides (PIs). They propose a dynamic model wherein amphisomes act as intermediates in SG maturation, promoting homotypic fusion events that regulate SG content and size. A critical aspect of this process is the lipid signaling cascade, particularly involving PI4K and CD63, which coordinates SG fusion and exosome release. These findings challenge the conventional view of SGs as static storage compartments, positioning them as dynamic hubs of vesicle trafficking and secretion. By elucidating the role of amphisomes and lipid signaling in SG biology, this study offers a significant shift in understanding and introduces new concepts that could drive future research. This commentary, while endorsing the authors’ key conclusions, also highlights important questions regarding the functional implications of these novel mechanisms and their potential therapeutic applications.

Keywords

Mast cells / secretory granules / amphisomes / exosomes / fusion / mechanisms

References

[1] Chieregatti E.Regulated exocytosis: new organelles for non-secretory purposes.Nat Rev Mol Cell Biol2005;6:181-7

[2] Tran DT.Real-time insights into regulated exocytosis.J Cell Sci2017;130:1355-63 PMCID:PMC5399783

[3] Burgoyne RD.Secretory granule exocytosis.Physiol Rev2003;83:581-632

[4] Mukai K,Saito H.Mast cells as sources of cytokines, chemokines and growth factors.Immunol Rev2018;282:121-50 PMCID:PMC5813811

[5] Pal S,Meininger CJ.Emerging roles of mast cells in the regulation of lymphatic immuno-physiology.Front Immunol2020;11:1234. PMCID:PMC7311670

[6] Vazquez TA, Lopez NL, Salinas Carmona MC. MASTer cell: chief immune modulator and inductor of antimicrobial immune response.Front Immunol2024;15:1360296 PMCID:PMC11024470

[7] Tei M. Role of IL-4 and IL-31 in mastocytosis. International Journal of Infection. 2024;8:18-19. Available from https://www.biolife-publisher.it/iji/role-of-il-4-and-il-31-in-mastocytosis/ [accessed 21 March 2025].

[8] Omari S,Eisenberg M.Mast cell secretory granule fusion with amphisomes coordinates their homotypic fusion and release of exosomes.Cell Rep2024;43:114482

[9] Tanaka S.A method for detailed analysis of the structure of mast cell secretory granules by negative contrast imaging.Sci Rep2016;6:23369 PMCID:PMC4800307

[10] Hummer BH,Soltero-Gutierrez M,Asensio CS.Differential sorting behavior for soluble and transmembrane cargoes at the trans-Golgi network in endocrine cells.Mol Biol Cell2020;31:157-66 PMCID:PMC7001476

[11] Gangadaran P,Madhyastha R.The emerging role of exosomes in innate immunity, diagnosis and therapy.Front Immunol2023;13:1085057 PMCID:PMC9885214

[12] Leidal AM.LC3-dependent extracellular vesicle loading and secretion (LDELS).Autophagy2020;16:1162-3 PMCID:PMC7469500