The lysosomal channel RECS1 regulates extracellular vesicle biogenesis

Milani, M.; Montes-Bravo, N.; Sepulveda-Quinenao, C.; Burton, J.; Molina, E.; Glavic, A.; Schilling, B.; Ellerby, L. M.; Hetz, C.

doi:10.64898/2026.08.18.745524

bioRxiv · 10.64898/2026.08.18.745524

The lysosomal channel RECS1 regulates extracellular vesicle biogenesis

Milani, M.·Montes-Bravo, N.·Sepulveda-Quinenao, C.·Burton, J.·Molina, E.·Glavic, A.·Schilling, B.·Ellerby, L. M.·Hetz, C.

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Abstract

Lysosomal ion channels play key roles in regulating membrane trafficking, autophagy, and cell death. RECS1 is a pH-sensitive lysosomal calcium channel previously implicated in lysosome-mediated apoptosis. Here, we identify a novel role for RECS1 in exosome biology. Using immunoprecipitation followed by mass spectrometry, we mapped RECS1 interactors under apoptotic and lysosomal stress conditions. Notably, Syntenin-1, a key scaffolding protein in ESCRT-independent exosome biogenesis, emerged as the top hit. We validated the physical interaction between RECS1-Syntenin-1 using various approaches. RECS1 localized to secreted exosomes, and its overexpression increased exosome production, as measured by nanoparticle tracking analysis. Intriguingly, a channel-dead RECS1 retained both Syntenin-1 interaction and the ability to promote exosome release, suggesting a channel-independent mechanism. Our findings identify RECS1 as a structural component of the exosomal trafficking machinery and a modulator of extracellular vesicle biogenesis. This work connects lysosomal signalling with intercellular communication and suggests a broader role for RECS1 in stress-responsive secretion.

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Milani, M., Montes-Bravo, N., Sepulveda-Quinenao, C., Burton, J., Molina, E., Glavic, A., Schilling, B., Ellerby, L. M., Hetz, C.. 2026-08-19. The lysosomal channel RECS1 regulates extracellular vesicle biogenesis. https://doi.org/10.64898/2026.08.18.745524

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