A conserved VPS34-PIKfyve-TRPML1-myosin II axis regulates the speed of amoeboid cell migration.

DOI
Publisher DOI
PubMed ID
42414599
Abstract
Amoeboid cell migration is key to efficient T cell immunity. Spatial polarization of organelles within cells, including endo-lysosomes, is a prerequisite of migration. However, how ultrastructural polarization is linked to the signaling requirements governing T cell migration remains unknown. Here we show that signaling molecules generated by endo-lysosome-localized kinases regulate velocity of amoeboid migration. Specifically, imaging of T cells identifies accumulation of endo-lysosomes decorated with the lipid kinases VPS34-PIKfyve at the uropod of polarized cells. Activity of VPS34 and PIKfyve regulates speed, but not directedness, of migrating T cells. Mechanistically, PI(3,5)P2 generated by the sequential action of VPS34 and PIKfyve, mediates Ca2+ efflux from lysosomes via the mucolipin TRP cation channel 1 (TRPML1), thus controlling activity of myosin IIA and hence the generation of propulsive force through retrograde actin flow. The VPS34-PIKfyve kinases also regulate velocity of myeloid cells, as well as of the amoeba Dictyostelium discoideum - establishing the axis as an evolutionarily conserved speed control system of amoeboid cell migration.
Date Issued
2026-07-07
Publication Type
Article
Language(s)
en
Author(s)
Dehio, Philippe
Michard, Céline
Yam-Puc, Juan Carlos
Martí I Líndez, Adrià-Arnau
Jandke, Anett
Unterstab, Gunhild
Fabre, Lucien
Sauteur, Loïc
Artinger, Marc
Sixt, Michael
Schaefer, Thorsten
Wymann, Matthias P.
Okkenhaug, Klaus
Soldati, Thierry
Mehling, Matthias
Hess, Christoph
Additional Credits
Journal
EMBO Reports
Publisher
Springer Nature
ISSN
1469-3178
Access(Rights)
open.access
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