article epub_ahead yes Philippe G Dehio author b769738e-a003-11ee-b1b8-9030316e0d59 Céline Michard author Juan Carlos Yam-Puc author Adrià Arnau Martí I Líndez author Anett Jandke author Gunhild Unterstab author Lucien Fabre author Loïc Sauteur author Marc Artinger author Daniel F. Legler author Michael K Sixt author 41E9FBEA-F248-11E8-B48F-1D18A9856A870000-0002-6620-9179 Thorsten Schaefer author Matthias P. Wymann author Klaus Okkenhaug author Thierry Soldati author Matthias Mehling author 3C23B994-F248-11E8-B48F-1D18A9856A870000-0001-8599-1226 Christoph Hess author MiSi department 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. Springer Nature2026 eng 1469-3178 4241459910.1038/s44319-026-00861-x Dehio, Philippe G, Céline Michard, Juan Carlos Yam-Puc, Adrià Arnau Martí I Líndez, Anett Jandke, Gunhild Unterstab, Lucien Fabre, et al. “A Conserved VPS34-PIKfyve-TRPML1-Myosin II Axis Regulates the Speed of Amoeboid Cell Migration.” <i>EMBO Reports</i>. Springer Nature, 2026. <a href="https://doi.org/10.1038/s44319-026-00861-x">https://doi.org/10.1038/s44319-026-00861-x</a>. Dehio PG, Michard C, Yam-Puc JC, Martí I Líndez AA, Jandke A, Unterstab G, Fabre L, Sauteur L, Artinger M, Legler DF, Sixt MK, Schaefer T, Wymann MP, Okkenhaug K, Soldati T, Mehling M, Hess C. 2026. A conserved VPS34-PIKfyve-TRPML1-myosin II axis regulates the speed of amoeboid cell migration. EMBO Reports. P. G. Dehio <i>et al.</i>, “A conserved VPS34-PIKfyve-TRPML1-myosin II axis regulates the speed of amoeboid cell migration,” <i>EMBO Reports</i>. Springer Nature, 2026. Dehio, Philippe G., et al. “A Conserved VPS34-PIKfyve-TRPML1-Myosin II Axis Regulates the Speed of Amoeboid Cell Migration.” <i>EMBO Reports</i>, Springer Nature, 2026, doi:<a href="https://doi.org/10.1038/s44319-026-00861-x">10.1038/s44319-026-00861-x</a>. P.G. Dehio, C. Michard, J.C. Yam-Puc, A.A. Martí I Líndez, A. Jandke, G. Unterstab, L. Fabre, L. Sauteur, M. Artinger, D.F. Legler, M.K. Sixt, T. Schaefer, M.P. Wymann, K. Okkenhaug, T. Soldati, M. Mehling, C. Hess, EMBO Reports (2026). Dehio, P. G., Michard, C., Yam-Puc, J. C., Martí I Líndez, A. A., Jandke, A., Unterstab, G., … Hess, C. (2026). A conserved VPS34-PIKfyve-TRPML1-myosin II axis regulates the speed of amoeboid cell migration. <i>EMBO Reports</i>. Springer Nature. <a href="https://doi.org/10.1038/s44319-026-00861-x">https://doi.org/10.1038/s44319-026-00861-x</a> Dehio PG, Michard C, Yam-Puc JC, et al. A conserved VPS34-PIKfyve-TRPML1-myosin II axis regulates the speed of amoeboid cell migration. <i>EMBO Reports</i>. 2026. doi:<a href="https://doi.org/10.1038/s44319-026-00861-x">10.1038/s44319-026-00861-x</a> 223712026-07-19T22:01:48Z2026-07-20T14:28:59Z