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.

Effector T lymphocytes are avid nutrient consumers, but can function in nutrient-poor tumor microenvironments. Availability of key nutrients such as glucose inside the tumor is not homogeneous, and ho...

EMBO Reports - US federal policies to establish a ‘gold standard science’ threaten to undermine academic freedom. Individual scientists and institutions must re-articulate why the...