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...

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Patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency typically suffer from severe B cell dysfunction. However, the underlying mechanisms remain incompletely understo...

The chemical composition of membrane lipids differs between eukarya, bacteria and archaea. The central dogma posits that the stereochemistry of phospholipids in bacteria is distinct from archaea. Bact...

Stress granules (SGs) are transient cytoplasmic biomolecular condensates that play a role in the cellular response to proteotoxic stress. It has been previously shown that ubiquitination regulates SG ...

Predicting the fitness effects of mutations is central to understanding molecular evolution and interpreting genome sequence data. Such predictions remain challenging due to the inter-dependent roles ...

The MINDY family of deubiquitinases (DUBs) are exemplified by their preference for cleaving K48-linked polyubiquitin. MINDY3 is architecturally distinct from other MINDY DUBs as its catalytic domain s...