NAADP-regulated two-pore channels drive phagocytosis through endo-lysosomal Ca²⁺ nanodomains, calcineurin and dynamin.

Macrophages clear pathogens by phagocytosis and lysosomes that fuse with phagosomes are traditionally regarded as to a source of membranes and luminal degradative enzymes. Here, we reveal that endo-lysosomes act as platforms for a new phagocytic signalling pathway in which FcγR activation recruits the second messenger NAADP and thereby promotes the opening of Ca²⁺ -permeable two-pore channels (TPCs). Remarkably, phagocytosis is driven by these local endo-lysosomal Ca²⁺ nanodomains rather than global cytoplasmic or ER Ca²⁺ signals. Motile endolysosomes contact nascent phagosomes to promote phagocytosis, whereas endo-lysosome immobilization prevents it. We show that TPC-released Ca²⁺ rapidly activates calcineurin, which in turn dephosphorylates and activates the GTPase dynamin-2. Finally, we find that different endo-lysosomal Ca²⁺ channels play diverse roles, with TPCs providing a universal phagocytic signal for a wide range of particles and TRPML1 being only required for phagocytosis of large targets.

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