| Summary: | 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 (TPC s). 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 GTP ase dynamin‐2. Finally, we find that different endo‐lysosomal Ca2+ channels play diverse roles, with TPC s providing a universal phagocytic signal for a wide range of particles and TRPML 1 being only required for phagocytosis of large targets.
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