NAADP-regulated two-pore channels drive phagocytosis through endo-lysosomal Ca2+ nanodomains, calcineurin and dynamin.
EMBO J
; 39(14): e104058, 2020 07 15.
Article
em En
| MEDLINE
| ID: mdl-32510172
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fagocitose
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Endossomos
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Calcineurina
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Dinamina II
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Lisossomos
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Macrófagos
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NADP
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article