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

The EMBO Journal
Lianne C DavisAntony Galione

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.

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Citations

Sep 16, 2020·Pharmacology Research & Perspectives·Paula M Heister, Robin N Poston
Dec 18, 2020·Journal of Cell Science·Anthony J Morgan, Antony Galione
Mar 12, 2021·Current Opinion in Cell Biology·Sarah R ChadwickSpencer A Freeman
Apr 20, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·Anthony J MorganAntony Galione
May 15, 2021·Frontiers in Immunology·Abeer F Alharbi, John Parrington
May 23, 2021·Scientific Reports·Paula Maria HeisterAntony Galione
Aug 26, 2021·Journal of Cell Science·Anthony J Morgan, Antony Galione
Dec 7, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Cheng-Chang ChenChristian Grimm
Oct 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Bhavyashree SureshYamuna Krishnan

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Datasets Mentioned

BETA
BC058951
BC015484

Methods Mentioned

BETA
transfection
GTPase
FRET
biosensor
FCS

Software Mentioned

Winmax
Instat
GraphPad Prism
Magipix
GeneArt synthesis

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