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.
Highlights
In professional phagocytic cells such as macrophages, phagocytosis is the process of the engulfment and internalization of pathogens and other large particles (> 0.5 lm) into vesicular phagosomes
Frustrated phagocytosis can be induced by dropping bone marrow-derived macrophages (BMDMs) onto IgG-coated coverslips, engaging Fcc receptors as they come into contact though they are unable to engulf the target
The substantial global signals measured with cytosolic Ca2+ reporters are predominantly comprised of Ca2+ release from the ER and Ca2+ entry across the plasma membrane (Demaurex & Nunes, 2016; Westman et al, 2019), but these potentially mask local Ca2+ nanodomains that are invisible in global recordings
Summary
In professional phagocytic cells such as macrophages, phagocytosis is the process of the engulfment and internalization of pathogens and other large particles (> 0.5 lm) into vesicular phagosomes. Phagocytosis is a multi-step process that involves signal transduction pathways, rearrangements of the actin cytoskeleton and membrane trafficking (Flannagan et al, 2012). Endo-lysosomes have traditionally been assigned multiple roles as downstream effectors. Endo-lysosomes may provide additional membrane to the growing, nascent phagosome (Bajno et al, 2000; Czibener et al, 2006; Samie et al, 2013). Phagosomes mature by fusing with endolysosomes to transform the phagosome into an acidic and digestive phagolysosome where the enclosed pathogen is degraded (Flannagan et al, 2012). Lysosome upregulation via TFEB activation primes the bactericidal competency of macrophages (Gray et al, 2016)
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