Phagocytosis is an essential function of many immune cells. Phagosomes fuse with endosomes and lysosomes along the phagocytic pathway – a process that requires ATP and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) membrane fusion complexes. Membrane fusion can be regulated by Ca2+, but it is unclear whether this occurs in phagosome-lysosome fusion (PLF). In this study (Becker et al., 2023), Albert Haas and colleagues use in vitro reconstitution of PLF with phagosomes and lysosomes purified from macrophages to demonstrate that it can be driven by micromolar Ca2+ in the absence of ATP. Interestingly, Ca2+-driven fusion (CaFu) occurs more rapidly than standard ATP-dependent fusion. To dissect at which stage of PLF Ca2+ acts, the authors test which of the factors involved in diverse membrane fusion processes have a role in CaFu. They show that this process likely requires Q-SNARE subcomplex function in late fusion events, but not Rab GTPases or annexins that canonically assist in earlier membrane priming and tethering steps. Although the specific Ca2+-dependent factor in PLF has not yet been identified, the authors hypothesise that it mediates SNARE complex interactions to facilitate membrane fusion in response to Ca2+ efflux from lysosomes. This study uncovers a previously overlooked step in the phagocytic pathway that can bypass earlier stages of fusion complex assembly to rapidly promote PLF.
