Bohdanowicz et al. describe how different phosphatidylinositol phosphates (PIPs) promote actin polymerization on specific phagosome membranes to move the organelles through the cell.
Cells recognize phagocytic cargoes using distinct receptors, and engulf them in actin-rich pseudopods. Actin disassembles once the phagosome has internalized, but Bohdanowicz et al. noticed that a second wave of actin polymerization occurred on phagosomes formed by the phagocytic receptor CR3, forming “comet tails” that propelled the vacuoles through the cytoplasm. Phagosomes formed by a different receptor, FcγR, didn't induce a second burst of actin assembly.
Comet tail formation required the small GTPase Rac1 and the PIP PI(3,4,5)P3, both of which accumulated on CR3 phagosome membranes. PI(3,4,5)P3 was generated by class I PI3-kinases, which phosphorylated the precursor phospholipid PI(4,5)P2. Yet PI(3,4,5)P3 accumulation and comet-tail formation also required the production of PI(3)P by class III PI3-kinases. This monophosphorylated PIP displaced an inositol 5-phosphatase from phagosomes, allowing their membranes to accrue PI(4,5)P2 and PI(3,4,5)P3.
Why do only CR3 phagosomes form a comet tail? Bohdanowicz et al. found that phagosomes formed by this receptor retained PIP5-kinase, whereas FcγR phagosomes did not. PIP5-kinase generates PI(4,5)P2 as a precursor for PI(3,4,5)P3. Forcing PIP5-kinase onto FcγR phagosomes induced these vacuoles to accumulate PI(3,4,5)P3 and assemble comet tails.
Senior author Sergio Grinstein now wants to investigate why PIP5-kinase preferentially localizes to CR3 phagosomes. The specific assembly of actin on these vacuoles may help them mature faster, potentially explaining why cargoes—such as the pathogen Mycobacterium tuberculosis—can have different fates depending on the phagocytic receptor that internalizes them.