Solid particles such as pathogens, dying cells, and debris are engulfed by macrophages
and neutrophils and sequestered into a phagosome. Phagosomes fuse with early and
late endosomes and ultimately with lysosomes to mature into phagolysosomes, a
process known as phagosome maturation. The formation of highly acidic and
degradative phagolysosomes plays an important role in degradation of the internalized
particle. We employed siRNA and pharmacological tools to demonstrate that
phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2], synthesized by the PIKfyve lipid
kinase, is required for phagosome maturation. However, the mechanism by which
PI(3,5)P2 controls phagosome maturation remained uncharacterized. We hypothesized
that PI(3,5)P2 may control phagosome-lysosome fusion partly by stimulating TRPML1, a
lysosomal Ca2+ channel gated by PI(3,5)P2. Upon opening of the channel, lysosomal Ca2+
would diffuse and trigger phagosome-lysosome fusion since Ca2+ is known to induce
membrane fusion post-docking of SNARE proteins. In addition, we also demonstrated
that the lipid kinase PIKfyve coordinates the neutrophils immune response by
controlling phagosome maturation and regulating Rac GTPase activity. PIKfyve produces
both PI(3,5)P2 and phosphatidylinositol-5-phosphate (PI5P); therefore, it might control
phagosome maturation through production of PI(3,5)P2 and activation of TRPML1 as
well as regulates ROS production and chemotaxis through synthesis of PI5P, which leads
to the activation of Tiam1, and Rac GTPase.
The Lipid Kinase PIKfyve Coordinates the Neutrophil Immune Response through the Activation of the Rac GTPase