The role of the lipid kinase PIKfyve in the endosomal and phagosomal systems in macrophages

Macrophages engulf pathogens into phagosomes for degradation through a process known as phagocytosis. Nascent phagosomes progressively mature and fuse with early and late endosomes and lysosomes to form phagolysosomes, where pathogens are degraded by hydrolytic enzymes. Phosphatidylinositol-3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] are signaling lipids that recruit a unique set of effector proteins involved in distinct stages of membrane traffic to govern the function of early and late endosomes, respectively. Phagosome maturation requires the transient expression of PtdIns(3)P on early phagosomal membranes. Subsequently, PtdIns(3)P can be converted to PtdIns(3,5)P2 by the lipid kinase PIKfyve. Thus, it remains unclear if the role of PtdIns(3)P in phagosome maturation is direct and/or indirect, through the synthesis of PtdIns(3,5)P2. The role of PtdIns(3,5)P2 in the endosomal system in macrophages also requires further investigation. My thesis employs a pharmacological approach to address the role of PIKfyve in macrophage biology. In general, PtdIns(3,5)P2 appears to principally coordinate the later stages of endosome and phagosome maturation.