PIKfyve: Partners, significance, debates and paradoxes

Key components of membrane trafficking and signaling machinery in eukaryotic cells are proteins that bind or synthesize phosphoinositides. PIKfyve, a product of an evolutionarily conserved single-copy gene has both these features. It binds to membrane phosphatidylinositol (PtdIns)3P and synthesizes PtdIns(3,5)P2 and PtdIns5P. Molecular functions of PIKfyve are elusive but recent advances are consistent with a key role in the course of endosomal transport. PIKfyve dysfunction induces endosome enlargement and profound cytoplasmic vacuolation, likely as a result of impaired normal endosome processing and membrane exit out of endosomes. Multicellular organisms with genetically impaired function of PIKfyve or that of the PIKfyve protein partners regulating PtdIns(3,5)P2 homeostasis display severe disorders, including embryonic/perinatal death. This review describes recent advances on PIKfyve functionality in higher eukaryotes, with particular reference to biochemical and genetic insights in PIKfyve protein partners.