PtdIns(3,5)P2 is one of the seven regulatory PPIn (polyphosphoinositides) that are ubiquitous in eukaryotes. It controls membrane trafficking at multiple points in the endosomal/lysosomal system and consequently regulates the size, shape and acidity of at least one endo-lysosomal compartment. PtdIns(3,5)P2 appears to exert this control via multiple effector proteins, with each effector specific for a subset of the various PtdIns(3,5)P2-dependent processes. Some putative PtdIns(3,5)P2 effectors have been identified, including Atg18p-related PROPPIN [β-propeller(s) that bind PPIn] proteins and the epsin-like proteins Ent3p and Ent5p, whereas others remain to be defined. One of the principal functions of PtdIns(3,5)P2 is to regulate the fission/fragmentation of endo-lysosomal sub-compartments. PtdIns(3,5)P2 is required for vesicle formation during protein trafficking between endo-lysosomes and also for fragmentation of endo-lysosomes into smaller compartments. In yeast, hyperosmotic stress accelerates the latter process. In the present review we highlight and discuss recent studies that reveal the role of the HOPS–CORVET complex and the vacuolar H+-ATPase in the process of endo-lysosome fission, and speculate on connections between these machineries and the Fab1p pathway. We also discuss new evidence linking PtdIns(3,5)P2 and PtdIns5P to the regulation of exocytosis.

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