GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion.

ABSTRACT: The Atg8 autophagy proteins are essential for autophagosome biogenesis and maturation. The ?-aminobutyric acid receptor-associated protein (GABARAP) Atg8 family is much less understood than the LC3 Atg8 family, and the relationship between the GABARAPs' previously identified roles as modulators of transmembrane protein trafficking and autophagy is not known. Here we report that GABARAPs recruit palmitoylated PI4KII?, a lipid kinase that generates phosphatidylinositol 4-phosphate (PI4P) and binds GABARAPs, from the perinuclear Golgi region to autophagosomes to generate PI4P in situ. Depletion of either GABARAP or PI4KII?, or overexpression of a dominant-negative kinase-dead PI4KII? mutant, decreases autophagy flux by blocking autophagsome:lysosome fusion, resulting in the accumulation of abnormally large autophagosomes. The autophagosome defects are rescued by overexpressing PI4KII? or by restoring intracellular PI4P through "PI4P shuttling." Importantly, PI4KII?'s role in autophagy is distinct from that of PI4KIII? and is independent of subsequent phosphatidylinositol 4,5 biphosphate (PIP2) generation. Thus, GABARAPs recruit PI4KII? to autophagosomes, and PI4P generation on autophagosomes is critically important for fusion with lysosomes. Our results establish that PI4KII? and PI4P are essential effectors of the GABARAP interactome's fusion machinery.

SUBMITTER: Wang H 

PROVIDER: S-EPMC4460452 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature