title: Regulation of lysosomal phosphoinositide balance by INPP5E is essential for autophagosome-lysosome fusion.
abstract: Macroautophagy (autophagy) is a multistep intracellular degradation system. Autophagosomes form, mature, and ultimately fuse with lysosomes, where their sequestered cargo molecules are digested. In contrast to autophagosome formation, our knowledge of autophagosome-lysosome fusion is limited. In a recent study, we identified a novel regulator of autophagy, INPP5E (inositol polyphosphate-5-phosphatase E), which is essential for autophagosome-lysosome fusion. INPP5E primarily functions in neuronal cells, and knockdown of the corresponding gene causes accumulation of autophagosomes by impairing fusion with lysosomes. Some INPP5E molecules localize at the lysosome, and both lysosomal localization and INPP5E enzymatic activity are crucial for autophagy. In addition, INPP5E decreases PtdIns(3,5)P2levels on lysosomes, leading to activation of CTTN (cortactin) and stabilization of actin filaments, which are also essential for autophagosome-lysosome fusion. Mutations in INPP5E are causative for Joubert syndrome, a rare brain abnormality, and our results indicate that defects in autophagy play a critical role in pathogenesis.
authors.affiliation: a Department of Genetics , Graduate School of Medicine, Osaka University , Osaka , Japan.|b Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University , Osaka , Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: a Department of Genetics , Graduate School of Medicine, Osaka University , Osaka , Japan.|b Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University , Osaka , Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Hasegawa
authors.affiliation: a Department of Genetics , Graduate School of Medicine, Osaka University , Osaka , Japan.|b Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University , Osaka , Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008561:Membrane Fusion; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases
keywords: INPP5E; Joubert syndrome; autophagosome; lysosome; phosphoinositides