title: Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome.
abstract: Autophagy is a multistep membrane traffic pathway. In contrast to autophagosome formation, the mechanisms underlying autophagosome-lysosome fusion remain largely unknown. Here, we describe a novel autophagy regulator, inositol polyphosphate-5-phosphatase E (INPP5E), involved in autophagosome-lysosome fusion process. In neuronal cells, INPP5E knockdown strongly inhibited autophagy by impairing the fusion step. A fraction of INPP5E is localized to lysosomes, and its membrane anchoring and enzymatic activity are necessary for autophagy. INPP5E decreases lysosomal phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), one of the substrates of the phosphatase, that counteracts cortactin-mediated actin filament stabilization on lysosomes. Lysosomes require actin filaments on their surface for fusing with autophagosomes. INPP5E is one of the genes responsible for Joubert syndrome, a rare brain abnormality, and mutations found in patients with this disease caused defects in autophagy. Taken together, our data reveal a novel role of phosphoinositide on lysosomes and an association between autophagy and neuronal disease.
authors.affiliation: Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences Osaka University, Osaka, Japan Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Hasegawa
authors.affiliation: Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences Osaka University, Osaka, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.affiliation: Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otomo
authors.affiliation: Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nezu
authors.affiliation: Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences Osaka University, Osaka, Japan Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Hamasaki
authors.affiliation: Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences Osaka University, Osaka, Japan Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan tamyoshi@fbs.osaka-u.ac.jp.
authors.forename: Tamotsu
authors.identifier: 0000-0002-7041-890X
authors.initials: T
authors.lastname: Yoshimori
mesh_terms: D000015:Abnormalities, Multiple / Q000473:pathology; D000071182:Autophagosomes / Q000378:metabolism*; D002531:Cerebellum / Q000002:abnormalities / Q000473:pathology; D005124:Eye Abnormalities / Q000473:pathology; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008561:Membrane Fusion; D009474:Neurons / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D012160:Retina / Q000002:abnormalities / Q000473:pathology; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases
keywords: Joubert syndrome; autophagosomes; lysosomes; phosphoinositides