Graduate School of Frontier Biosciences, Osaka University

Japanese

Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome

Journal EMBO J, e201593148 (2016)
Authors Hasegawa J (1), Iwamoto R (2), Otomo T (3), Nezu A (3), Hamasaki M (1), Yoshimori T (4).
  1. 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.
  2. Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences Osaka University, Osaka, Japan.
  3. Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan.
  4. 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.
Title Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome
PubMed 27340123
Laboratory Laboratory of Intracellular Membrane Dynamics 〈Prof. Yoshimori〉
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 filaments stabilization on lysosomes. Lysosomes requires 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.