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EMBO J. 2016 Sep 1;35(17):1853-67. doi: 10.15252/embj.201593148. Epub 2016 Jun 23.

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

Author information

  • 1Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences Osaka University, Osaka, Japan Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan.
  • 2Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences Osaka University, Osaka, Japan.
  • 3Department of Genetics, Graduate School of Medicine Osaka University, Osaka, Japan.
  • 4Laboratory 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.

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.

KEYWORDS:

Joubert syndrome; autophagosomes; lysosomes; phosphoinositides

PMID:
27340123
PMCID:
PMC5007553
[Available on 2017-09-01]
DOI:
10.15252/embj.201593148
[PubMed - in process]
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