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Autophagosome–lysosome fusion in neurons requires INPP 5E, a protein associated with Joubert syndrome
Author(s) -
Hasegawa Junya,
Iwamoto Ryo,
Otomo Takanobu,
Nezu Akiko,
Hamasaki Maho,
Yoshimori Tamotsu
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593148
Subject(s) - biology , lysosome , joubert syndrome , fusion protein , microbiology and biotechnology , neuroscience , biochemistry , recombinant dna , gene , enzyme , cilium
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 ( INPP 5E), involved in autophagosome–lysosome fusion process. In neuronal cells, INPP 5E knockdown strongly inhibited autophagy by impairing the fusion step. A fraction of INPP 5E is localized to lysosomes, and its membrane anchoring and enzymatic activity are necessary for autophagy. INPP 5E decreases lysosomal phosphatidylinositol 3,5‐bisphosphate ( PI (3,5)P 2 ), 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. INPP 5E 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.