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Autophagosome formation is initiated at phosphatidylinositol synthase‐enriched ER subdomains
Author(s) -
Nishimura Taki,
Tamura Norito,
Kono Nozomu,
Shimanaka Yuta,
Arai Hiroyuki,
Yamamoto Hayashi,
Mizushima Noboru
Publication year - 2017
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.201695189
Subject(s) - biology , phosphatidylinositol , microbiology and biotechnology , atp synthase , biochemistry , signal transduction , enzyme
The autophagosome, a double‐membrane structure mediating degradation of cytoplasmic materials by macroautophagy, is formed in close proximity to the endoplasmic reticulum ( ER ). However, how the ER membrane is involved in autophagy initiation and to which membrane structures the autophagy‐initiation complex is localized have not been fully characterized. Here, we were able to biochemically analyze autophagic intermediate membranes and show that the autophagy‐initiation complex containing ULK and FIP 200 first associates with the ER membrane. To further characterize the ER subdomain, we screened phospholipid biosynthetic enzymes and found that the autophagy‐initiation complex localizes to phosphatidylinositol synthase ( PIS )‐enriched ER subdomains. Then, the initiation complex translocates to the ATG 9A‐positive autophagosome precursors in a PI 3P‐dependent manner. Depletion of phosphatidylinositol ( PI ) by targeting bacterial PI ‐specific phospholipase C to the PIS domain impairs recruitment of downstream autophagy factors and autophagosome formation. These findings suggest that the autophagy‐initiation complex, the PIS ‐enriched ER subdomain, and ATG 9A vesicles together initiate autophagosome formation.