Spatiotemporal control of Atg2 association with the ER during autophagosome formation
成果类型：
Article
署名作者：
Kotani, Tetsuya; Tanabe, Haruki; Kitta, Shinri; Higashi, Momoko; Niwa, Tatsuya; Kaminishi, Tatsuya; Kakuta, Chika; Shimasaki, Junko; Kosako, Hidetaka; Yoshimori, Tamotsu; Kuma, Akiko; Nakatogawa, Hitoshi
署名单位：
University of Osaka; University of Osaka; Tokushima University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-8424; 1091-6490
DOI：
10.1073/pnas.2606606123
发表日期：
2026-08-04
页码：
e2606606123
关键词：
Atg2
autophagy
lipid transfer protein
phospho-FFAT motif
VAP protein
protein-kinase
induction
motif
activation
membranes
sequence
摘要：
Autophagy degrades various intracellular components by sequestering them within membrane vesicles called autophagosomes and delivering them to lysosomes or vacuoles. Previous studies have revealed that the conserved, bridge-like lipid transfer protein Atg2 tethers autophagosome precursors to the endoplasmic reticulum (ER) and mediates lipid supply from the ER to drive their expansion into autophagosomes. However, how Atg2 docks onto the ER has remained unclear. Here, we show in Saccharomyces cerevisiae that Atg2 interacts with the ER-resident VAP family protein Scs2. This interaction is mediated by a phospho-FFAT motif in Atg2 and the major sperm protein domain of Scs2 and enhanced by phosphorylation of the motif by the autophagy-initiating kinase Atg1, which is activated at the autophagosome formation site upon autophagy induction. This interaction cooperates with the N-terminal region of Atg2, which contains a weakly amphipathic helix, to mediate Atg2 association with the ER. Thus, the Atg2-Scs2 interaction functions as a spatiotemporal switch that controls Atg2-ER association. We also show that mammalian ATG2 interacts with the VAP-like proteins MOSPD1 and MOSPD3 to promote autophagosome formation. Collectively, this study reveals a conserved mechanism that initiates lipid transfer during autophagosome formation.
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