Proceedings of the National Academy of Sciences of the United States of AmericaJul 29, 2026

Timing and location of Atg2 joining the cell's membrane system during autophagosome formation

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Updated Aug 3, 2026

Abstract

Atg2 interacts with the ER-resident protein Scs2 to facilitate lipid transfer for autophagosome formation.

The interaction between Atg2 and Scs2 is mediated by a specific motif in Atg2 and a domain in Scs2.
Phosphorylation of Atg2 by the kinase Atg1 enhances its interaction with Scs2.
This Atg2-Scs2 interaction acts as a spatiotemporal switch that regulates Atg2's association with the endoplasmic reticulum.
Mammalian ATG2 shows similar interactions with VAP-like proteins MOSPD1 and MOSPD3, contributing to autophagosome formation.
The findings suggest a conserved mechanism for initiating lipid transfer during the formation of autophagosomes.

Simplified

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 <i>Saccharomyces cerevisiae</i> 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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Timing and location of Atg2 joining the cell's membrane system during autophagosome formation

Abstract

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