Underlying mechanism of Atg2-mediated lipid transfer in autophagy identified

Autophagy, the intracellular degradation mechanism in eukaryotes, relies on the transfer of lipids from the endoplasmic reticulum (ER) to form autophagosomes. The protein Atg2, which plays a key role in this lipid transfer, was found to be activated upon localization to the pre-autophagosomal structure (PAS). This activation occurs through phosphorylation of a specific region called FFAT (two phenylalanines in an acidic tract).

When phosphorylated, FFAT can bind to the major sperm protein (MSP) domain of an ER-resident protein called Scs2, anchoring the PAS to the ER and facilitating lipid transfer. This phosphorylation serves as a spatiotemporal switch, ensuring that lipid transfer only occurs at sites of autophagosome formation. In yeast and mammals, the Atg2-Scs2 interaction is crucial for autophagosome formation, while in humans, Atg2 interacts with proteins similar to Scs2.

The research also highlights an independent N-terminal ER-binding mechanism, which, when combined with the phosphorylation-VAP interaction, synergistically modulates Atg2's association with the ER and subsequent lipid transfer. These findings suggest that the N-terminal region of Atg2, along with its binding to Scs2 through the phosphorylation-VAP mechanism, plays a vital role in autophagosome formation across all eukaryotes.