ER membrane receptors engage core autophagy machinery to initiate ER-phagy

Endoplasmic reticulum (ER) phagy is the form of selective autophagy that governs ER abundance and integrity by targeting dysfunctional ER fragments for degradation. How the recognition of ER fragments as autophagy substrates is coupled to engagement of the core autophagic machinery is largely unknown. Here, using a combination of in vitro reconstitution systems, structural modeling, and cell biology, we demonstrate that ER membrane receptors directly engage the core autophagy component ATG9A, as well as the PI3P-binding protein WIPI2, to initiate ER-associated autophagosome biogenesis. ER-phagy receptor–ATG9A association nucleates the recruitment of the other key autophagy proteins required to initiate ER-phagy. In parallel, ER-phagy receptor–WIPI2 engagement promotes rapid LC3 lipidation for autophagic membrane expansion. These data show how ER-phagy receptors trigger the cascade of events leading to ER autophagosome formation.