CALCOCO1 acts with VAMP-associated proteins to mediate ER-phagy

The endoplasmic reticulum (ER) plays important roles in protein synthesis and folding, and calcium storage. The volume of theERand expression of its resident proteins are increased in response to nutrient stress.ER-phagy, a selective form of autophagy, is involved in the degradation of the excess components of theERto restore homeostasis. SixER-resident proteins have been identified asER-phagy receptors so far. In this study, we have identifiedCALCOCO1 as a novelER-phagy receptor for the degradation of the tubularERin response to proteotoxic and nutrient stress.CALCOCO1 is a homomeric protein that binds directly toATG8 proteins viaLIR- andUDS-interacting region (UIR) motifs acting co-dependently.CALCOCO1-mediatedER-phagy requires interaction withVAMP-associated proteinsVAPAandVAPBon theERmembranes via a conservedFFAT-like motif. Depletion ofCALCOCO1 causes expansion of theERand inefficient basal autophagy flux. Unlike the otherER-phagy receptors,CALCOCO1 is peripherally associated with theER. Therefore, we defineCALCOCO1 as a solubleER-phagy receptor.