CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis

Mechanisms of selective autophagy of the ER, known as ER-phagy, require molecular delineation, particularly in vivo. It is unclear how these events control ER proteostasis and cellular health. Here, we identify cell-cycle progression gene 1 (CCPG1), an ER-resident protein with no known physiological role, as a non-canonical cargo receptor that directly binds to core autophagy proteins via an LIR motif to mammalian ATG8 proteins and, independently and via a discrete motif, to FIP200. These interactions facilitate ER-phagy. The CCPG1 gene is inducible by the unfolded protein response and thus directly links ER stress to ER-phagy. In vivo, CCPG1 protects against ER luminal protein aggregation and consequent unfolded protein response hyperactivation and tissue injury of the exocrine pancreas. Thus, via identification of this autophagy protein, we describe an unexpected molecular mechanism of ER-phagy and provide evidence that this may be physiologically relevant in ER luminal proteostasis. [Display omitted] •CCPG1 is an ER stress-inducible ER-phagy cargo receptor in mammals•CCPG1 binds directly to ATG8 proteins and FIP200 via distinct peptide motifs•CCPG1 lysosomal degradation and ER-phagy both require these interactions•CCPG1 maintains normal ER luminal proteostasis in pancreatic acinar cells in vivo The mechanisms and physiological functions of ER autophagy (ER-phagy) are incompletely understood. Smith et al. show that the ER membrane-resident protein CCPG1 is an effector of ER stress responses, driving ER-phagy via interaction with ATG8 and FIP200. CCPG1 maintains ER luminal proteostasis within pancreatic acinar cells in vivo.