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

Dev Cell. 2018 Jan 22;44(2):217-232.e11. doi: 10.1016/j.devcel.2017.11.024. Epub 2017 Dec 28.


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.

Keywords: Atg8; CCPG1; ER-phagy; FIP200; autophagy; pancreas; proteostasis; tissue homeostasis; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / metabolism
  • Autophagy*
  • Autophagy-Related Protein 8 Family / metabolism
  • Autophagy-Related Proteins
  • Biological Transport
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cytosol / metabolism
  • Endoplasmic Reticulum / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • Pancreas / metabolism*
  • Pancreas / ultrastructure
  • Phenotype
  • Protein Interaction Domains and Motifs
  • Protein-Tyrosine Kinases / metabolism
  • Proteostasis*
  • Unfolded Protein Response


  • Autophagy-Related Protein 8 Family
  • Autophagy-Related Proteins
  • CCPG1 protein, human
  • Ccpg1 protein, mouse
  • Cell Cycle Proteins
  • RB1CC1 protein, human
  • Protein-Tyrosine Kinases