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

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

Author information

1
Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
2
Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, München, Germany.
3
Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK. Electronic address: s.wilkinson@ed.ac.uk.

Abstract

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

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PMID:
29290589
PMCID:
PMC5791736
DOI:
10.1016/j.devcel.2017.11.024
[Indexed for MEDLINE]
Free PMC Article

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