Journal
DEVELOPMENTAL CELL
Volume 44, Issue 2, Pages 217-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2017.11.024
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Funding
- Cancer Research UK Career Development Fellowship [C20685/A12825]
- BBSRC grant [BB/N000315/1]
- Deutsche Forschungsgemeinschaft (German Research Foundation) within Munich Cluster for Systems Neurology [EXC 1010 SyNergy]
- Medical Research Council [MR/K01563X/1]
- BBSRC [BB/N000315/1] Funding Source: UKRI
- MRC [MR/K01563X/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N000315/1] Funding Source: researchfish
- Cancer Research UK [12825] Funding Source: researchfish
- Medical Research Council [MR/K01563X/1] Funding Source: researchfish
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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.
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