Editors' ChoiceCell Biology

ER-phagy to alleviate stress

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Sci. Signal.  06 Feb 2018:
Vol. 11, Issue 516, eaat1772
DOI: 10.1126/scisignal.aat1772

Selective autophagy of the endoplasmic reticulum protects the secretory cells of the pancreas.

Selective autophagy rids cells of protein aggregates, pathogens, and damaged or dysfunctional organelles. It is mediated by cargo receptors that bind to both the material that is to be degraded and the machinery that drives the formation of autophagosomes. A few cargo receptors have been identified for the selective degradation of the endoplasmic reticulum (ER-phagy); however, the physiological role of ER-phagy remains unclear (see Mizushima). Smith et al. found that the ER-resident protein cell cycle progression gene 1 (CCPG1) trafficked between the ER and autophagosomes in cultured lung cancer cells and bound to both FIP200 and ATG8, proteins that are recruited to sites of autophagosome formation, in vitro. Pharmacological agents that induce ER stress and the unfolded protein response reduced the peripheral ER content and stimulated ER-phagy in HeLa cells in a manner dependent on endogenous CCPG1 and the autophagy machinery component ATG5. Because the acinar cells of the pancreas produce and secrete large amounts of digestive enzymes, they are particularly sensitive to ER stress. The authors examined the pancreases of Ccpg1 knockout mice and found that these organs were filled with opaque masses of insoluble proteins. Acinar cells from Ccpg1-deficient mice contained more protein aggregates than those from wild-type mice and exhibited defects in ER morphology. The aggregates contained mainly secreted proteins that are synthesized in the ER and ER luminal proteins that are important for processing proteins in the ER. These findings identify CCPG1 as a cargo receptor for ER-phagy and demonstrate that ER-phagy is physiologically important for ER proteostasis in pancreatic acinar cells, suggesting that it may also play an important role in other secretory cell types, such as osteoblasts and goblet cells.

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