Journal
JOURNAL OF CELL SCIENCE
Volume 126, Issue 18, Pages 4136-4146Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.123000
Keywords
UPR; Caenorhabditis elegans; ER stress; ERAD; Coelomocytes; Alzheimer's disease
Categories
Funding
- National Institutes of Health [R37 AG011816]
- United States-Israel Binational Science Foundation [2009356]
- Israel Science Foundation [1749/11]
- Marie Curie International Reintegration Grant [256551]
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The unfolded protein response (UPR) allows cells to cope with endoplasmic reticulum (ER) stress by adjusting the capacity of the ER to the load of ER-associated tasks. The UPR is important for maintaining ER homeostasis under extreme ER stress. UPR genes are important under normal growth conditions as well, but what they are required for under these conditions is less clear. Using C. elegans, we show that the ire-1/xbp-1 arm of the UPR plays a crucial role in maintaining ER plasticity and function also in the absence of external ER stress. We find that during unstressed growth conditions, loss of ire-1 or xbp-1 compromises basic ER functions required for the metabolism of secreted proteins, including translation, folding and secretion. Notably, by compromising ER-associated degradation (ERAD) and phagocytosis, loss of ire-1 hinders the clearance of misfolded proteins from the ER as well as the clearance of proteins that were secreted into the pseudocoleom. Whereas the basal activity of the UPR is beneficial under normal conditions, it accelerates the pathology caused by toxic A beta protein in a C. elegans model of Alzheimer's disease. Taken together, our findings indicate that UPR genes are critical for maintaining secretory protein metabolism under normal growth conditions.
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