The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans

Modi Safra, Shani Ben-Hamo, Cynthia Kenyon, Sivan Henis-Korenblit

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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 Aβ 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.

Original languageEnglish
Pages (from-to)4136-4146
Number of pages11
JournalJournal of Cell Science
Volume126
Issue number18
DOIs
StatePublished - 15 Sep 2013

Funding

FundersFunder number
National Institutes of Health
United States - Israel Binational Science Foundation2009356
National Institute on AgingR37AG011816
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK063720

    Keywords

    • Alzheimer's disease
    • Caenorhabditis elegans
    • Coelomocytes
    • ER stress
    • ERAD
    • UPR

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