title: The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans.
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.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Life Sciences Building 212, Room 408, Bar-Ilan University, Ramat Gan, Israel.
authors.forename: Modi
authors.initials: M
authors.lastname: Safra
authors.forename: Shani
authors.initials: S
authors.lastname: Ben-Hamo
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kenyon
authors.forename: Sivan
authors.initials: S
authors.lastname: Henis-Korenblit
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D056811:Unfolded Protein Response
chemical_list: D029742:Caenorhabditis elegans Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C541905:IRE-1 protein, C elegans
keywords: Alzheimer's disease; Caenorhabditis elegans; Coelomocytes; ER stress; ERAD; UPR