Endoplasmic reticulum (ER) stress activates the Unfolded Protein Response, a compensatory signaling response that is mediated by the IRE-1, PERK/PEK-1, and ATF-6 pathways in metazoans. Genetic studies have implicated roles for UPR signaling in animal development and disease, but the function of the UPR under physiological conditions, in the absence of chemical agents administered to induce ER stress, is not well understood. Here, we show that in Caenorhabditis elegans XBP-1 deficiency results in constitutive ER stress, reflected by increased basal levels of IRE-1 and PEK-1 activity under physiological conditions. We define a dynamic, temperature-dependent requirement for XBP-1 and PEK-1 activities that increases with immune activation and at elevated physiological temperatures in C. elegans. Our data suggest that the negative feedback loops involving the activation of IRE-1-XBP-1 and PEK-1 pathways serve essential roles, not only at the extremes of ER stress, but also in the maintenance of ER homeostasis under physiological conditions.
Proteins destined for secretion outside of eukaryotic cells are trafficked through the endoplasmic reticulum (ER). Protein folding in the ER involves the activity of chaperones, as well as catalysis of post-translational modifications such as disulfide bond formation and glycosylation. When the folding capacity of the ER is exceeded, the resulting accumulation of misfolded proteins activates the Unfolded Protein Response (UPR), a conserved signaling response that functions to restore protein folding homeostasis in the ER. Genetic studies have established that the UPR is required for the development of specific cell types in mammals, such as antibody-secreting plasma cells, and recent studies implicate a critical role for UPR signaling in the pathogenesis of metabolic and inflammatory diseases. In this paper we show that innate immunity and elevated physiological temperatures each necessitate UPR activity for C. elegans survival. Furthermore, we show that, under physiological conditions of larval development, basal activity of the UPR is required for the maintenance of ER homeostasis. Our data support the idea not only that the UPR functions as a “stress response” pathway, protecting against the extremes of unfolded protein accumulation, but also that the UPR plays a more general role in animal physiology and development.