The lumen of the endoplasmic reticulum (ER) is a highly specialized compartment in eukaryotic cells. Here, secretory and most membrane proteins are folded, covalently modified, and oligomerized with the assistance of specialized ER resident proteins (1 ). Perturbation of the ER lumen interferes with the production of many essential cellular components and can thus be highly deleterious. Indeed, in humans, defects in protein folding in the ER can lead to devastating diseases, such as cystic fibrosis, alpha1-antitrypsin deficiency, and osteogenesis imperfecta (2 ). One way in which cells cope with the accumulation of unfolded proteins in the ER is by activating the unfolded protein response (UPR), an ER-to-nucleus signal transduction pathway (3 –5 ). In the yeastSaccharomyces cerevisiae, Ire1p is an essential component of this pathway.
