Tight regulation of Ire1

The unfolded protein response (UPR) is a cellular stress response that is initiated when unfolded or misfolded proteins accumulate in the lumen of the endoplasmic reticulum (ER). The ER-resident transmembrane protein Ire1 functions as an ER-stress sensor that triggers the UPR. Its lumenal domain has a tightly folded region called the core stress-sensing region (CSSR), and the dimeric form of the CSSR can capture unfolded proteins, leading to Ire1 oligomerization and activation. Inappropriate activation of Ire1 or the UPR can lead to cell death, so understanding how Ire1 is regulated is important. Here (p. 1762), Rubwad Mathuranyanon and co-workers show, by analyzing the efficiency of the UPR in cells with mutations in Ire1, that Saccharomyces cerevisiae Ire1 has an intrinsically disordered subdomain at its N-terminus (known as the N-terminal unconserved region, NUCR) that can act as an autoinhibitory regulator when the cells are not under ER stress. NUCR domains from other fungal Ire1 orthologues and from the mammalian Ire1 family protein PERK could also inhibit the activation of yeast Ire1. In addition, PERK itself was hyperactivated upon removal of its NUCR in mouse cells. An in vitro competition assay revealed that the NUCR had an affinity for the CSSR, suggesting that it acts by preventing CSSR self-association when unfolded proteins are not abundant. These findings provide clear evidence for a new regulatory mechanism for yeast Ire1.