Tight regulation of the unfolded protein sensor Ire1 by its intramolecularly antagonizing subdomain

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) accompanies ER stress and causes the type‐I transmembrane protein Ire1 (also known as ERN1) to trigger the unfolded protein response (UPR). When dimerized, the core stress‐sensing region (CSSR) of Ire1 directly captures unfolded proteins and forms a high‐order oligomer, leading to clustering and activation of Ire1. The CSSR is N‐terminally flanked by an intrinsically disordered subdomain, which we previously named Subregion I, in Saccharomyces cerevisiae Ire1. In this study, we describe tight repression of Ire1 activity by Subregion I under conditions of no or weak stress. Weak hyperactivation of an Ire1 mutant lacking Subregion I slightly retarded growth of yeast cells cultured under unstressed conditions. Fungal Ire1 orthologs and the animal Ire1 family protein PERK (also known as EIF2AK3) carry N‐terminal intrinsically disordered subdomains with a similar structure and function to that of Subregion I. Our observations presented here cumulatively indicate that Subregion I is captured by the CSSR as an unfolded protein substrate. This intramolecular subdomain interaction is likely to compromise self‐association of the CSSR, explaining why Subregion I can suppress Ire1 activity when ER‐accumulated unfolded proteins are not abundant