Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering

Abstract

(Figure presented.) Proteotoxic stress causes the endoplasmic reticulum (ER) stress sensor IRE1α to cluster, but the mechanistic basis of its cluster formation remains poorly understood. This study reveals that disordered regions within the protein’s ER lumenal domain (LD) mediate its assembly into signaling clusters. IRE1α LD forms biomolecular condensates in solution. Disordered regions within IRE1α LD drive the formation of condensates through weak multivalent interactions. Binding of unfolded polypeptide ligands and membrane-tethering leads to the formation of stable IRE1α LD clusters. The integrity of the disordered regions in its lumenal domain is critical for IRE1α clustering and unfolded protein response (UPR) signaling in cells.