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

J Cell Sci. 2015 May 1;128(9):1762-72. doi: 10.1242/jcs.164111. Epub 2015 Mar 13.


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.

Keywords: Endoplasmic reticulum; Intrinsically disordered region; Misfolded protein; Molecular chaperone; Stress response; Unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mammals
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • NIH 3T3 Cells
  • Peptides / metabolism
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Structure, Tertiary
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sequence Deletion
  • Time Factors
  • Two-Hybrid System Techniques
  • Unfolded Protein Response*
  • eIF-2 Kinase / metabolism


  • Membrane Glycoproteins
  • Mutant Proteins
  • Peptides
  • Saccharomyces cerevisiae Proteins
  • IRE1 protein, S cerevisiae
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase