Fine-tuning of the unfolded protein response: Assembling the IRE1alpha interactome

Mol Cell. 2009 Sep 11;35(5):551-61. doi: 10.1016/j.molcel.2009.08.021.


Endoplasmic reticulum (ER) stress is a hallmark feature of secretory cells and many diseases, including cancer, neurodegeneration, and diabetes. Adaptation to protein-folding stress is mediated by the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). The UPR signals through three distinct stress sensors located at the ER membrane-IRE1alpha, ATF6, and PERK. Although PERK and IRE1alpha share functionally similar ER-luminal sensing domains and both are simultaneously activated in cellular paradigms of ER stress in vitro, they are selectively engaged in vivo by the physiological stress of unfolded proteins. The differences in terms of tissue-specific regulation of the UPR may be explained by the formation of distinct regulatory protein complexes. This concept is supported by the recent identification of adaptor and modulator proteins that directly interact with IRE1alpha. In this Review, we discuss recent evidence supporting a model where IRE1alpha signaling emerges as a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Autophagy
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum / enzymology*
  • Endoplasmic Reticulum / pathology
  • Endoribonucleases / chemistry
  • Endoribonucleases / metabolism*
  • Humans
  • Mice
  • Models, Molecular
  • Multienzyme Complexes
  • Protein Conformation
  • Protein Folding
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Stability
  • RNA, Messenger / metabolism
  • Regulatory Factor X Transcription Factors
  • Signal Transduction*
  • Stress, Physiological* / genetics
  • Time Factors
  • Transcription Factors / genetics
  • eIF-2 Kinase / metabolism


  • Activating Transcription Factor 6
  • DNA-Binding Proteins
  • Multienzyme Complexes
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • ERN1 protein, human
  • Ern1 protein, mouse
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases