The unfolded protein response: integrating stress signals through the stress sensor IRE1α

Physiol Rev. 2011 Oct;91(4):1219-43. doi: 10.1152/physrev.00001.2011.


Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.

Publication types

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

MeSH terms

  • DNA-Binding Proteins / physiology
  • Endoplasmic Reticulum / physiology
  • Endoribonucleases / physiology*
  • Homeostasis / physiology
  • Humans
  • Protein Serine-Threonine Kinases / physiology*
  • Protein Unfolding*
  • Regulatory Factor X Transcription Factors
  • Signal Transduction / physiology*
  • Stress, Physiological / physiology*
  • Transcription Factors / physiology
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases