The unfolded protein response: from stress pathway to homeostatic regulation

Science. 2011 Nov 25;334(6059):1081-6. doi: 10.1126/science.1209038.


The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Apoptosis
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress*
  • Endoplasmic Reticulum-Associated Degradation
  • Endoribonucleases / metabolism
  • Gene Expression Regulation
  • Homeostasis
  • Humans
  • Protein Serine-Threonine Kinases / metabolism
  • Proteolysis
  • Signal Transduction
  • Unfolded Protein Response*
  • Yeasts / genetics
  • Yeasts / metabolism
  • eIF-2 Kinase / metabolism


  • Activating Transcription Factor 6
  • ERN1 protein, human
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases