Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death

Am J Pathol. 2015 Jul;185(7):1800-8. doi: 10.1016/j.ajpath.2015.03.009. Epub 2015 May 5.


Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded proteins are released from the ER, and poorly folded proteins are retained until they achieve stable conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological insults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaperones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review discusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis*
  • Awards and Prizes
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / metabolism
  • Eukaryotic Cells / physiology*
  • Humans
  • Mammals
  • Models, Biological
  • Molecular Chaperones / metabolism
  • Pathology
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction*
  • Societies, Medical
  • Unfolded Protein Response*
  • United States
  • eIF-2 Kinase / metabolism


  • Molecular Chaperones
  • ERN1 protein, human
  • PERK kinase
  • Protein-Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases