Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death

Mol Cell. 2004 Sep 10;15(5):767-76. doi: 10.1016/j.molcel.2004.08.025.


A variety of debilitating diseases including diabetes, Alzheimer's, Huntington's, Parkinson's, and prion-based diseases are linked to stress within the endoplasmic reticulum (ER). Using S. cerevisiae, we sought to determine the relationship between protein misfolding, ER stress, and cell death. In the absence of ERV29, a stress-induced gene required for ER associated degradation (ERAD), misfolded proteins accumulate in the ER leading to persistent ER stress and subsequent cell death. Cells alleviate ER stress through the unfolded protein response (UPR); however, if stress is sustained the UPR contributes to cell death by causing the accumulation of reactive oxygen species (ROS). ROS are generated from two sources: the UPR-regulated oxidative folding machinery in the ER and mitochondria. Our results demonstrate a direct mechanism(s) by which misfolded proteins lead to cellular damage and death.

Publication types

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

MeSH terms

  • Cell Death / physiology
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism*
  • Energy Metabolism / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism
  • Oxidative Stress / physiology*
  • Protein Folding*
  • Reactive Oxygen Species / metabolism*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Vesicular Transport Proteins


  • Erv29 protein, S cerevisiae
  • Membrane Proteins
  • Reactive Oxygen Species
  • Saccharomyces cerevisiae Proteins
  • Vesicular Transport Proteins