Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1/Nrf2 Antioxidant Response

Mol Cell. 2016 Aug 18;63(4):553-566. doi: 10.1016/j.molcel.2016.07.019.


Emerging evidence suggests that many proteins may be regulated through cysteine modification, but the extent and functions of this signaling remain largely unclear. The endoplasmic reticulum (ER) transmembrane protein IRE-1 maintains ER homeostasis by initiating the unfolded protein response (UPR(ER)). Here we show in C. elegans and human cells that IRE-1 has a distinct redox-regulated function in cytoplasmic homeostasis. Reactive oxygen species (ROS) that are generated at the ER or by mitochondria sulfenylate a cysteine within the IRE-1 kinase activation loop. This inhibits the IRE-1-mediated UPR(ER) and initiates the p38/SKN-1(Nrf2) antioxidant response, thereby increasing stress resistance and lifespan. Many AGC-family kinases (AKT, p70S6K, PKC, ROCK1) seem to be regulated similarly. The data reveal that IRE-1 has an ancient function as a cytoplasmic sentinel that activates p38 and SKN-1(Nrf2) and indicate that cysteine modifications induced by ROS signals can direct proteins to adopt unexpected functions and may coordinate many cellular processes.

Publication types

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

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cysteine / metabolism*
  • Cytoplasm / enzymology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum / enzymology
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Hep G2 Cells
  • Humans
  • Longevity
  • Mitochondria / enzymology
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Unfolded Protein Response
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antioxidants
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • Transcription Factors
  • skn-1 protein, C elegans
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • IRE-1 protein, C elegans
  • p38 Mitogen-Activated Protein Kinases
  • Endoribonucleases
  • Cysteine