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.

Abstract

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

Substances

  • 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