title: Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1/Nrf2 Antioxidant Response.
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.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hourihan
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lorenza E
authors.initials: LE
authors.lastname: Moronetti Mazzeo
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: L Paulette
authors.initials: LP
authors.lastname: Fernández-Cárdenas
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: keith.blackwell@joslin.harvard.edu.
authors.forename: T Keith
authors.initials: TK
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008136:Longevity; D008928:Mitochondria / Q000201:enzymology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D056811:Unfolded Protein Response; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; C541905:IRE-1 protein, C elegans; D048051:p38 Mitogen-Activated Protein Kinases; D004722:Endoribonucleases; D003545:Cysteine