title: Mitochondrial Sulfide Quinone Oxidoreductase Prevents Activation of the Unfolded Protein Response in Hydrogen Sulfide.
abstract: Hydrogen sulfide (H2S) is an endogenously produced gaseous molecule with important roles in cellular signaling. In mammals, exogenous H2S improves survival of ischemia/reperfusion. We have previously shown that exposure to H2S increases the lifespan and thermotolerance in Caenorhabditis elegans, and improves protein homeostasis in low oxygen. The mitochondrial SQRD-1 (sulfide quinone oxidoreductase) protein is a highly conserved enzyme involved in H2S metabolism. SQRD-1 is generally considered important to detoxify H2S. Here, we show that SQRD-1 is also required to maintain protein translation in H2S. In sqrd-1 mutant animals, exposure to H2S leads to phosphorylation of eIF2α and inhibition of protein synthesis. In contrast, global protein translation is not altered in wild-type animals exposed to lethally high H2S or in hif-1(ia04) mutants that die when exposed to low H2S. We demonstrate that both gcn-2 and pek-1 kinases are involved in the H2S-induced phosphorylation of eIF2α. Both ER and mitochondrial stress responses are activated in sqrd-1 mutant animals exposed to H2S, but not in wild-type animals. We speculate that SQRD-1 activity in H2S may coordinate proteostasis responses in multiple cellular compartments.
authors.affiliation: From the Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington 98195.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Horsman
authors.affiliation: From the Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington 98195 DLM16@uw.edu.
authors.forename: Dana L
authors.identifier: http://orcid.org/0000-0003-3983-0493
authors.initials: DL
authors.lastname: Miller
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism* / Q000633:toxicity; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; C541178:HIF-1 protein, C elegans; D014157:Transcription Factors; C578468:gcn-1 protein, C elegans; D050862:Oxidoreductases Acting on Sulfur Group Donors; C499574:pek-1 protein, C elegans; D048369:MAP Kinase Kinase 1; D006862:Hydrogen Sulfide
keywords: Caenorhabditis elegans (C. elegans); eukaryotic initiation factor 2 (eIF2); hydrogen sulfide; proteostasis; translation initiation