title: The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans.
abstract: Reactive oxygen species (ROS) play important signaling roles in metazoans, but also cause significant molecular damage. Animals tightly control ROS levels using sophisticated defense mechanisms, yet the transcriptional pathways that induce ROS defense remain incompletely understood. In the nematode Caenorhabditis elegans, the transcription factor SKN-1 is considered a master regulator for detoxification and oxidative stress responses. Here, we show that MDT-15, a subunit of the conserved Mediator complex, is also required for oxidative stress responses in nematodes. Specifically, mdt-15 is required to express SKN-1 targets upon chemical and genetic increase in SKN-1 activity. mdt-15 is also required to express genes in SKN-1-dependent and SKN-1-independent fashions downstream of insulin/IGF-1 signaling and for the longevity of daf-2/insulin receptor mutants. At the molecular level, MDT-15 binds SKN-1 through a region distinct from the classical transcription-factor-binding KIX-domain. Moreover, mdt-15 is essential for the transcriptional response to and survival on the organic peroxide tert-butyl-hydroperoxide (tBOOH), a largely SKN-1-independent response. The MDT-15 interacting nuclear hormone receptor, NHR-64, is specifically required for tBOOH but not arsenite resistance, but NHR-64 is dispensable for the transcriptional response to tBOOH. Hence, NHR-64 and MDT-15's mode of action remain elusive. Lastly, the role of MDT-15 in oxidative stress defense is functionally separable from its function in fatty acid metabolism, as exogenous polyunsaturated fatty acid complementation rescues developmental, but not stress sensitivity phenotypes of mdt-15 worms. Our findings reveal novel conserved players in the oxidative stress response and suggest a broad cytoprotective role for MDT-15.
authors: Graduate Program in Cell and Developmental Biology, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Child & Family Research Institute, Vancouver, BC, Canada.
authors: Grace Y S
authors: GY
authors: Goh
authors: Katherine L
authors: KL
authors: Martelli
authors: Kulveer S
authors: KS
authors: Parhar
authors: Ada W L
authors: AW
authors: Kwong
authors: Marcus A
authors: MA
authors: Wong
authors: Allan
authors: A
authors: Mah
authors: Nicole S
authors: NS
authors: Hou
authors: Stefan
authors: S
authors: Taubert
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D017238:Genes, Helminth; D008954:Models, Biological; D018384:Oxidative Stress / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017384:Sequence Deletion; D016019:Survival Analysis; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D018053:Arsenites; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; C571065:MDT-15 protein, C elegans; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; D020122:tert-Butylhydroperoxide; C015001:arsenite
keywords: MDT-15; Mediator complex; SKN-1; daf-2; nuclear hormone receptor; oxidative stress
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