RRC ID 45975
Author Goh GY, Martelli KL, Parhar KS, Kwong AW, Wong MA, Mah A, Hou NS, Taubert S.
Title The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans.
Journal Aging Cell
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.
Volume 13(1)
Pages 70-9
Published 2014-2-1
DOI 10.1111/acel.12154
PMID 23957350
PMC PMC4326869
MeSH Animals Arsenites / toxicity Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Conserved Sequence* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Fatty Acids / metabolism Gene Expression Regulation / drug effects Genes, Helminth Models, Biological Oxidative Stress* / genetics Protein Binding / drug effects Protein Structure, Tertiary Receptors, Cytoplasmic and Nuclear / metabolism Sequence Deletion Survival Analysis Transcription Factors / chemistry Transcription Factors / genetics Transcription Factors / metabolism* Transcription, Genetic / drug effects tert-Butylhydroperoxide / pharmacology
IF 7.238
Times Cited 28
C.elegans tm2182 tm1817 tm331