title: The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification.
abstract: Metazoans protect themselves from environmental toxins and virulent pathogens through detoxification and immune responses. We previously identified a small molecule xenobiotic toxin that extends survival of Caenorhabditis elegans infected with human bacterial pathogens by activating the conserved p38 MAP kinase PMK-1 host defense pathway. Here we investigate the cellular mechanisms that couple activation of a detoxification response to innate immunity. From an RNAi screen of 1,420 genes expressed in the C. elegans intestine, we identified the conserved Mediator subunit MDT-15/MED15 and 28 other gene inactivations that abrogate the induction of PMK-1-dependent immune effectors by this small molecule. We demonstrate that MDT-15/MED15 is required for the xenobiotic-induced expression of p38 MAP kinase PMK-1-dependent immune genes and protection from Pseudomonas aeruginosa infection. We also show that MDT-15 controls the induction of detoxification genes and functions to protect the host from bacteria-derived phenazine toxins. These data define a central role for MDT-15/MED15 in the coordination of xenobiotic detoxification and innate immune responses.
authors.affiliation: Division of Infectious Diseases; Massachusetts General Hospital; Harvard Medical School; Boston, Massachusetts, United States of America; Department of Molecular Biology; Massachusetts General Hospital; Harvard Medical School; Boston, Massachusetts, United States of America; Department of Genetics; Harvard Medical School; Boston, Massachusetts, United States of America.
authors.forename: Read
authors.initials: R
authors.lastname: Pukkila-Worley
authors.affiliation: Department of Molecular Biology; Massachusetts General Hospital; Harvard Medical School; Boston, Massachusetts, United States of America; Department of Genetics; Harvard Medical School; Boston, Massachusetts, United States of America.
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Feinbaum
authors.affiliation: Department of Molecular Biology; Massachusetts General Hospital; Harvard Medical School; Boston, Massachusetts, United States of America; Department of Genetics; Harvard Medical School; Boston, Massachusetts, United States of America.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: McEwan
authors.affiliation: Department of Molecular Biology; Massachusetts General Hospital; Harvard Medical School; Boston, Massachusetts, United States of America; Department of Genetics; Harvard Medical School; Boston, Massachusetts, United States of America.
authors.forename: Annie L
authors.initials: AL
authors.lastname: Conery
authors.affiliation: Department of Molecular Biology; Massachusetts General Hospital; Harvard Medical School; Boston, Massachusetts, United States of America; Department of Genetics; Harvard Medical School; Boston, Massachusetts, United States of America.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000382:microbiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D019143:Evolution, Molecular; D007113:Immunity, Innate / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000235:genetics; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C513281:ARC105 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C571065:MDT-15 protein, C elegans; D014157:Transcription Factors