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PLoS Pathog. 2014 May 29;10(5):e1004143. doi: 10.1371/journal.ppat.1004143. eCollection 2014 May.

The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification.

Author information

1
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.
2
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.

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.

PMID:
24875643
PMCID:
PMC4038581
DOI:
10.1371/journal.ppat.1004143
[Indexed for MEDLINE]
Free PMC Article

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