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.

Author Summary

Metazoans respond to environmental threats in part through conserved pathways that coordinate protective transcriptional responses. During infection with an invasive pathogen, for example, innate immune pathways regulate the secretion of antimicrobial immune effectors. Likewise, exposure to toxic molecules leads to the induction of detoxification mechanisms that protect the host from the deleterious effects of these compounds. Here we find that a conserved transcriptional regulator MDT-15/MED15 links xenobiotic detoxification and immune responses in a manner that is important for protection during bacterial infection. We also show that MDT-15/MED15 is necessary for the host to resist the lethal effects of secreted toxins produced by pathogenic bacteria. Rapid coordination of these protective host responses through MDT-15/MED15 may therefore be part of a conserved survival strategy in the wild.