Date Published: May 29, 2014
Publisher: Public Library of Science
Author(s): Read Pukkila-Worley, Rhonda L. Feinbaum, Deborah L. McEwan, Annie L. Conery, Frederick M. Ausubel, Robin Charles May.
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.
In nature, organisms encounter environmental insults, such as chemical toxins, secreted microbial virulence factors and invasive pathogens, that threaten their ability to survive and reproduce. As a result, metazoans have evolved protective pathways to counter these challenges. For example, gene families such as cytochrome P450s (CYPs), glutathione-s-transferases (GSTs), and UDP-glucuronosyltransferases (UDPs) detoxify xenobiotic small molecule toxins and are conserved from nematodes to humans . Likewise, innate immune defenses provide protection from invasive pathogens . Recent publications have suggested that recognition of xenobiotic toxins is involved in the activation of immune response pathways , . From an evolutionary perspective, it is logical that hosts respond to threats encountered in the wild at least in part through surveillance pathways that monitor the integrity of core cellular machinery, which are often the targets of xenobiotic small molecules or microbe-generated toxins. These studies predict that organisms may integrate detoxification and immune responses as a means to respond rapidly to such challenges, but the mechanisms underlying this coordinated host response have not been reported.
Detecting and countering environmental threats is central to the ability of organisms to survive and reproduce in the wild. We examined the C. elegans response to the xenobiotic RPW-24, which is able to induce a host immune response that is protective for animals infected with the lethal bacterial pathogen P. aeruginosa. In an RNAi screen with RPW-24, we identified a number of genes, including mdt-15/MED15, which are required for induction of p38 MAP kinase PMK-1-dependent immune effectors. mdt-15 encodes a subunit of the highly conserved Mediator complex that controls the activation of a variety of genes involved in the response to external stress. We demonstrate that: (i) MDT-15 is required for the induction of p38 MAP kinase PMK-1-dependent immune effectors following exposure to a xenobiotic toxin, as well as during infection with P. aeruginosa, (ii) MDT-15 controls the expression of some p38 MAP kinase PMK-1-independent immune effectors, but not all defense genes, (iii), MDT-15 functions downstream of the p38 MAP kinase PMK-1 cascade to control the induction of at least two immune effectors, (iv) the induction of xenobiotic detoxification genes and protection from the toxic effects of RPW-24 requires MDT-15, but not the p38 MAP kinase PMK-1, and (iv) MDT-15 is necessary for protection during P. aeruginosa infection and from phenazine toxins secreted by this organism.