The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification.
The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification.
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DOI：
10.1371/journal.ppat.1004143
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发表时间：
2014-05
期刊：
影响因子：
6.7
通讯作者：
Ausubel FM
中科院分区：
文献类型：
--
作者：
Pukkila-Worley R;Feinbaum RL;McEwan DL;Conery AL;Ausubel FM
后生动物通过解毒和免疫反应保护自己免受环境毒素和有毒病原体的侵害。我们以前确定了一种小分子外源毒素，通过激活保守的p38 MAP激酶PMK-1宿主防御途径延长感染人类细菌病原体的秀丽隐杆线虫的存活。在这里，我们调查的细胞机制，夫妇激活解毒反应的先天免疫。从1,420个在C.在elegans肠中，我们鉴定了保守的介体亚基MDT-15/MED 15和28种其他基因失活，其消除了这种小分子对PMK-1依赖性免疫效应物的诱导。我们证明MDT-15/MED 15是外源性诱导的p38 MAP激酶PMK-1依赖性免疫基因表达和保护铜绿假单胞菌感染所必需的。我们还表明，MDT-15控制解毒基因的诱导和功能，以保护宿主免受细菌来源的吩嗪毒素。这些数据定义了MDT-15/MED 15在协调异生物质解毒和先天免疫应答中的核心作用。后生动物对环境威胁的反应部分是通过协调保护性转录反应的保守途径。例如，在感染侵入性病原体期间，先天免疫途径调节抗微生物免疫效应物的分泌。同样，暴露于有毒分子导致诱导解毒机制，保护宿主免受这些化合物的有害影响。在这里，我们发现一个保守的转录调节因子MDT-15/MED 15链接异生物质解毒和免疫反应的方式，是重要的保护在细菌感染。我们还表明，MDT-15/MED 15是必要的宿主抵抗致病菌产生的分泌毒素的致死作用。因此，通过MDT-15/MED 15快速协调这些保护性宿主反应可能是野生环境中保守的生存策略的一部分。
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. 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.
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