p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans.
p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans.
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DOI：
10.1371/journal.pgen.0020183
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发表时间：
2006-11-10
期刊：
影响因子：
4.5
通讯作者：
Kim DH
中科院分区：
文献类型：
--
作者：
Troemel ER;Chu SW;Reinke V;Lee SS;Ausubel FM;Kim DH
PMK-1 p38 丝裂原激活蛋白激酶通路和 DAF-2–DAF-16 胰岛素信号通路控制秀丽隐杆线虫肠道先天免疫。 pmk-1 功能丧失突变体增强了对病原体的敏感性，而 daf-2 功能丧失突变体增强了对需要上调 DAF-16 转录因子的病原体的抵抗力。我们通过遗传分析表明daf-2突变体的病原体抗性也需要PMK-1。然而，全基因组微阵列分析表明，PMK-1和DAF-16正向调节的基因之间基本上没有重叠，这表明它们形成了促进免疫的平行途径。我们发现 PMK-1 控制候选分泌型抗菌剂的表达，包括 C 型凝集素、ShK 毒素和 CUB 样基因。微阵列分析表明，25% 的 PMK-1 正向调节基因是由铜绿假单胞菌感染诱导的。使用定量 PCR，我们发现 PMK-1 调节病原体反应基因的基础表达和感染诱导的表达，而 DAF-16 则不然。最后，我们使用遗传分析表明 PMK-1 有助于延长 daf-2 突变体的寿命。我们认为 PMK-1 途径是一种特定的、不可或缺的免疫途径，介导分泌性免疫反应基因的表达，而 DAF-2–DAF-16 途径似乎作为更普遍的应激反应的一部分来调节免疫。 PMK-1 途径对延长 daf-2 突变体寿命的贡献表明先天免疫是长寿的重要决定因素。先天免疫系统提供了抵御病原体感染的第一道防线，并依赖于哺乳动物、昆虫和线虫中保守的途径。在这里，作者分析了线虫秀丽隐杆线虫对人类病原体铜绿假单胞菌感染的转录反应。他们在参与病原体防御的两条保守通路的背景下研究了这种转录反应：PMK-1 p38 丝裂原激活蛋白激酶 (p38 MAPK) 通路和 DAF-2–DAF-16 胰岛素信号通路。具体来说，作者发现 p38 MAPK 通路在感染诱导的分泌性免疫反应基因的表达中发挥着关键作用。这些基因包括 C 型凝集素、溶菌酶和抗菌肽，可抵抗许多物种的感染。相比之下，他们发现 DAF-16 通路不是免疫反应基因表达所必需的，并且可能作为与 p38 MAPK 平行发挥作用的一般应激反应的一部分来调节免疫。此外，作者观察到 p38 MAPK 有助于延长 daf-2 突变体的寿命，这表明 p38 MAPK 信号传导可能通过其在免疫中的作用来调节寿命。
The PMK-1 p38 mitogen-activated protein kinase pathway and the DAF-2–DAF-16 insulin signaling pathway control Caenorhabditis elegans intestinal innate immunity. pmk-1 loss-of-function mutants have enhanced sensitivity to pathogens, while daf-2 loss-of-function mutants have enhanced resistance to pathogens that requires upregulation of the DAF-16 transcription factor. We used genetic analysis to show that the pathogen resistance of daf-2 mutants also requires PMK-1. However, genome-wide microarray analysis indicated that there was essentially no overlap between genes positively regulated by PMK-1 and DAF-16, suggesting that they form parallel pathways to promote immunity. We found that PMK-1 controls expression of candidate secreted antimicrobials, including C-type lectins, ShK toxins, and CUB-like genes. Microarray analysis demonstrated that 25% of PMK-1 positively regulated genes are induced by Pseudomonas aeruginosa infection. Using quantitative PCR, we showed that PMK-1 regulates both basal and infection-induced expression of pathogen response genes, while DAF-16 does not. Finally, we used genetic analysis to show that PMK-1 contributes to the enhanced longevity of daf-2 mutants. We propose that the PMK-1 pathway is a specific, indispensable immunity pathway that mediates expression of secreted immune response genes, while the DAF-2–DAF-16 pathway appears to regulate immunity as part of a more general stress response. The contribution of the PMK-1 pathway to the enhanced lifespan of daf-2 mutants suggests that innate immunity is an important determinant of longevity. The innate immune system provides the first line of defense against pathogen infection and relies upon pathways conserved across mammals, insects, and nematodes. Here, the authors have analyzed the transcriptional response of the nematode Caenorhabditis elegans to infection by the human pathogen Pseudomonas aeruginosa. They investigated this transcriptional response in the context of two conserved pathways involved in pathogen defense: the PMK-1 p38 mitogen-activated protein kinase (p38 MAPK) pathway and the DAF-2–DAF-16 insulin-signaling pathway. Specifically, the authors found that the p38 MAPK pathway plays a critical role in the infection-induced expression of secreted immune response genes. These genes include C-type lectins, lysozymes, and antimicrobial peptides that fight off infection in many species. In contrast, they found that the DAF-16 pathway is not required for immune response gene expression and may regulate immunity as part of a general stress response that functions in parallel to p38 MAPK. In addition, the authors observed that p38 MAPK contributes to the enhanced longevity of daf-2 mutants, implicating p38 MAPK signaling in the regulation of longevity, possibly through its role in immunity.
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影响因子：
56.9
作者：
Garsin, DA;Villanueva, JM;Ausubel, FM
通讯作者：
Ausubel, FM
DOI：
10.1073/pnas.041613098
发表时间：
2001-02-27
影响因子：
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影响因子：
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作者：
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