Troemel Emily R, Chu Stephanie W, Reinke Valerie, Lee Siu Sylvia, Ausubel Frederick M, Kim Dennis H
Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Genet. 2006 Nov 10;2(11):e183. doi: 10.1371/journal.pgen.0020183. Epub 2006 Sep 11.
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.
PMK-1 p38丝裂原活化蛋白激酶途径和DAF-2-DAF-16胰岛素信号通路控制秀丽隐杆线虫的肠道固有免疫。pmk-1功能丧失突变体对病原体的敏感性增强，而daf-2功能丧失突变体对病原体的抗性增强，这需要上调DAF-16转录因子。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正向调控的基因之间基本没有重叠，这表明它们形成平行途径来促进免疫。我们发现PMK-1控制候选分泌抗菌物质的表达，包括C型凝集素、ShK毒素和类CUB基因。微阵列分析表明，25%的PMK-1正向调控基因由铜绿假单胞菌感染诱导。通过定量PCR，我们表明PMK-1调节病原体反应基因的基础表达和感染诱导表达，而DAF-16则不调节。最后，我们通过遗传分析表明，PMK-1有助于daf-2突变体延长寿命。我们提出，PMK-1途径是一条特异性的、不可或缺的免疫途径，介导分泌免疫反应基因的表达，而DAF-2-DAF-16途径似乎作为更一般应激反应的一部分来调节免疫。PMK-1途径对daf-2突变体寿命延长的作用表明，固有免疫是寿命的一个重要决定因素。
