p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans

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（mitogen-activated protein kinase）通路与DAF-2–DAF-16胰岛素信号通路共同调控秀丽隐杆线虫（Caenorhabditis elegans）的肠道固有免疫。pmk-1功能丧失突变体对病原菌的敏感性显著增强，而daf-2功能丧失突变体的病原菌抗性提升，该过程依赖DAF-16转录因子的上调表达。我们通过遗传分析证实，daf-2突变体的病原菌抗性同样依赖PMK-1的参与。然而全基因组芯片分析（genome-wide microarray analysis）显示，受PMK-1与DAF-16正向调控的基因几乎不存在重叠，这提示二者通过平行通路协同促进免疫应答。研究发现，PMK-1可调控候选分泌型抗菌剂的表达，包括C型凝集素（C-type lectins）、ShK毒素（ShK toxins）以及CUB样基因（CUB-like genes）。芯片分析进一步证实，受PMK-1正向调控的基因中有25%可被铜绿假单胞菌（Pseudomonas aeruginosa）感染诱导。通过定量PCR（quantitative PCR）实验，我们证实PMK-1同时调控病原菌应答基因的基础表达水平与感染诱导后的表达水平，而DAF-16并无此类调控功能。最后，我们通过遗传分析证实PMK-1参与了daf-2突变体的寿命延长表型。本研究提出如下假说：PMK-1通路是一类特异性且不可或缺的免疫通路，介导分泌型免疫应答基因的表达；而DAF-2–DAF-16通路则作为更广泛的应激应答的一部分参与免疫调控。PMK-1通路对daf-2突变体寿命延长的贡献表明，固有免疫是影响生物体寿命的重要决定因素。