title: p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans.
abstract: 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Troemel
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Chu
authors.forename: Valerie
authors.initials: V
authors.lastname: Reinke
authors.forename: Siu Sylvia
authors.initials: SS
authors.lastname: Lee
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001424:Bacterial Infections; D001427:Bacterial Toxins / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D017238:Genes, Helminth; D007109:Immunity / Q000235:genetics*; D008136:Longevity / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018448:Models, Immunological; D009154:Mutation / Q000235:genetics; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D011972:Receptor, Insulin / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases; C463460:Pmk-1 protein, C elegans; D048051:p38 Mitogen-Activated Protein Kinases