The p38 mitogen-activated protein (MAP) kinase signaling cassette has been implicated in stress and immunity in evolutionarily diverse species. In response to a wide variety of physical, chemical and biological stresses p38 kinases phosphorylate various substrates, transcription factors of the ATF family and other protein kinases, regulating cellular adaptation to stress. The Drosophila genome encodes three p38 kinases named p38a, p38b and p38c. In this study, we have analyzed the role of p38c in the Drosophila intestine. The p38c gene is expressed in the midgut and upregulated upon intestinal infection. We showed that p38c mutant flies are more resistant to infection with the lethal pathogen Pseudomonas entomophila but are more susceptible to the non-pathogenic bacterium Erwinia carotovora 15 . This phenotype was linked to a lower production of Reactive Oxygen Species (ROS) in the gut of p38c mutants, whereby the transcription of the ROS-producing enzyme Duox is reduced in p38c mutant flies. Our genetic analysis shows that p38c functions in a pathway with Mekk1 and Mkk3 to induce the phosphorylation of Atf-2, a transcription factor that controls Duox expression. Interestingly, p38c deficient flies accumulate lipids in the intestine while expressing higher levels of antimicrobial peptide and metabolic genes. The role of p38c in lipid metabolism is mediated by the Atf3 transcription factor. This observation suggests that p38c and Atf3 function in a common pathway in the intestine to regulate lipid metabolism and immune homeostasis. Collectively, our study demonstrates that p38c plays a central role in the intestine of Drosophila . It also reveals that many roles initially attributed to p38a are in fact mediated by p38c . Author Summary The p38 mitogen-activated protein (MAP) kinase is a signaling pathway that is involved in both stress and immunity in various species from yeast to human. p38 kinases regulate transcription factors of the ATF family and other protein kinases that then induce cellular adaptation to stress to a wide variety of physical, chemical and biological stresses. The Drosophila genome encodes three p38 kinases named p38a, p38b and p38c. In this study, we have analyzed the role of p38c in the Drosophila intestine. The p38c gene is expressed in the digestive tract and up-regulated upon intestinal infection. We observed a lower production of Reactive Oxygen Species (ROS) in the gut of p38c mutants upon bacterial infection. Consistent with this observation, the transcription of the Duox , a gene encoding an enzyme that produces ROS, is reduced in p38c mutant flies. Our analysis shows that p38c induces the phosphorylation of Atf-2, a transcription factor that controls Duox expression. Interestingly, our study also shows that p38c and Atf3 function in a common pathway in the intestine to regulate lipid metabolism and immune homeostasis. Collectively, our study demonstrates that p38c plays a central role in the intestine of Drosophila .
【초록키워드】 Stress, Immunity, Human, Genome, Transcription, Infection, peptide, oxygen, metabolism, Protein, pathogen, intestine, Phosphorylation, Immune homeostasis, Control, pathway, Bacterial infection, phenotype, ROS, mutants, signaling pathway, mutant, lipids, expression, yeast, function, reactive oxygen species, cellular, Signaling, Lipid, Analysis, regulate, lipid metabolism, Gut, protein kinase, transcription factor, transcription factors, kinases, protein kinases, digestive tract, observation, Drosophila, enzyme, substrates, gene encoding, antimicrobial peptide, Atf3, cassette, Mekk1, metabolic genes, midgut, genetic analysis, kinase, ENCODE, susceptible, physical, intestinal, analyzed, involved, reduced, Specy, variety, expressed, induce, upregulated, reveal, expressing, up-regulated, implicated, accumulate, phosphorylate, Pseudomona, 【제목키워드】 Lipid, MAPK,