title: Drosophila Ras/MAPK signalling regulates innate immune responses in immune and intestinal stem cells.
abstract: Immune signalling pathways need to be tightly regulated as overactivation of these pathways can result in chronic inflammatory diseases and cancer. NF-κB signalling and associated innate immune pathways are crucial in the first line of defense against infection in all animals. In a genome-wide RNAi screen for modulators of Drosophila immune deficiency (IMD)/NF-κB signalling, we identified components of the Ras/MAPK pathway as essential for suppression of IMD pathway activity, even in the absence of an immune challenge. Downregulation of Ras/MAPK activity mimics the induction of innate immune responses by microbial patterns. Conversely, ectopic Ras/MAPK pathway activation results in the suppression of Drosophila IMD/NF-κB signalling. Mechanistically, we show that the Ras/MAPK pathway acts by inducing transcription of the IMD pathway inhibitor Pirk/Rudra/PIMS. Finally, in vivo experiments demonstrate a requirement for Ras/MAPK signalling in restricting innate immune responses in haemocytes, fat body and adult intestinal stem cells. Our observations provide an example of a pathway that promotes cell proliferation and has simultaneously been utilized to limit the immune response.
authors.affiliation: German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, Department of Cell and Molecular Biology, University of Heidelberg, Faculty of Medicine Mannheim, Heidelberg, Germany.
authors.forename: Anan
authors.initials: A
authors.lastname: Ragab
authors.forename: Tina
authors.initials: T
authors.lastname: Buechling
authors.forename: Viola
authors.initials: V
authors.lastname: Gesellchen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Spirohn
authors.forename: Anna-Lisa
authors.initials: AL
authors.lastname: Boettcher
authors.forename: Michael
authors.initials: M
authors.lastname: Boutros
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000276:immunology*; D005216:Fat Body / Q000276:immunology; D005786:Gene Expression Regulation; D006434:Hemocytes / Q000276:immunology; D007113:Immunity, Innate; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013234:Stem Cells / Q000276:immunology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D016328:NF-kappa B; C439909:imd protein, Drosophila; C438368:Pvr protein, Drosophila; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins