title: RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans.
abstract: In Caenorhabditis elegans the Toll-interleukin receptor domain adaptor protein TIR-1 via a conserved mitogen-activated protein kinase (MAPK) signaling cascade induces innate immunity and upregulates serotonin (5-HT) biosynthesis gene tph-1 in a pair of ADF chemosensory neurons in response to infection. Here, we identify transcription factors downstream of the TIR-1 signaling pathway. We show that common transcription factors control the innate immunity and 5-HT biosynthesis. We demonstrate that a cysteine to tyrosine substitution in an ARM motif of the HEAT/Arm repeat region of the TIR-1 protein confers TIR-1 hyperactivation, leading to constitutive tph-1 upregulation in the ADF neurons, increased expression of intestinal antimicrobial genes, and enhanced resistance to killing by the human opportunistic pathogen Pseudomonas aeruginosa PA14. A forward genetic screen for suppressors of the hyperactive TIR-1 led to the identification of DAF-19, an ortholog of regulatory factor X (RFX) transcription factors that are required for human adaptive immunity. We show that DAF-19 concerts with ATF-7, a member of the activating transcription factor (ATF)/cAMP response element-binding B (CREB) family of transcription factors, to regulate tph-1 and antimicrobial genes, reminiscent of RFX-CREB interaction in human immune cells. daf-19 mutants display heightened susceptibility to killing by PA14. Remarkably, whereas the TIR-1-MAPK-DAF-19/ATF-7 pathway in the intestinal immunity is regulated by DKF-2/protein kinase D, we found that the regulation of tph-1 expression is independent of DKF-2 but requires UNC-43/Ca(2+)/calmodulin-dependent protein kinase (CaMK) II. Our results suggest that pathogenic cues trigger a common core-signaling pathway via tissue-specific mechanisms and demonstrate a novel role for RFX factors in neuronal and innate immune responses to infection.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Yusu
authors.initials: Y
authors.lastname: Xie
authors.forename: Mustapha
authors.initials: M
authors.lastname: Moussaif
authors.forename: Sunju
authors.initials: S
authors.lastname: Choi
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.forename: Ji Ying
authors.initials: JY
authors.lastname: Sze
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity; D043562:Receptors, G-Protein-Coupled; D012701:Serotonin / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; C410596:DAF-19 protein, C elegans; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C485906:tir-1 protein, C elegans; D012701:Serotonin; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1