RFX Transcription Factor DAF-19 Regulates 5-HT and Innate Immune Responses to Pathogenic Bacteria in Caenorhabditis elegans

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/ca2+/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. © 2013 xie et al.