RRC ID 46474
Author Xie Y, Moussaif M, Choi S, Xu L, Sze JY.
Title RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans.
Journal PLoS Genet
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.
Volume 9(3)
Pages e1003324
Published 2013-1-1
DOI 10.1371/journal.pgen.1003324
PMID 23505381
PMC PMC3591283
MeSH Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / immunology Caenorhabditis elegans* / microbiology Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / immunology Caenorhabditis elegans Proteins* / metabolism Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics Calcium-Calmodulin-Dependent Protein Kinase Type 1 / metabolism Cytoskeletal Proteins / genetics Cytoskeletal Proteins / metabolism Humans Immunity, Innate* Intestines / immunology Intestines / microbiology Neurons / cytology Neurons / metabolism Neurons / microbiology Pseudomonas aeruginosa* / metabolism Pseudomonas aeruginosa* / pathogenicity Receptors, G-Protein-Coupled Serotonin* / biosynthesis Serotonin* / genetics Signal Transduction Transcription Factors* / genetics Transcription Factors* / immunology Tryptophan Hydroxylase / metabolism
IF 5.175
Times Cited 14
C.elegans tm3036