RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans

PLoS Genet. 2013;9(3):e1003324. doi: 10.1371/journal.pgen.1003324. Epub 2013 Mar 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans Proteins* / genetics
  • Caenorhabditis elegans Proteins* / immunology
  • Caenorhabditis elegans Proteins* / metabolism
  • Caenorhabditis elegans* / genetics
  • Caenorhabditis elegans* / immunology
  • Caenorhabditis elegans* / microbiology
  • 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

Substances

  • Caenorhabditis elegans Proteins
  • Cytoskeletal Proteins
  • DAF-19 protein, C elegans
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • tir-1 protein, C elegans
  • Serotonin
  • TPH1 protein, human
  • Tryptophan Hydroxylase
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1