title: Tribbles ortholog NIPI-3 and bZIP transcription factor CEBP-1 regulate a Caenorhabditis elegans intestinal immune surveillance pathway.
abstract: Many pathogens secrete toxins that target key host processes resulting in the activation of immune pathways. The secreted Pseudomonas aeruginosa toxin Exotoxin A (ToxA) disrupts intestinal protein synthesis, which triggers the induction of a subset of P. aeruginosa-response genes in the nematode Caenorhabditis elegans.
  
  
  
  We show here that one ToxA-induced C. elegans gene, the Tribbles pseudokinase ortholog nipi-3, is essential for host survival following exposure to P. aeruginosa or ToxA. We find that NIPI-3 mediates the post-developmental expression of intestinal immune genes and proteins and primarily functions in parallel to known immune pathways, including p38 MAPK signaling. Through mutagenesis screening, we identify mutants of the bZIP C/EBP transcription factor cebp-1 that suppress the hypersusceptibility defects of nipi-3 mutants.
  
  
  
  NIPI-3 is a negative regulator of CEBP-1, which in turn negatively regulates protective immune mechanisms. This pathway represents a previously unknown innate immune signaling pathway in intestinal epithelial cells that is involved in the surveillance of cellular homeostasis. Because NIPI-3 and CEBP-1 are also essential for C. elegans development, NIPI-3 is analogous to other key innate immune signaling molecules such as the Toll receptors in Drosophila that have an independent role during development.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.|Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: McEwan
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.|Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Feinbaum
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stroustrup
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.|Department of Genetics, Harvard Medical School, Boston, MA, USA.|Present Address: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Annie L
authors.initials: AL
authors.lastname: Conery
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.|Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Anselmo
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.|Department of Genetics, Harvard Medical School, Boston, MA, USA.|Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Sadreyev
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. ausubel@molbio.mgh.harvard.edu.|Department of Genetics, Harvard Medical School, Boston, MA, USA. ausubel@molbio.mgh.harvard.edu.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000276:immunology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D005098:Exotoxins / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011550:Pseudomonas aeruginosa; D015398:Signal Transduction; D037521:Virulence Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D050976:Basic-Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D029742:Caenorhabditis elegans Proteins; D005098:Exotoxins; D011494:Protein Kinases; D037521:Virulence Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000097668:Pseudomonas aeruginosa Exotoxin A; C000623282:Cebp-1 protein, C elegans; C530373:NIPI-3 protein, C elegans
keywords: C/EBP; Caenorhabditis elegans; Exotoxin A; Innate epithelial immunity; Lifespan machine; Pseudomonas aeruginosa; Surveillance immunity; Translational inhibition; Tribbles-like kinase