title: Coordinated inhibition of C/EBP by Tribbles in multiple tissues is essential for Caenorhabditis elegans development.
abstract: Tribbles proteins are conserved pseudokinases that function to control kinase signalling and transcription in diverse biological processes. Abnormal function in human Tribbles has been implicated in a number of diseases including leukaemia, metabolic syndromes and cardiovascular diseases. Caenorhabditis elegans Tribbles NIPI-3 was previously shown to activate host defense upon infection by promoting the conserved PMK-1/p38 mitogen-activated protein kinase (MAPK) signalling pathway. Despite the prominent role of Tribbles proteins in many species, our knowledge of their mechanism of action is fragmented, and the in vivo functional relevance of their interactions with other proteins remains largely unknown.
  
  
  
  Here, by characterizing nipi-3 null mutants, we show that nipi-3 is essential for larval development and viability. Through analyses of genetic suppressors of nipi-3 null mutant lethality, we show that NIPI-3 negatively controls PMK-1/p38 signalling via transcriptional repression of the C/EBP transcription factor CEBP-1. We identified CEBP-1's transcriptional targets by ChIP-seq analyses and found them to be enriched in genes involved in development and stress responses. Unlike its cell-autonomous role in innate immunity, NIPI-3 is required in multiple tissues to control organismal development.
  
  
  
  Together, our data uncover an unprecedented crosstalk involving multiple tissues, in which NIPI-3 acts as a master regulator to inhibit CEBP-1 and the PMK-1/p38 MAPK pathway. In doing so, it keeps innate immunity in check and ensures proper organismal development.
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA. k9kim@ucsd.edu.
authors.forename: Kyung Won
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
authors.forename: Nishant
authors.initials: N
authors.lastname: Thakur
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Piggott
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
authors.forename: Shizue
authors.initials: S
authors.lastname: Omi
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Polanowska
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA. yijin@ucsd.edu.|Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA. yijin@ucsd.edu.
authors.forename: Yishi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France. pujol@ciml.univ-mrs.fr.
authors.forename: Nathalie
authors.identifier: 0000-0001-8889-3197
authors.initials: N
authors.lastname: Pujol
mesh_terms: D000483:Alleles; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D002470:Cell Survival; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D063185:Epigenetic Repression; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D029742:Caenorhabditis elegans Proteins; C000623282:Cebp-1 protein, C elegans; D011494:Protein Kinases; C530373:NIPI-3 protein, C elegans; D020928:Mitogen-Activated Protein Kinases; C463460:Pmk-1 protein, C elegans; D048051:p38 Mitogen-Activated Protein Kinases
keywords: C/EBP transcription factor; Development; Genetic suppression; Signal transduction; Stress responses; Transcriptional regulation; Tribbles; p38 MAP kinase