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BMC Biol. 2016 Dec 7;14(1):104.

Coordinated inhibition of C/EBP by Tribbles in multiple tissues is essential for Caenorhabditis elegans development.

Author information

1
Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA. k9kim@ucsd.edu.
2
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
3
Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
4
Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92093, USA. yijin@ucsd.edu.
5
Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, 92093, USA. yijin@ucsd.edu.
6
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France. pujol@ciml.univ-mrs.fr.

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

C/EBP transcription factor; Development; Genetic suppression; Signal transduction; Stress responses; Transcriptional regulation; Tribbles; p38 MAP kinase

PMID:
27927209
PMCID:
PMC5141650
DOI:
10.1186/s12915-016-0320-z
[Indexed for MEDLINE]
Free PMC Article

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