Abstract
BackgroundTribbles 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.ResultsHere, 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.ConclusionsTogether, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0320-z) contains supplementary material, which is available to authorized users.
Highlights
Tribbles proteins are conserved pseudokinases that function to control kinase signalling and transcription in diverse biological processes
C. elegans Tribbles nipi-3 is required for larval development and viability To better understand the biological roles of nipi-3, we used clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing [24,25,26,27] to generate two deletion alleles of nipi-3 and a green fluorescent protein (GFP) knock-in (KI) (Fig. 1a; see Methods and below)
We rescued the larval lethality and sterility of nipi-3(0) by expressing the wild-type nipi-3 genomic DNA as high-copy-number extrachromosomal arrays (Fig. 1a, e, h; Methods). As expression from such transgenes is silenced in the germline [28], this result indicates that the larval lethality and germline development defects of nipi-3(0) are both primarily due to its function in somatic tissues
Summary
Tribbles proteins are conserved pseudokinases that function to control kinase signalling and transcription in diverse biological processes. 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. Trib binds to and inhibits the transcriptional activity of both activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) in cultured cell lines [16,17,18,19], the in vivo functional relevance of such protein interactions remains unknown
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