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RNPS1 inhibits excessive TNF/TNFR signaling to support hematopoiesis in mice

ABSTRACT: Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic mutations provide an opportunity to understand the physiological impact of individual splicing proteins. We describe a viable missense allele of Rnps1, encoding an essential regulator of splicing and nonsense-mediated decay, identified in a mouse genetic screen for altered immune cell development. Homozygous mice displayed a stem cell-intrinsic defect in hematopoiesis of all lineages due to excessive apoptosis induced by TNF-dependent death signaling. Numerous splicing variants were observed in Rnps1 mutant splenic CD8+ T and HSC cells, potentially driven by dysregulated splicing, characterized by magnification of both intron retention and exon skipping. Strikingly, Tnf knockout rescued all hematopoietic cells to normal or near-normal levels in Rnps1 mutant mice. Thus, RNPS1 is necessary for accurate splicing, without which disinhibited TNF signaling triggers hematopoietic cell death.

ORGANISM(S): Mus musculus

PROVIDER: GSE155492 | GEO | 2022/03/31

REPOSITORIES: GEO

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RNPS1 inhibits excessive TNF/TNFR signaling to support hematopoiesis in mice

Project description:RNPS1 inhibits excessive TNF/TNFR signaling to support hematopoiesis in mice

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The exon junction complex controls transposable element activity by ensuring the faithful splicing of the piwi transcript

Project description:The exon junction complex (EJC) is a highly conserved ribonucleoprotein complex which binds RNAs at a late stage of the splicing reaction and remains associated following export to the cytoplasm. This complex is involved in several cellular post-transcriptional processes including mRNA localization, translation and degradation. The EJC plays an additional role in the splicing of a subset of genes in Drosophila and in human cells but the underlying mechanism remains to be elucidated. Here, we have found a novel function for the EJC and its splicing subunit RnpS1 in preventing transposon accumulation in both Drosophila germline and surrounding follicular cells. This function is mediated specifically through the control of the splicing of the piwi transcript. In absence of RnpS1 one of the piwi intron is retained. This intron contains a weak 5’ splice site as well as degenerate transposon fragments, reminiscent of heterochromatic introns. In addition, we identified a small A/T rich region, which alters its polypyrimidine tract (PPT) and confers the RnpS1’s dependency. Finally, we showed that the removal of this intron by RnpS1 requires the initial splicing of the flanking introns, suggesting a model in which the EJC facilitates the splicing of challenging introns following its initial deposition to adjacent exon junctions. In total there are 4 different conditions. Comparisons were made between piwi mutant vs control piwi and rnps1 KD vs controls RnpS1

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The exon junction complex controls transposable element activity by ensuring faithful splicing of the piwi transcript

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