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Tristetraprolin mediates interferon-gamma mRNA decay.

ABSTRACT: Tristetraprolin (TTP) regulates expression at the level of mRNA decay of several cytokines, including the T cell-specific cytokine, interleukin-2. We performed experiments to determine whether another T cell-specific cytokine, interferon-gamma (IFN-gamma), is also regulated by TTP and found that T cell receptor-activated T cells from TTP knock-out mice overproduced IFN-gamma mRNA and protein compared with activated T cells from wild-type mice. The half-life of IFN-gamma mRNA was 23 min in anti-CD3-stimulated T cells from wild-type mice, whereas it was 51 min in anti-CD3-stimulated T cells from TTP knock-out mice, suggesting that the overexpression of IFN-gamma mRNA in TTP knock-out mice was due to stabilization of IFN-gamma mRNA. Insertion of a 70-nucleotide AU-rich sequence from the murine IFN-gamma 3'-untranslated region, which contained a high affinity binding site for TTP, into the 3'-untranslated region of a beta-globin reporter transcript conferred TTP-dependent destabilization on the beta-globin transcript. Together these results suggest that TTP binds to a functional AU-rich element in the 3'-untranslated region of IFN-gamma mRNA and mediates rapid degradation of the IFN-gamma transcript. Thus, TTP plays an important role in turning off IFN-gamma expression at the appropriate time during an immune response.

SUBMITTER: Ogilvie RL

PROVIDER: S-EPMC2670126 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Tristetraprolin mediates interferon-gamma mRNA decay.

Ogilvie Rachel L RL Sternjohn Julius R JR Rattenbacher Bernd B Vlasova Irina A IA Williams Darlisha A DA Hau Heidi H HH Blackshear Perry J PJ Bohjanen Paul R PR

The Journal of biological chemistry 20090303 17

Tristetraprolin (TTP) regulates expression at the level of mRNA decay of several cytokines, including the T cell-specific cytokine, interleukin-2. We performed experiments to determine whether another T cell-specific cytokine, interferon-gamma (IFN-gamma), is also regulated by TTP and found that T cell receptor-activated T cells from TTP knock-out mice overproduced IFN-gamma mRNA and protein compared with activated T cells from wild-type mice. The half-life of IFN-gamma mRNA was 23 min in anti-C ...[more]

PMID: 19258311

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Project description:BackgroundIn mammals, maternal gene products decay and zygotic genome activation (ZGA) during maternal to zygotic transition (MZT) is critical for the early embryogenesis. Y-box binding protein YBX1 plays vital roles in RNA stabilization and transcriptional regulation, but its roles remain to be elucidated during pre-implantation development.MethodsIn the present study, we re-analyzed transcriptional level of YBX1 in mice, human, bovine, and goat embryos using public RNA-seq datasets. We further performed siRNA microinjection to knock down the expression of YBX1, and RNA sequencing of the 8-cell stage embryos in the control and YBX1 knockdown group. To reveal the regulation mechanisms of YBX1, we conducted differentially expression analysis, alternative splicing (AS) analysis, enrichment analysis, and 5-EU staining using DESeq2, rMATs, clusterProfiler, and immunofluorescence technique, respectively.ResultsThe expression of YBX1 was increased during MZT in goat, bovine, human, and mice, but significantly decreased in YBX1 knockdown embryos compared with the controls, suggesting successfully knockdown of YBX1. The percentage of blastocyst was decreased, while embryos blocked at the 2- and 4-cell stage were increased in YBX1 knockdown embryos compared to the controls. Using RNA-seq, we identified 1623 up-regulated and 3531 down-regulated genes in the 8-cell stage YBX1 knockdown embryos. Of note, the down-regulated genes were enriched in regulation of RNA/mRNA stability and spliceosome, suggesting that YBX1 might medicate RNA stability and AS. To this end, we identified 3284 differential AS events and 1322 differentially expressed maternal mRNAs at the 8-cell stage YBX1 knockdown embryos. Meanwhile, the splicing factors and mRNA decay-related genes showed aberrant expression, and the transcriptional activity during ZGA in goat and mice was compromised when YBX1 was knocked down.ConclusionYBX1 serves an important role in maternal mRNA decay, alternative splicing, and the transcriptional activity required for early embryogenesis, which will broaden the current understanding of YBX1 functions during the stochastic reprogramming events.

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Tristetraprolin mediates interferon-gamma mRNA decay.

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Tristetraprolin mediates interferon-gamma mRNA decay.

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