Control of specificity and magnitude of NF-κB and STAT1-mediated gene activation through PIASy and PIAS1 cooperation
Control of specificity and magnitude of NF-κB and STAT1-mediated gene activation through PIASy and PIAS1 cooperation
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DOI：
10.1073/pnas.0701877104
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发表时间：
2007-07-10
影响因子：
11.1
通讯作者：
Shuai, Ke
中科院分区：
文献类型：
--
作者：
Tahk, Samuel;Liu, Bin;Shuai, Ke
NF-κ B和STAT通过转录激活具有多种功能的基因来调节多种细胞过程。尽管已经广泛地研究了能够开启/关闭总体NF-κ B/STAT信号传导的分子机制，但是对NF-κ B/STAT靶基因如何能够被差异调节知之甚少。在这里，我们报告，PIASy，一个成员的皮亚斯（蛋白抑制剂激活STAT）蛋白家族，是一个生理上重要的转录抑制因子NF-κ B和STAT 1。树突状细胞中的Piasy缺失分别导致响应于LPS或IFN-γ处理的NF-κ B和STAT 1依赖性基因的子集的表达增强。因此，Piasy基因敲除小鼠对LPS诱导的内毒素休克具有高度敏感性。此外，PIASy和PIAS 1对NF-κ B/STAT 1信号传导的调节显示出特异性以及冗余的作用。Pias 1（-/-）-Piasy（-/-）胚胎在第11.5天前死亡。在Piasy（-/-）背景中Pias 1的一个等位基因的破坏显著增强了Piasy耗竭对NF-κ B/STAT 1依赖性基因的转录诱导的作用，反之亦然。我们的研究结果表明，PIASy与PIAS 1合作，调节NF-κ B/STAT 1介导的基因激活的特异性和幅度。
NF-kappa B and STATs regulate multiple cellular processes through the transcriptional activation of genes with diversified functions. Although the molecular mechanisms that can turn on/off the overall NF-kappa B/STAT signaling have been extensively studied, how NF-kappa B/ STAT-target genes can be differentially regulated is poorly understood. Here we report that PIASy, a member of the PIAS (for protein inhibitor of activated STAT) protein family, is a physiologically important transcriptional repressor of NF-kappa B and STAT1. Piasy deletion in dendritic cells resulted in enhanced expression of a subset of NF-kappa B and STAT1-dependent genes in response to LPS or IFN-gamma treatment, respectively. Consistently, Piasy null mice are hypersensitive to the LPS-induced endotoxic shock. Furthermore, PIASy and PIAS1 display specific as well as redundant effects on the regulation of NF-kappa B/STAT1 signaling. Pias1(-/-)-Piasy(-/-) embryos died before day 11.5. The disruption of one allele of Pias1 in the Piasy(-/-) background significantly enhanced the effect of Piasy depletion on the transcriptional induction of NF-kappa B/STAT1-dependent genes, and vice versa. Our results demonstrate that PIASy cooperates with PIAS1 to regulate the specificity and magnitude of NF-kappa B/STAT1-mediated gene activation.