A phosphorylation-acetylation switch regulates STAT1 signaling
A phosphorylation-acetylation switch regulates STAT1 signaling
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DOI：
10.1101/gad.479209
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发表时间：
2009-01-15
影响因子：
10.5
通讯作者：
Heinzel, Thorsten
中科院分区：
文献类型：
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作者：
Kraemer, Oliver H.;Knauer, Shirley K.;Heinzel, Thorsten
干扰素等细胞因子通过磷酸化激活信号转导和转录激活因子。组蛋白脱乙酰酶(HDACs)和组蛋白乙酰转移酶(HAT)CBP动态调节STAT1乙酰化。在这里，我们表明，STAT1的乙酰化抵消了干扰素诱导的STAT1磷酸化、核转位、DNA结合和靶基因表达。改变HAT/HDAC活性比和STAT1突变体的生化和遗传学实验表明，磷酸乙酰基开关通过CBP、HDAC3和T细胞蛋白酪氨酸磷酸酶(TCP45)调节STAT1信号。值得注意的是，通过CBP介导的乙酰化抑制STAT1信号与这种HAT在转录激活中的功能是不同的。STAT1乙酰化诱导TCP45结合，TCP45催化STAT1去磷酸化和潜伏期。我们的结果为我们对STAT1活性的调控提供了更深入的理解。这些发现揭示了一层新的与生理相关的STAT1调节，并表明先前未知的磷酸化和乙酰化之间的平衡影响细胞因子信号转导。
Cytokines such as interferons (IFNs) activate signal transducers and activators of transcription (STATs) via phosphorylation. Histone deacetylases (HDACs) and the histone acetyltransferase (HAT) CBP dynamically regulate STAT1 acetylation. Here we show that acetylation of STAT1 counteracts IFN-induced STAT1 phosphorylation, nuclear translocation, DNA binding, and target gene expression. Biochemical and genetic experiments altering the HAT/HDAC activity ratio and STAT1 mutants reveal that a phospho-acetyl switch regulates STAT1 signaling via CBP, HDAC3, and the T-cell protein tyrosine phosphatase (TCP45). Strikingly, inhibition of STAT1 signaling via CBP-mediated acetylation is distinct from the functions of this HAT in transcriptional activation. STAT1 acetylation induces binding of TCP45, which catalyzes dephosphorylation and latency of STAT1. Our results provide a deeper understanding of the modulation of STAT1 activity. These findings reveal a new layer of physiologically relevant STAT1 regulation and suggest that a previously unidentified balance between phosphorylation and acetylation affects cytokine signaling.