A238L inhibits NF-ATc2, NF-κB, and c-Jun activation through a novel mechanism involving protein kinase C-θ-mediated up-regulation of the amino-terminal transactivation domain of p300
A238L inhibits NF-ATc2, NF-κB, and c-Jun activation through a novel mechanism involving protein kinase C-θ-mediated up-regulation of the amino-terminal transactivation domain of p300
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DOI：
10.4049/jimmunol.180.4.2429
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发表时间：
2008-02-15
影响因子：
4.4
通讯作者：
Revilla, Yolanda
中科院分区：
文献类型：
--
作者：
Granja, Aitor G.;Perkins, Neil D.;Revilla, Yolanda
转录共激活因子CREB结合蛋白和p300调节多种细胞过程中的诱导转录以及炎症和免疫反应的建立。几种病毒已被证明干扰CREB结合蛋白/p300的功能，调节它们的转录活性。在这项研究中，我们报道了病毒蛋白A238L与p300的氨基末端区域相互作用，抑制刺激的人T细胞中核因子-ATc2、核因子-kappaB和c-jun的乙酰化和转录激活。我们证明A238L在不改变其固有的组蛋白乙酰转移酶活性的情况下调节p300的自乙酰化。此外，我们还证明了病毒蛋白抑制的分子机制是通过阻断蛋白激酶C(PKC)-p300的相互作用和在辅活化子的氨基末端反式激活区域进一步的乙酰化来实现的，而在CH1结构域中的Ser(384)对于辅活化子的完全转录激活是必不可少的。此外，我们发现，一种活性形式的PKC-0的过度表达逆转了A238L介导的对p300转录活性的抑制，首次显示了PKC-theta介导的共激活因子的上调。这些发现提供了新的策略，以开发潜在有用的治疗方法来控制与p300放松调控相关的疾病。
The transcriptional coactivators CREB-binding protein and p300 regulate inducible transcription in multiple cellular processes and during the establishment of inflammatory and immune response. Several viruses have been shown to interfere with CREB-binding protein/p300 function, modulating their transcriptional activity. In this study, we report that the viral protein A238L interacts with the amino-terminal region of p300, inhibiting the acetylation and transcriptional activation of NF-ATc2, NF-kappa B, and c-Jun in stimulated human T cells. We demonstrate that A238L modulates the autoacetylation of p300 without altering its intrinsic histone acetyl transferase activity. Furthermore, we show that the molecular mechanism of the inhibition executed by the viral protein is conducted through blocking protein kinase C (PKC)-p300 interaction and further acetylation in the amino-terminal transactivation domain of the coactivator, and that Ser(384), within the CH1 domain, is essential for the full transcriptional activation of the coactivator. Moreover, we show that overexpression of an active form of PKC-0 reverts the A238L-mediated inhibition of the transcriptional activity of p300, showing, for the first time, a PKC-theta-mediated up-regulation of the coactivator. These findings provide new strategies to develop therapies potentially useful in the control of disorders related to p300 deregulation.