Inhibition of Histone Deacetylase Activity Suppresses IFN-γ Induction of Tripartite Motif 22 via CHIP-Mediated Proteasomal Degradation of IRF-1
Inhibition of Histone Deacetylase Activity Suppresses IFN-γ Induction of Tripartite Motif 22 via CHIP-Mediated Proteasomal Degradation of IRF-1
复制标题
组蛋白脱乙酰酶活性的抑制通过 CHIP 介导的 IRF-1 蛋白酶体降解抑制三联基序 22 的 IFN-γ 诱导
DOI：
10.4049/jimmunol.1203533
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发表时间：
2013-07-01
影响因子：
4.4
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
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作者：
Gao, Bo;Wang, Yaxin;Xiong, Sidong
三联基序（TRIM）22在干扰素（IFN）介导的抗病毒活性中起重要作用。我们先前证明，干扰素调节因子（IRF）-1通过与一种名为5'延伸的干扰素刺激反应元件的新型顺式元件结合，对基础的以及干扰素诱导的TRIM22转录至关重要。在本研究中，我们探讨了组蛋白去乙酰化酶（HDAC）活性在干扰素 -γ诱导TRIM22中的作用及其潜在机制。我们发现HDAC活性，尤其是HDAC6所赋予的活性，是干扰素 -γ诱导TRIM22转录所必需的。重要的是，曲古抑菌素A（TSA）对HDAC活性的抑制增强了热休克蛋白（HSP）90的高度乙酰化，并抑制了其对IRF -1的分子伴侣活性。进一步的研究表明，TSA处理通过增强IRF -1与热休克蛋白70相互作用蛋白的羧基末端（Hsc70 - interacting protein）这一泛素E3连接酶的结合，促进了IRF -1蛋白的蛋白酶体降解。此外，发现热休克蛋白70相互作用蛋白的羧基末端参与了TSA介导的对干扰素 -γ诱导TRIM22以及其他IRF -1依赖性干扰素刺激基因的抑制作用。这项研究可能为HDAC活性在干扰素刺激基因诱导的转录调控中的作用提供新的见解。
Tripartite motif (TRIM) 22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IFN regulatory factor (IRF)-1 was crucial for basal and IFN-induced TRIM22 transcription via binding to a novel cis-element named 5' extended IFN-stimulating response element. In this study, we investigated the role of histone deacetylase (HDAC) activity in TRIM22 induction by IFN-gamma and its underlying mechanism. We found that the HDAC activity, especially that conferred by HDAC6, was required for IFN-gamma-induced TRIM22 transcription. Importantly, inhibition of HDAC activity by trichostatin A (TSA) enhanced the hyperacetylation of heat shock protein (HSP)90 and suppressed its chaperone activity for IRF-1. Further study showed that TSA treatment promoted the proteasomal degradation of IRF-1 protein via enhancing the association of IRF-1 with the ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein. Moreover, carboxyl terminus of Hsc70-interacting protein was found to be involved in the TSA-mediated inhibitory effect on IFN-gamma induction of TRIM22 as well as other IRF-1-dependent IFN-stimulated genes. This study may provide novel insight into the role of HDAC activity in the transcriptional control of IFN-stimulated gene induction.