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Positive and Negative Regulation of the Innate Antiviral Response and Beta Interferon Gene Expression by Deacetylation

机译：通过脱乙酰作用对先天抗病毒应答和β干扰素基因表达的正负调节

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Beta interferon (IFN-β) gene expression in response to virus infection relies on the dynamic assembly of a multiprotein enhanceosome complex that is initiated by the activation of two inducible transcription factors, interferon regulatory factor 3 (IRF3) and NF-κB. Virus or double-stranded RNA-induced activation of IFN-β gene expression is prevented by the addition of protein deacetylase inhibitors. The isolated IRF-responsive positive regulatory domain was found to require deacetylation for its activity, but IRF3 protein activation leading to its nuclear translocation and DNA binding was not impaired by deacetylase inhibition. In contrast, NF-κB activity was not affected by deacetylase inhibitors. RNA interference indicated that several deacetylase enzymes, including histone deacetylase 1 (HDAC1), HDAC8, and HDAC6, influence IFN-β gene expression with opposing effects. While HDAC1 and HDAC8 repress IFN-β expression, HDAC6 acts as a coactivator essential for enhancer activity. Virus replication is enhanced in HDAC6-depleted cells, demonstrating HDAC6 is an essential component of innate antiviral immunity.
机译：响应病毒感染的β干扰素（IFN-β）基因表达依赖于一种多蛋白增强体复合物的动态组装，该复合物是通过激活两种可诱导的转录因子干扰素调节因子3（IRF3）和NF-κB来启动的。病毒或双链RNA诱导的IFN-β基因表达激活可通过添加蛋白质脱乙酰酶抑制剂来预防。发现分离的IRF应答性正调节结构域需要脱乙酰基来实现其活性，但是脱乙酰基酶抑制不会削弱导致其核易位和DNA结合的IRF3蛋白活化。相反，NF-κB的活性不受脱乙酰基酶抑制剂的影响。 RNA干扰表明，包括组蛋白脱乙酰基酶1（HDAC1），HDAC8和HDAC6在内的几种脱乙酰基酶会影响IFN-β基因的表达，并具有相反的作用。虽然HDAC1和HDAC8抑制IFN-β表达，但HDAC6充当增强子活性必不可少的共激活因子。在HDAC6耗尽的细胞中，病毒复制得以增强，这表明HDAC6是先天抗病毒免疫力的重要组成部分。

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