Gcn5 and PCAF negatively regulate interferon-β production through HAT-independent inhibition of TBK1
Gcn5 and PCAF negatively regulate interferon-β production through HAT-independent inhibition of TBK1
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DOI：
10.15252/embr.201438990
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发表时间：
2014-11-01
期刊：
影响因子：
7.7
通讯作者：
Ge, Kai
中科院分区：
文献类型：
--
作者：
Jin, Qihuang;Zhuang, Lenan;Ge, Kai
病毒感染触发先天免疫信号，进而诱导干扰素的产生，从而建立先天抗病毒免疫。以往的研究表明，与PCAF功能部分冗余的组蛋白乙酰转移酶(HAT)Gcn5(Kat2a)和Gcn5/PCAF介导的组蛋白H3K9乙酰化(H3K9ac)富含在激活的IFNB基因启动子上。然而，Gcn5/PCAF和H3K9ac是否调节干扰素的产生尚不清楚。在这里，我们表明Gcn5/PCAF介导的H3K9ac与内源性IFNB和成纤维细胞中绝大多数活性基因的表达有很好的相关性，但令人惊讶的是它是可有可无的。相反，Gcn5/PCAF以一种不依赖于HAT和非转录的方式抑制几种细胞类型的干扰素产生和先天抗病毒免疫：通过抑制细胞质中的先天免疫信号激酶TBK1。因此，我们的结果确定Gcn5和PCAF是干扰素产生和先天免疫信号的负调节因子。
Viral infection triggers innate immune signaling, which in turn induces interferon- (IFN-) production to establish innate antiviral immunity. Previous studies showed that Gcn5 (Kat2a), a histone acetyltransferase (HAT) with partial functional redundancy with PCAF (Kat2b), and Gcn5/PCAF-mediated histone H3K9 acetylation (H3K9ac) are enriched on the active IFNB gene promoter. However, whether Gcn5/PCAF and H3K9ac regulate IFN- production is unknown. Here, we show that Gcn5/PCAF-mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous IFNB and the vast majority of active genes in fibroblasts. Instead, Gcn5/PCAF repress IFN- production and innate antiviral immunity in several cell types in a HAT-independent and non-transcriptional manner: by inhibiting the innate immune signaling kinase TBK1 in the cytoplasm. Our results thus identify Gcn5 and PCAF as negative regulators of IFN- production and innate immune signaling.