Inhibition of viral pathogenesis and promotion of the septic shock response to bacterial infection by IRF-3 are regulated by the acetylation and phosphorylation of its coactivators.
Inhibition of viral pathogenesis and promotion of the septic shock response to bacterial infection by IRF-3 are regulated by the acetylation and phosphorylation of its coactivators.
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DOI：
10.1128/mbio.00636-12
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发表时间：
2013-03-26
期刊：
影响因子：
6.4
通讯作者：
Sen GC
中科院分区：
文献类型：
--
作者：
Chattopadhyay S;Fensterl V;Zhang Y;Veleeparambil M;Wetzel JL;Sen GC
干扰素（IFN）是保护小鼠免受病毒致病所必需的；反过来，它介导对细菌感染的有害脓毒症休克反应。在这两种情况下，干扰素诱导的关键转录因子都是IRF - 3，它在病毒感染时通过TLR3或RIG - I信号激活，在细菌感染时通过TLR4信号激活。在此，我们报道IRF - 3的转录活性需要其共激活因子β - 连环蛋白和CBP分别被HDAC6介导的去乙酰化和蛋白激酶C同工酶β（PKC - β）介导的磷酸化修饰，以便激活的核IRF - 3能够在靶基因启动子处形成稳定的转录起始复合物。β - 连环蛋白连接IRF - 3和CBP，并且这些修饰是β - 连环蛋白与CBP之间相互作用所特需的，而不是β - 连环蛋白与IRF - 3之间相互作用所特需的。因此，像IRF - 3 - / -小鼠一样，HDAC6 - / -小鼠对细菌脂多糖诱导的脓毒症休克具有抗性。相反，它们对仙台病毒感染引起的发病机制高度敏感。因此，HDAC6是对微生物感染的先天免疫反应的一个重要组成部分。
了解我们如何保护自己免受微生物感染是很重要的。哺乳动物细胞中存在的特定受体，称为Toll样受体，被用于感知不同的微生物化学物质，如细菌脂多糖或病毒双链RNA。这些受体的激活导致关键转录因子IRF - 3的激活，它驱动干扰素的诱导合成，干扰素是我们受到保护所必需的一种分泌蛋白。在此，我们报道干扰素的合成不仅受IRF - 3激活的调节，还受两种蛋白质β - 连环蛋白和CBP激活的调节，它们与IRF - 3共同发挥作用。β - 连环蛋白通过被HDAC6去乙酰化而激活，CBP通过被蛋白激酶C同工酶β（PKC - β）磷酸化而激活。这些调节不仅在细胞培养中起作用，在小鼠中也起作用。
Interferon (IFN) is required for protecting mice from viral pathogenesis; reciprocally, it mediates the deleterious septic shock response to bacterial infection. The critical transcription factor for IFN induction, in both cases, is IRF-3, which is activated by TLR3 or RIG-I signaling in response to virus infection and TLR4 signaling in response to bacterial infection. Here, we report that IRF-3’s transcriptional activity required its coactivators, β-catenin and CBP, to be modified by HDAC6-mediated deacetylation and protein kinase C isozyme β (PKC-β)-mediated phosphorylation, respectively, so that activated nuclear IRF-3 could form a stable transcription initiation complex at the target gene promoters. β-Catenin bridges IRF-3 and CBP, and the modifications were required specifically for the interaction between β-catenin and CBP but not β-catenin and IRF-3. Consequently, like IRF-3−/− mice, HDAC6−/− mice were resistant to bacterial lipopolysaccharide-induced septic shock. Conversely, they were highly susceptible to pathogenesis caused by Sendai virus infection. Thus, HDAC6 is an essential component of the innate immune response to microbial infection. It is important to understand how we protect ourselves against microbial infection. Specific receptors present in mammalian cells, called Toll-like receptors, are assigned to sense different microbial chemicals, such as bacterial lipopolysaccharides or viral double-stranded RNA. Activation of these receptors leads to the activation of a critical transcription factor, IRF-3, which drives the induced synthesis of interferon, a secreted protein required for our protection. Here, we report that interferon synthesis is regulated not only by IRF-3 activation but also by activation of two proteins, β-catenin and CBP, which function together with IRF-3. β-Catenin is activated by its deacetylation by HDAC6, and CBP is activated by its phosphorylation by protein kinases C isozyme β (PKC-β). These regulations are operative not only in cell cultures but also in mice.