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首页> 外文期刊>MBio >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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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

机译：IRF-3对病毒发病机理的抑制和对细菌感染的败血症性休克反应的促进受其共激活剂的乙酰化和磷酸化作用的调节

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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. >IMPORTANCE 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.
机译：干扰素（IFN）是保护小鼠免受病毒致病的必需物质。相反，它介导对细菌感染的有害的败血性休克反应。在两种情况下，IFN诱导的关键转录因子都是IRF-3，IRF-3被TLR3或RIG-I信号激活以响应病毒感染，而TLR4信号被细菌感染激活。在这里，我们报道IRF-3的转录活性需要分别通过HDAC6介导的脱乙酰基作用和蛋白激酶C同工酶β（PKC-β）介导的磷酸化来修饰其共激活因子β-catenin和CBP，从而激活核IRF -3可以在靶基因启动子上形成稳定的转录起始复合物。 β-连环蛋白桥接IRF-3和CBP，对于β-catenin和CBP之间的相互作用特别需要进行修饰，而β-catenin和IRF-3则不需要。因此，像IRF-3 α/β小鼠一样，HDAC6 α/β小鼠对细菌脂多糖诱导的败血性休克具有抗性。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是对微生物感染的固有免疫反应的重要组成部分。 >重要性，重要的是要了解我们如何保护自己免受微生物感染。存在于哺乳动物细胞中的特定受体，称为Toll样受体，被分配来感知不同的微生物化学物质，例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，IRF-3驱动诱导的干扰素合成，干扰素是我们保护所需的分泌蛋白。在这里，我们报告说，干扰素的合成不仅受IRF-3激活的调节，还受与IRF-3一起起作用的两种蛋白质β-catenin和CBP的激活的调节。 β-连环蛋白通过HDAC6的脱乙酰作用而被激活，CBP通过其蛋白激酶C同工酶β（PKC-β）的磷酸化而被激活。这些规定不仅适用于细胞培养，而且适用于小鼠。

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