Histone Deacetylase 6 Inhibits Influenza A Virus Release by Downregulating the Trafficking of Viral Components to the Plasma Membrane via Its Substrate, Acetylated Microtubules
Histone Deacetylase 6 Inhibits Influenza A Virus Release by Downregulating the Trafficking of Viral Components to the Plasma Membrane via Its Substrate, Acetylated Microtubules
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DOI：
10.1128/jvi.00727-14
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发表时间：
2014-10-01
影响因子：
5.4
通讯作者：
Cheung, Chen-Yi
中科院分区：
文献类型：
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作者：
Husain, Matloob;Cheung, Chen-Yi
哺乳动物细胞产生许多抑制甲型流感病毒（IAV）感染的蛋白质，如IFITM 3、ISG 15、MxA和蝰蛇蛋白。在这里，我们表明，一类新的宿主蛋白，组蛋白脱乙酰酶6（HDAC 6），抑制IAV感染。我们发现，HDAC 6过表达细胞释放约3倍的IAV后代，而HDAC 6耗尽细胞释放约6倍的IAV后代。HDAC 6的去乙酰化酶活性在其抗IAV功能中起作用，因为HDAC 6的特异性小分子抑制剂tubacin以剂量依赖性方式增加IAV子代的释放。此外，如通过电子显微镜观察到的，微管菌素处理的细胞显示出IAV在质膜（IAV组装的位点）处出芽的增加。Tubacin是一种结构域特异性抑制剂，与具有微管蛋白脱乙酰酶活性的两个HDAC 6催化结构域之一结合。这表明乙酰化微管可能参与病毒组分向质膜的运输。事实上，如通过流式细胞术定量的，存在于微管蛋白处理的/HDAC 6耗尽的和HDAC 6过表达的细胞的质膜上的病毒包膜蛋白血凝素的量分别增加约2.0至2.5倍和约2.0倍减少。此外，病毒核糖核蛋白复合物与乙酰化微管丝共定位，病毒核蛋白与乙酰化微管蛋白共免疫沉淀。总之，我们的研究结果表明，HDAC 6是一种抗IAV宿主因子，并发挥其抗IAV功能，负调控的病毒成分的运输到宿主细胞质膜通过其基板，乙酰化microtubules.IMPORTANCEHost细胞产生许多蛋白质，具有天然的能力，以限制流感病毒感染。在这里，我们发现另一种宿主蛋白，组蛋白脱乙酰基酶6（HDAC 6），抑制流感病毒感染。我们证明，HDAC 6发挥其抗流感病毒的功能，通过负调控贩运的病毒成分的网站，流感病毒组装通过其基板，乙酰化微管。HDAC 6是一种多底物酶，调节多种细胞途径，包括导致各种癌症，神经退行性疾病和炎症性疾病的途径。因此，几种靶向HDAC 6的药物正在临床开发中，用于治疗多种疾病。由于人类中经常出现耐药性和新型流感病毒株，流感病毒仍然是一个主要的全球公共卫生问题。作为一种替代的抗病毒策略，HDAC 6调节剂可用于刺激内源性HDAC 6的抗流感病毒潜力以抑制流感病毒感染。
Mammalian cells produce many proteins, such as IFITM3, ISG15, MxA, and viperin, that inhibit influenza A virus (IAV) infection. Here, we show that a new class of host protein, histone deacetylase 6 (HDAC6), inhibits IAV infection. We found that HDAC6-overexpressing cells release about 3-fold less IAV progeny, whereas HDAC6-depleted cells release about 6-fold more IAV progeny. The deacetylase activity of HDAC6 played a role in its anti-IAV function as tubacin, a specific small-molecule inhibitor of HDAC6, increased the release of IAV progeny in a dose-dependent manner. Further, as visualized by electron microscopy, tubacin-treated cells showed an increase in IAV budding at the plasma membrane, the site of IAV assembly. Tubacin is a domain-specific inhibitor and binds to one of the two HDAC6 catalytic domains possessing tubulin deacetylase activity. This indicated the potential involvement of acetylated microtubules in the trafficking of viral components to the plasma membrane. Indeed, as quantified by flow cytometry, there was about a 2.0- to 2.5- fold increase and about a 2.0- fold decrease in the amount of viral envelope protein hemagglutinin present on the plasma membrane of tubacin-treated/HDAC6- depleted and HDAC6-overexpressing cells, respectively. In addition, the viral ribonucleoprotein complex was colocalized with acetylated microtubule filaments, and viral nucleoprotein coimmunoprecipitated with acetylated tubulin. Together, our findings indicate that HDAC6 is an anti-IAV host factor and exerts its anti-IAV function by negatively regulating the trafficking of viral components to the host cell plasma membrane via its substrate, acetylated microtubules.IMPORTANCEHost cells produce many proteins that have the natural ability to restrict influenza virus infection. Here, we discovered that another host protein, histone deacetylase 6 (HDAC6), inhibits influenza virus infection. We demonstrate that HDAC6 exerts its anti-influenza virus function by negatively regulating the trafficking of viral components to the site of influenza virus assembly via its substrate, acetylated microtubules. HDAC6 is a multisubstrate enzyme and regulates multiple cellular pathways, including the ones leading to various cancers, neurodegenerative diseases, and inflammatory disorders. Therefore, several drugs targeting HDAC6 are under clinical development for the treatment of a wide range of diseases. Influenza virus continues to be a major global public health problem due to regular emergence of drug-resistant and novel influenza virus strains in humans. As an alternative antiviral strategy, HDAC6 modulators could be employed to stimulate the anti-influenza virus potential of endogenous HDAC6 to inhibit influenza virus infection.