Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection.
Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection.
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DOI：
10.1016/j.immuni.2015.12.017
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发表时间：
2016-01-19
期刊：
影响因子：
32.4
通讯作者：
Marazzi I
中科院分区：
文献类型：
--
作者：
Heaton NS;Moshkina N;Fenouil R;Gardner TJ;Aguirre S;Shah PS;Zhao N;Manganaro L;Hultquist JF;Noel J;Sachs D;Hamilton J;Leon PE;Chawdury A;Tripathi S;Melegari C;Campisi L;Hai R;Metreveli G;Gamarnik AV;García-Sastre A;Greenbaum B;Simon V;Fernandez-Sesma A;Krogan NJ;Mulder LCF;van Bakel H;Tortorella D;Taunton J;Palese P;Marazzi I
病毒是专性寄生虫，因为它们需要宿主细胞的机器来复制。在活动性感染期间抑制宿主因子是抑制病毒复制的策略和潜在的泛抗病毒治疗。因此，确定病毒在感染过程中所需的细胞蛋白和过程对于理解病毒诱导疾病的机制至关重要。在这份报告中，我们产生了完全传染性的标记流感病毒，并使用基于感染的蛋白质组学来确定流感病毒生长和感染性所需的细胞信号传导的关键臂。使用数学建模，遗传学和药理学方法，我们发现，Sec 61介导的共翻译易位的调制选择性地损害流感病毒以及艾滋病毒和登革热病毒的糖蛋白蛋白质稳定，并导致病毒生长和感染性的抑制。因此，通过研究病毒-人蛋白质-蛋白质相互作用的背景下，积极复制，我们已经确定了广谱抗病毒治疗的靶向宿主因子。
Viruses are obligate parasites as they require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy to suppress viral replication and a potential pan antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity. Using mathematical modeling, genetic, and pharmacologic approaches, we revealed that modulation of Sec61-mediated cotranslational translocation selectively impaired glycoprotein proteostasis of influenza as well as HIV and dengue viruses, and led to inhibition of viral growth and infectivity. Thus, by studying virus-human protein-protein interactions in the context of active replication we have identified targetable host factors for broad-spectrum antiviral therapies.