Porcine Reproductive and Respiratory Syndrome Virus nsp1α Inhibits NF-κB Activation by Targeting the Linear Ubiquitin Chain Assembly Complex
Porcine Reproductive and Respiratory Syndrome Virus nsp1α Inhibits NF-κB Activation by Targeting the Linear Ubiquitin Chain Assembly Complex
复制标题
猪繁殖与呼吸综合征病毒 nsp1 alpha 通过靶向线性泛素链组装复合物抑制 NF-kappa B 激活
DOI：
10.1128/jvi.01911-16
复制
发表时间：
2017-02-01
影响因子：
5.4
通讯作者：
Xiao, Shaobo
中科院分区：
文献类型：
--
作者：
Jing, Huiyuan;Fang, Liurong;Xiao, Shaobo
线性泛素化是一种新发现的翻译后修饰，它由三个亚基组成：一个催化亚基HOIP和两个辅助分子HOIL-1L和SHARPIN。越来越多的证据表明，线性泛素化在先天免疫信号传导中起着至关重要的作用，特别是通过将线性多泛素链偶联到NF-kappa B必需调节剂（NEMO，也称为IKK γ） （IKK复合物的调节亚基）来激活NF-kappa B途径。猪繁殖与呼吸综合征病毒（PRRSV）是一种破坏全球养猪业的动脉病毒，是研究病毒感染后宿主无序炎症反应的理想模型。本研究发现，lubac诱导的NF-kappa B和促炎细胞因子的表达在PRRSV感染的早期可以被抑制。prrsv编码蛋白的筛选表明，非结构蛋白1 α (nsp1 α)抑制lubac介导的NF-kappa B激活，其CTE结构域是抑制NF-kappa B激活的必要条件。从机制上说，nsp1 α结合到HOIP/HOIL-1L上，并破坏HOIP和SHARPIN之间的相互作用，从而减少了lubac依赖性NEMO的线性泛素化。此外，PRRSV感染还阻断LUBAC复合物的形成和NEMO线性泛素化，这是NF-kappa B信号转导的重要步骤。这一意想不到的发现证明了PRRSV nsp1 α在调节LUBAC信号传导中的作用，并解释了PRRSV免疫调节的另一种机制。猪繁殖与呼吸综合征（PRRS）是养猪业集约化国家最重要的兽医传染病之一。PRRS病毒（PRRSV）感染通常在感染早期抑制促炎细胞因子的表达，而在感染后期诱导炎症风暴。然而，这种病毒究竟是如何做到这一点的，目前尚不清楚。在本研究中，我们发现PRRSV通过阻断其催化亚基HOIP和辅助分子SHARPIN的相互作用，可以在感染早期抑制NF-kappa B信号转导。我们的发现不仅揭示了PRRSV调控炎症反应的新机制，而且强调了线性泛素化修饰在病毒感染过程中的重要作用。
Linear ubiquitination, a newly discovered posttranslational modification, is catalyzed by the linear ubiquitin chain assembly complex (LUBAC), which is composed of three subunits: one catalytic subunit HOIP and two accessory molecules, HOIL-1L and SHARPIN. Accumulating evidence suggests that linear ubiquitination plays a crucial role in innate immune signaling and especially in the activation of the NF-kappa B pathway by conjugating linear polyubiquitin chains to NF-kappa B essential modulator (NEMO, also called IKK gamma), the regulatory subunit of the IKK complex. Porcine reproductive and respiratory syndrome virus (PRRSV), an Arterivirus that has devastated the swine industry worldwide, is an ideal model to study the host's disordered inflammatory responses after viral infection. Here, we found that LUBAC-induced NF-kappa B and proinflammatory cytokine expression can be inhibited in the early phase of PRRSV infection. Screening the PRRSV-encoded proteins showed that nonstructural protein 1 alpha (nsp1 alpha) suppresses LUBAC-mediated NF-kappa B activation and its CTE domain is required for the inhibition. Mechanistically, nsp1 alpha binds to HOIP/HOIL-1L and impairs the interaction between HOIP and SHARPIN, thus reducing the LUBAC-dependent linear ubiquitination of NEMO. Moreover, PRRSV infection also blocks LUBAC complex formation and NEMO linear-ubiquitination, the important step for transducing NF-kappa B signaling. This unexpected finding demonstrates a previously unrecognized role of PRRSV nsp1 alpha in modulating LUBAC signaling and explains an additional mechanism of immune modulation by PRRSV.IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS) is one of the most important veterinary infectious diseases in countries with intensive swine industries. PRRS virus (PRRSV) infection usually suppresses proinflammatory cytokine expression in the early stage of infection, whereas it induces an inflammatory storm in the late stage. However, precisely how the virus is capable of doing so remains obscure. In this study, we found that by blocking the interaction of its catalytic subunit HOIP and accessory molecule SHARPIN, PRRSV can suppress NF-kappa B signal transduction in the early stage of infection. Our findings not only reveal a novel mechanism evolved by PRRSV to regulate inflammatory responses but also highlight the important role of linear ubiquitination modification during virus infection.