Role of TRIM79 in innate immunity to tick-borne encephalitis virus

描述(由申请人提供)： 摘要 PI：Taylor，Roger Travis项目：1K22AI099020-01标题：TRIM79在森林脑炎病毒天然免疫中的作用登录号：3398464 = 注意：此摘要摘自应用程序，未经SRA校对。如果应用程序扫描过程有问题，提取的文本可能不正确或不完整。 = 黄病毒给人类带来了巨大的疾病负担，包括登革热病毒、西尼罗河病毒(WNV)和森林脑炎病毒(TBEV)。这些病毒对I型干扰素的抗病毒作用高度敏感。然而，干扰素ASA的治疗效果受到这些病毒抑制干扰素依赖的信号转导能力的限制。 从而抑制干扰素刺激基因(ISGs)的表达。ISG负责干扰素的抗病毒作用，尽管对单个基因产物的功能知之甚少。需要对病毒特异性抗病毒分子的分子了解，以确定宿主干扰素(干扰素)反应如何有效地对抗病毒感染。虽然许多ISGs作为病毒感染的一般抑制物发挥作用，但存在保护特定病毒所必需的ISGs，它们进化成选择性地靶向独特的病毒蛋白序列。TRIM蛋白家族的成员除了作为先天免疫信号通路的调节者外，还作为有效的但病毒特异性的检测和抗病毒因子而出现。我们的工作已经确定了一种病毒特异性的TRIM蛋白，TRIM79，作为一种ISG，它能与森林脑炎病毒(TBEV)的NS5蛋白结合，并针对它进行降解，导致病毒限制。TRIM79不能与西尼罗河病毒的NS5结合，也不能限制西尼罗河病毒的复制。因此，TRIM79/NS5的相互作用代表了一个独特的模型，可以在全球范围内探索蛋白质识别和降解所需的分子和细胞决定因素，以及对与人类健康直接相关的病毒的限制。这项工作的总体目标是通过解剖TRIM79/NS5的关系来确定细胞内抗病毒分子对特定病毒的限制机制，从中获得的洞察力将使识别具有类似机制的其他抗病毒分子成为可能。我们将通过确定TRIM79和NS5的结构和功能决定因素来实现这一目标，这些决定因素对于结合、蛋白质降解和随后的病毒限制是必要的。从初步研究中获得的洞察力将被用来合理地设计黄病毒对TRIM79介导的限制的抗性(TBEV)或易感(WNV)的NS5突变，并测量突变对病毒复制和干扰素敏感性的影响。这些研究将确定TRIM79在TBEV限制中的作用，以及正常的细胞功能。黄病毒，包括TBEV、WNV和DENV，在世界范围内造成了压倒性的疾病负担，治疗选择有限。从机制上理解单一的TBEV特异性抗病毒基因是如何对固有的抗病毒反应起核心作用的，将有助于开发有效对抗黄病毒的治疗药物，从而特异性地禁用干扰素依赖的信号转导。

DESCRIPTION (provided by applicant): Abstract PI: TAYLOR, ROGER TRAVIS Project: 1K22AI099020-01 Title: Role of TRIM79 in innate immunity to tick-borne encephalitis virus Accession Number: 3398464 ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== The flaviviruses represent a tremendous disease burden to humans, including dengue virus, West Nile virus (WNV) and tick-borne encephalitis virus (TBEV). These viruses are highly sensitive to the antiviral effects of type I interferon (IFN). However, the effectiveness of IFN asa therapeutic is limited by the ability of these viruses to inhibit IFN-dependent signal transduction and therefore dampen the expression of IFN-stimulated genes (ISGs). ISGs are responsible for the antiviral effects of IFN, although little is known regarding the function of individual gene products. A molecular understanding of virus-specific antiviral molecules is needed to define how host interferon (IFN) responses are effective against virus infections. Although many ISGs function as general inhibitors of virus infection, ISGs necessary for protection against specific viruses exist, evolved to selectively target unique viral protein sequences. Members of the TRIM family of proteins are emerging as potent but virus-specific detection and antiviral factors, in addition to regulators of innate immune signal pathways. Our work has identified a virus-specific TRIM protein, TRIM79, as an ISG that binds the NS5 protein from tick-borne encephalitis virus (TBEV) and targets it for degradation, resulting in virus restriction. TRIM79 was not able to bind to NS5 from the closely related West Nile virus (WNV), nor restrict WNV replication. Thus, the TRIM79/NS5 interaction represents a unique model to explore the molecular and cellular determinants required for protein recognition and degradation as well as restriction of viruses directly relevant to human health on a global scale. The overall goal of this work is to identify mechanisms of specific virus restriction by cellular antiviral molecules by dissecting apart the TRIM79/NS5 relationship, insight from which will enable identification of other antiviral molecules with similar mechanisms. We will accomplish this goal by identifying the structural and functional determinants for both TRIM79 and NS5 necessary for binding, protein degradation and subsequent virus restriction. Insight gained from initial studies will be used to rationally engineer mutations into the NS5 from flaviviruses either resistant (TBEV) or susceptible (WNV) to TRIM79- mediated restriction and measure effect of mutation on virus replication and interferon sensitivity. These studies will define the role of TRIM79 for TBEV restriction, as well as normal cellular functions. Flaviviruses, including TBEV, WNV and DENV, account for an overwhelming worldwide disease burden, with limited treatment options. A mechanistic understanding of how a single TBEV-specific antiviral gene that is central to the innate antiviral response will enable development of therapeutics effective against flaviviruses evolved to specifically disable IFN-dependent signal transduction.