Protein Deamidation in Innate Immune Evasion Regulated by Viral Pseudo Enzymes

疱疹病毒在人类中普遍存在，它们与多种 恶性肿瘤。人类卡波西肉瘤相关疱疹病毒(KSHV)和EB病毒 与淋巴系、上皮性和内皮源性肿瘤相关的免疫受损 病人。口腔是伽玛疱疹病毒感染的关键部位，尤其是 对病毒复制、传播和致病很重要。使用人类口腔角质形成细胞 和淋巴管内皮细胞，我们将描述启用的多种病毒免疫逃避机制 通过调节蛋白质去酰胺化，最简单的蛋白质翻译后修饰。 宿主的先天免疫是第一道防线，疱疹病毒已经进化出一系列 逃避先天免疫反应的机制。在研究人类KSHV和小鼠γHV 68时，我们有 发现了一种新的免疫逃避机制，该机制由一系列病毒伪酶和一种 细胞代谢谷氨酰胺氨基转移酶。病毒假酶与细胞相互作用 谷氨酰胺氨基转移酶，并改变其活性，有效地去除细胞和病毒蛋白 多步骤避免干扰素诱导。我们已发表和未发表的研究结果 支持脱酰胺是调节先天免疫反应的关键机制这一结论 疱疹病毒利用这种机制来使自己的感染受益。在这项研究中，我们将调查 蛋白质去酰胺化如何调节感受病毒RNA的胞浆受体(Aim 1)及其活性 病毒蛋白在对抗干扰素诱导中的作用(目标2)。此外，我们还将定义 KSHV和γHV68部署vGAT蛋白选择性调节PFAS的分子作用 使细胞和病毒蛋白去胺化以逃避先天免疫检测(目标3)。总而言之，这 研究将阐明一种新的机制，即蛋白质去酰胺化调节多个步骤 干扰素诱导，一种关键的先天性免疫信号级联反应。我们的工作将建立更普遍的 蛋白质脱酰胺化在免疫等基本生物过程中的调节作用 回应。从这项研究中收集的发现将促进我们对宿主免疫的理解 识别和干扰素诱导，并有可能指导我们未来在疫苗设计和 用于治疗与人类KSHV和EBV相关的恶性肿瘤的抗病毒疗法。

Herpesviruses are ubiquitous in humans and they have been implicated in diverse malignancies. Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are associated with tumors of lymphoid, epithelial, and endothelial origin in immuno-compromised patients. The oral cavity is a crucial compartment for gamma herpesvirus infection, particularly important for viral replication, transmission and pathogenesis. Employing human oral keratinocytes and lymphatic endothelial cells, we will delineate multiple viral immune evasion mechanisms enabled by regulated protein deamidation, the simplest post-translational modification of proteins. Host innate immunity is the first line of defense and herpesviruses have evolved an array of mechanisms to evade innate immune responses. Studying human KSHV and murine γHV68, we have uncovered a novel immune evasion mechanism enabled by a family of viral pseudoenzymes and a cellular metabolic glutamine amidotransferase. The viral pseudoenzymes interact with the cellular glutamine amidotransferase and alter its activity to deamidate both cellular and viral proteins, potently evading the interferon induction at multiple steps. Our published and unpublished findings collectively support the conclusion that deamidation is a key mechanism regulating innate immune responses and herpesviruses exploit this mechanism to benefit their infection. In this study, we will investigate how protein deamidation regulates a cytosolic receptor in sensing viral RNA (Aim 1) and the activity of a viral protein in antagonizing interferon induction (Aim 2). Furthermore, we will define the molecular action by which KSHV and γHV68 deploy vGAT proteins to regulate PFAS in selectively deamidating cellular and viral proteins to evade innate immune detection (Aim 3). Collectively, this study will elucidate a novel mechanism whereby protein deamidation regulates multiple steps of interferon induction, a key innate immune signaling cascade. Our work will establish more general regulatory roles of protein deamidation in fundamental biological processes, such as immune responses. Findings gleaned from this study will advance our understanding in host immune recognition and interferon induction, and potentially guide our future efforts in vaccine design and antiviral therapeutics to treat malignancies associated with human KSHV and EBV.