Regulatory mechanisms of the MDA5-mediated antiviral interferon response

描述（由申请人提供）：尽管在世界范围内共同努力控制病毒相关疾病，但它们仍然是一个主要的公共卫生问题。宿主对病毒感染的即时反应依赖于模式识别受体（PRRs），其感知入侵病毒的核酸或其他保守结构成分，随后激活信号级联，导致干扰素（IFN）介导的抗病毒防御机制。黑色素瘤分化相关基因5 （Melanoma differentiation-associated gene 5, MDA5）已成为RNA病毒（包括小核糖核酸病毒和某些黄病毒）的关键细胞质受体。在与病毒RNA结合后，MDA5的n端caspase募集域（CARDs）与MAVS/VISA/IPS-1/Cardif下游伙伴相互作用，触发I型IFN的产生，从而阻止病毒生命周期的完成和病毒在体内的传播。尽管最近在破译MDA5信号通路的分子成分方面取得了快速进展，但其抗病毒活性的调控在很大程度上仍不确定。然而，正是对宿主IFN产生的调控，决定了病毒感染的结果以及疾病的严重程度和发病机制。因此，本研究旨在研究胞质病毒RNA受体MDA5的信号转导活性是如何通过宿主编码因子调节ifn介导的宿主反应的。生化、细胞生物学和结构研究将侧重于定义翻译后修饰如何影响MDA5信号转导活性以限制病毒复制的机制细节（目的1）。本研究将进一步致力于鉴定调节MDA5抗病毒功能的新型宿主细胞因子，并研究它们在MDA5介导的RNA病毒感染免疫监视中的作用（目的2）。从这项研究中获得的见解不仅将大大扩展我们对先天免疫系统调节网络的理解，而且还将确定在抗病毒先天免疫中起关键作用的新信号分子，从而为治疗性干预病毒感染提供潜在的靶点。

DESCRIPTION (provided by applicant): Despite concerted efforts to control virus-associated diseases worldwide, they still remain a major public health problem. The host's immediate response to viral infections relies on pattern recognition receptors (PRRs) that sense nucleic acids or other conserved structural components of invading viruses and subsequently activate signaling cascades leading to interferon (IFN)- mediated antiviral defense mechanisms. Melanoma differentiation-associated gene 5 (MDA5) has emerged as a key cytosolic receptor for sensing RNA viruses, including picornaviruses and certain Flaviviruses. Upon binding of viral RNA, the N-terminal caspase recruitment domains (CARDs) of MDA5 interact with MAVS/VISA/IPS-1/Cardif downstream partner to trigger type I IFN production to prevent completion of the virus lifecycle as well as virus dissemination in vivo. Despite the recent rapid progress in deciphering molecular components in the MDA5 signaling pathway, the regulation of its antiviral activity remains largely undetermined. However, it is exactly the regulation of the host IFN production, which dictates the outcome of the viral infection as well as severity of disease and pathogenesis. Thus, the proposed study is directed toward investigating how the signal transducing activity of the cytosolic viral RNA receptor MDA5 is regulated by host-encoded factors to modulate IFN-mediated host responses. Biochemical, cell biological and structural studies will focus on defining in mechanistic detail how posttranslational modifications affect the MDA5 signal transducing activity to limit viral replication (Aim 1). This study will further aim at identifying novel host cell factors for regulating MDA5 antiviral function, and at investigating their roles in the MDA5-mediated immune surveillance against RNA virus infections (Aim 2). Insights gained from this study will not only greatly expand our understanding of the regulatory networks of the innate immune system, but also identify novel signaling molecules that play key roles in antiviral innate immunity, thereby providing potential targets for therapeutic intervention against viral infections. PUBLIC HEALTH RELEVANCE: Despite concerted efforts to control virus-associated diseases worldwide, they still remain a major public health problem. The cytosolic viral RNA sensor MDA5 plays a pivotal role in host cell defense against viral pathogens. The proposed study is targeted to delineate the molecular mechanisms underlying virus recognition and host innate immunity to viral infections, with a specific focus on the MDA5-mediated interferon response.