Investigating the role of novel RNA-binding protein TRIM25 in viral nucleic acids sensing and signalling.

RNA病毒是一类重要的病原体，在21世纪世纪继续引起毁灭性的流行病。以IAV为例，它威胁周期性大流行，即使在流行阶段，每年也会导致25万至50万人死亡，产生重大的社会经济负担（仅在美国每年就有200亿美元）。IAV感染对家畜的影响同样巨大。在2005年禽流感爆发期间，仅东南亚的经济损失总额就约为100亿美元。然而，我们仍然不知道所有的关键宿主蛋白的分子机制，感测和限制人类和动物IAV感染。针对这些类型病毒的第一道细胞防御是先天免疫系统。很少有RNA病毒，包括IAV，产生被细胞蛋白识别的RNA分子，触发抗病毒反应。TRIM 25是该过程中的关键宿主蛋白因子，其被提出通过激活关键宿主病原体识别受体来实现对RNA病毒的强大先天免疫应答。利用我们在RNA生物学方面的专业知识，我们发现TRIM25与宿主RNA结合并调节其稳定性。尽管如此，TRIM 25与IAV RNA的直接结合及其在先天免疫应答中的详细功能尚未被描述。我们的初步数据表明，TRIM 25直接与IAV RNA结合，并通过病原体识别受体非依赖性机制限制病毒。此外，我们表明，与人类TRIM25相比，来自家畜动物的Trim25降低了RNA结合潜力。这可能表现为家畜Trim25的抗病毒功能较弱。通过这个项目，我们的目标是利用一个组装的多学科团队来利用这些新的发现，以揭示TRIM 25的RNA结合活性在抗病毒反应中的作用。我们将剖析TRIM25在人类和动物细胞中响应IAV的RNA结合作用。这项研究的结果将揭示TRIM25如何利用其RNA结合活性来实现抗病毒功能。重要的是，TRIM25属于一个包含三重基序的蛋白质大家族（> 80个成员）。它们在细胞过程和疾病中具有各种功能，包括发育、凋亡、自噬、致癌和先天免疫。因此，我们的研究将为其他TRIM蛋白及其假定的RNA结合作用开辟新的研究路线。总的来说，我们的项目有可能为理解IAV的先天免疫反应做出重要贡献，并为开发新型基于RNA的抗病毒治疗药物和对RNA病毒更具抗性的牲畜提供平台。

RNA viruses are an important class of pathogen that continue to cause devastating epidemics in the 21st century. Taking IAV as an exemplar, it threatens periodic pandemics, kills 250,000 to 500,000 people annually even in epidemic phases, generating a significant socioeconomic burden ($20 billion dollars in every year in the US alone). The impact of IAV infections on livestock animals is equally tremendous. During a 2005 bird flu outbreak the total economic losses in South East Asia alone were calculated at around $10 billion. However, we still do not know all of the molecular mechanisms of key host proteins that sense and restrict human and animal IAV infections. The first line of cellular defence against these types of virus is the innate immune system. Few RNA viruses, including IAV, produces RNA molecules that are recognised by cellular proteins that trigger the anti-viral response. TRIM25 is a key host protein factor in this process that was proposed to enable robust innate immune response to RNA viruses by activating key host pathogen recognition receptors. Using our expertise in RNA biology we discovered that TRIM25 binds to host RNA and regulates its stability. Despite this, direct binding of TRIM25 to IAV RNAs and its detailed function in innate immune response have not yet been described.Our preliminary data suggests that TRIM25 binds directly to IAV RNA and that it restricts the virus using pathogen recognition receptor-independent mechanism. Moreover, we show that Trim25s from livestock animals reduced RNA-binding potential when compared to human TRIM25. This could manifest itself with weaker antiviral functions of livestock Trim25s. With this project, we aim to take advantage of an assembled multi-disciplinary team to exploit these novel findings to uncover the role of the RNA-binding activity of TRIM25 in the antiviral response to IAV infection. We will dissect the RNA-binding roles of TRIM25 in response to IAV in human and animal cells. The outcome of this research will reveal how TRIM25 uses its RNA-binding activity for anti-viral functions. Importantly, TRIM25 belongs to a large (> 80 members) family of tripartite motif-containing proteins. They have various functions in cellular processes and disease, including development, apoptosis, autophagy, carcinogenesis and innate immunity. Thus, our research will open new lines of investigations into other TRIM proteins and their putative RNA-binding roles. Overall, our project has the potential to make crucial contributions to understanding the innate immune response to IAV and provide a platform for the development of novel, RNA-based antiviral therapeutics and livestock animals more resistant to RNA viruses.