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

研究新型 RNA 结合蛋白 TRIM25 在病毒核酸传感和信号传导中的作用。

• 批准号: BB/T002751/1
• 负责人: Gracjan Michlewski
• 金额: $ 52.86万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT002751%2F1
• 关键词: Investigating; role; novel; RNA; binding

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.

RNA病毒是一类重要的病原体，在21世纪继续造成毁灭性的流行病。以IAV为例，它威胁着周期性大流行，即使在流行阶段，每年也会造成25万至50万人死亡，造成巨大的社会经济负担（仅在美国每年就造成200亿美元）。 IAV 感染对家畜的影响同样巨大。 2005年禽流感爆发期间，仅东南亚地区的经济损失总额就高达100亿美元左右。然而，我们仍然不知道感知和限制人类和动物 IAV 感染的关键宿主蛋白的所有分子机制。针对这些类型病毒的细胞防御的第一道防线是先天免疫系统。很少有 RNA 病毒（包括 IAV）产生的 RNA 分子可以被细胞蛋白识别，从而触发抗病毒反应。 TRIM25 是这一过程中的关键宿主蛋白因子，被认为可以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反应。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，TRIM25 与 IAV RNA 的直接结合及其在先天免疫反应中的详细功能尚未被描述。我们的初步数据表明 TRIM25 直接与 IAV RNA 结合，并使用病原体识别受体独立机制来限制病毒。此外，我们还发现，与人类 TRIM25 相比，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多学科团队的优势来利用这些新发现来揭示 TRIM25 的 RNA 结合活性在 IAV 感染的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 属于包含三部分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多种功能，包括发育、细胞凋亡、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方向。总体而言，我们的项目有可能为了解 IAV 的先天免疫反应做出重要贡献，并为开发新型基于 RNA 的抗病毒疗法和提高家畜对 RNA 病毒的抵抗力提供​​平台。

项目成果

TRIM25 inhibits influenza A virus infection, destabilizes viral mRNA, but is redundant for activating the RIG-I pathway.

• DOI: 10.1093/nar/gkac512
• 发表时间: 2022-07-08
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Choudhury, Nila Roy;Trus, Ivan;Heikel, Gregory;Wolczyk, Magdalena;Szymanski, Jacek;Bolembach, Agnieszka;Pinto, Rute Maria Dos Santos;Smith, Nikki;Trubitsyna, Maryia;Gaunt, Eleanor;Digard, Paul;Michlewski, Gracjan
• 通讯作者: Michlewski, Gracjan

Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain-of-function toxicity mechanism contributing to the pathogenesis of fragile X-associated premature ovarian insufficiency.

• DOI: 10.1096/fj.202200468rr
• 发表时间: 2022-11
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology

TRIM25 inhibits Influenza A infection by destabilising its mRNA and is redundant for the RIG-I pathway

• DOI: 10.1101/2021.09.13.460052
• 发表时间: 2021-09
• 期刊: bioRxiv
• 作者: Nila Roy Choudhury;Gregory Heikel;Ivan Trus;R. M. Dos Santos Pinto;M. Trubitsyna;E. Gaunt;P. Digard;G. Michlewski