MRC AMED - The HDAC6/USP7 axis in enveloped RNA viral infection

MRC AMED - 包膜 RNA 病毒感染中的 HDAC6/USP7 轴

• 批准号: MR/T028769/1
• 负责人: Anne Ridley
• 金额: $ 9.71万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT028769%2F1
• 关键词: MRC; AMED; HDAC6; USP7; axis

Influenza A virus (IAV) causes annual epidemics and occasional pandemics with continuous threat of emerging and potentially lethal strains derived from reassortment with avian or swine IAV. In addition to development of a universal influenza vaccine, a deeper understanding of cell biology of IAV infections is needed to discover antiviral strategies that target cellular proteins and pathways. Viral uncoating is an early step in infection that is poorly understood, but we think that the host cell factors involved can be targeted effectively as an antiviral strategy.IAV entry and uncoating is well-studied compared to many enveloped RNA viruses. Uncoating requires a ubiquitin-mediated, misfolded protein degradation pathway known as aggresome processing. Here, the key host player, the cytosolic histone deacetylase 6 (HDAC6), senses misfolded protein 'tags' and activates a cellular pathway that helps to break apart the viral shell during entry. In this study we will address the interplay between HDAC6 and ubiquitin-modifying enzymes, and target multiple host factors to block viral uncoating and thus block infectivity. Our findings may contribute to the understanding of general viral uncoating pathways and lead to conceptualisation of a broad spectrum antiviral that can combat emerging and re-emerging viruses of medical importance.

甲型流感病毒 (IAV) 每年都会引发流行病，偶尔还会造成大流行，并伴随着源自禽类或猪 IAV 重组的新出现的潜在致命毒株的持续威胁。除了开发通用流感疫苗外，还需要更深入地了解 IAV 感染的细胞生物学，以发现针对细胞蛋白和途径的抗病毒策略。病毒脱壳是感染的早期步骤，人们对此知之甚少，但我们认为所涉及的宿主细胞因子可以作为抗病毒策略有效地靶向。与许多有包膜 RNA 病毒相比，IAV 的进入和脱壳已得到充分研究。脱壳需要泛素介导的错误折叠的蛋白质降解途径，称为聚集体加工。在这里，关键的宿主细胞胞浆组蛋白脱乙酰酶 6 (HDAC6) 感知错误折叠的蛋白质“标签”并激活细胞途径，帮助在病毒进入过程中分解病毒外壳。在这项研究中，我们将解决 HDAC6 和泛素修饰酶之间的相互作用，并针对多种宿主因子来阻止病毒脱壳，从而阻止感染性。我们的研究结果可能有助于理解一般病毒脱衣途径，并导致广谱抗病毒药物的概念化，这种药物可以对抗具有医学重要性的新出现和重新出现的病毒。

项目成果

Disrupting the HDAC6-Ubiquitin Interaction Impairs Infection by Influenza and Zika Virus and Cellular Stress Pathways

破坏 HDAC6-泛素相互作用会损害流感和寨卡病毒的感染以及细胞应激途径

• DOI: 10.2139/ssrn.3773799
• 发表时间: 2021
• 期刊: SSRN Electronic Journal
• 作者: Wang L

Neuropilin-1 is a host factor for SARS-CoV-2 infection.

• DOI: 10.1126/science.abd3072
• 发表时间: 2020-11-13
• 期刊: Science (New York, N.Y.)
• 作者: Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
• 通讯作者: Yamauchi Y

Liquid Biomolecular Condensates and Viral Lifecycles: Review and Perspectives.

• DOI: 10.3390/v13030366
• 发表时间: 2021-02-25
• 期刊: Viruses
• 作者: Etibor TA;Yamauchi Y;Amorim MJ
• 通讯作者: Amorim MJ