Characterization of ACTN4 as a novel antiviral target against SARS-CoV-2

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-09-18 DOI:10.1038/s41392-024-01956-4
Miao Zhu, Fang Huang, Huize Sun, Kunpeng Liu, Zhen Chen, Baocheng Yu, Haojie Hao, Haizhou Liu, Shuang Ding, Xueyan Zhang, Lishi Liu, Kui Zhang, Jierao Ren, Yi Liu, Haibin Liu, Chao Shan, Wuxiang Guan
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Abstract

The various mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose a substantial challenge in mitigating the viral infectivity. The identification of novel host factors influencing SARS-CoV-2 replication holds potential for discovering new targets for broad-spectrum antiviral drugs that can combat future viral mutations. In this study, potential host factors regulated by SARS-CoV-2 infection were screened through different high-throughput sequencing techniques and further identified in cells. Subsequent analysis and experiments showed that the reduction of m6A modification level on ACTN4 (Alpha-actinin-4) mRNA leads to a decrease in mRNA stability and translation efficiency, ultimately inhibiting ACTN4 expression. In addition, ACTN4 was demonstrated to target nsp12 for binding and characterized as a competitor for SARS-CoV-2 RNA and the RNA-dependent RNA polymerase complex, thereby impeding viral replication. Furthermore, two ACTN4 agonists, YS-49 and demethyl-coclaurine, were found to dose-dependently inhibit SARS-CoV-2 infection in both Huh7 cells and K18-hACE2 transgenic mice. Collectively, this study unveils the pivotal role of ACTN4 in SARS-CoV-2 infection, offering novel insights into the intricate interplay between the virus and host cells, and reveals two potential candidates for future anti-SARS-CoV-2 drug development.

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ACTN4 作为抗击 SARS-CoV-2 的新型抗病毒靶点的特征描述
严重急性呼吸系统综合症冠状病毒 2(SARS-CoV-2)的各种变异对降低病毒传染性构成了巨大挑战。确定影响 SARS-CoV-2 复制的新型宿主因素,有可能为广谱抗病毒药物发现新的靶点,以应对未来的病毒变异。本研究通过不同的高通量测序技术筛选出受 SARS-CoV-2 感染调控的潜在宿主因子,并在细胞中进行了进一步鉴定。随后的分析和实验表明,ACTN4(α-肌动蛋白-4)mRNA上的m6A修饰水平降低会导致mRNA稳定性和翻译效率下降,最终抑制ACTN4的表达。此外,研究还证明 ACTN4 可与 nsp12 结合,成为 SARS-CoV-2 RNA 和 RNA 依赖性 RNA 聚合酶复合物的竞争者,从而阻碍病毒复制。此外,研究还发现两种 ACTN4 激动剂 YS-49 和去甲基可可碱对 Huh7 细胞和 K18-hACE2 转基因小鼠的 SARS-CoV-2 感染具有剂量依赖性抑制作用。总之,这项研究揭示了 ACTN4 在 SARS-CoV-2 感染中的关键作用,为病毒与宿主细胞之间错综复杂的相互作用提供了新的见解,并揭示了未来抗 SARS-CoV-2 药物开发的两种潜在候选药物。
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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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