State Key Laboratory of Proteomics, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100850, China.
Nanhu Laboratory, Jiaxing, Zhejiang Province, 314002, China.
Nat Commun. 2021 Apr 9;12(1):2114. doi: 10.1038/s41467-021-22297-8.
Lack of detailed knowledge of SARS-CoV-2 infection has been hampering the development of treatments for coronavirus disease 2019 (COVID-19). Here, we report that RNA triggers the liquid-liquid phase separation (LLPS) of the SARS-CoV-2 nucleocapsid protein, N. By analyzing all 29 proteins of SARS-CoV-2, we find that only N is predicted as an LLPS protein. We further confirm the LLPS of N during SARS-CoV-2 infection. Among the 100,849 genome variants of SARS-CoV-2 in the GISAID database, we identify that ~37% (36,941) of the genomes contain a specific trio-nucleotide polymorphism (GGG-to-AAC) in the coding sequence of N, which leads to the amino acid substitutions, R203K/G204R. Interestingly, N exhibits a higher propensity to undergo LLPS and a greater effect on IFN inhibition. By screening the chemicals known to interfere with N-RNA binding in other viruses, we find that (-)-gallocatechin gallate (GCG), a polyphenol from green tea, disrupts the LLPS of N and inhibits SARS-CoV-2 replication. Thus, our study reveals that targeting N-RNA condensation with GCG could be a potential treatment for COVID-19.
对 SARS-CoV-2 感染缺乏详细了解一直阻碍着针对 2019 年冠状病毒病（COVID-19）的治疗方法的发展。在这里，我们报告 RNA 触发了 SARS-CoV-2 核衣壳蛋白 N 的液-液相分离（LLPS）。通过分析 SARS-CoV-2 的所有 29 种蛋白，我们发现只有 N 被预测为 LLPS 蛋白。我们进一步确认了 SARS-CoV-2 感染过程中 N 的 LLPS。在 GISAID 数据库中 SARS-CoV-2 的 100,849 个基因组变体中，我们鉴定出编码序列中 N 的特定三核苷酸多态性（GGG 到 AAC）约占 37%（36,941），导致氨基酸取代，R203K/G204R。有趣的是，N 表现出更高的进行 LLPS 的倾向和对 IFN 抑制的更大影响。通过筛选已知可干扰其他病毒中 N-RNA 结合的化学物质，我们发现（-）-没食子儿茶素没食子酸酯（GCG），一种来自绿茶的多酚，破坏了 N 的 LLPS 并抑制了 SARS-CoV-2 的复制。因此，我们的研究表明，用 GCG 靶向 N-RNA 凝聚可能是 COVID-19 的一种潜在治疗方法。
