SARS-CoV-2 evolution balances conflicting roles of N protein phosphorylation.

IF 5.5 1区 医学 Q1 MICROBIOLOGY
Abdullah M Syed, Alison Ciling, Irene P Chen, Christopher R Carlson, Armin N Adly, Hannah S Martin, Taha Y Taha, Mir M Khalid, Nathan Price, Mehdi Bouhaddou, Manisha R Ummadi, Jack M Moen, Nevan J Krogan, David O Morgan, Melanie Ott, Jennifer A Doudna
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Abstract

All lineages of SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, contain mutations between amino acids 199 and 205 in the nucleocapsid (N) protein that are associated with increased infectivity. The effects of these mutations have been difficult to determine because N protein contributes to both viral replication and viral particle assembly during infection. Here, we used single-cycle infection and virus-like particle assays to show that N protein phosphorylation has opposing effects on viral assembly and genome replication. Ancestral SARS-CoV-2 N protein is densely phosphorylated, leading to higher levels of genome replication but 10-fold lower particle assembly compared to evolved variants with low N protein phosphorylation, such as Delta (N:R203M), Iota (N:S202R), and B.1.2 (N:P199L). A new open reading frame encoding a truncated N protein called N*, which occurs in the B.1.1 lineage and subsequent lineages of the Alpha, Gamma, and Omicron variants, supports high levels of both assembly and replication. Our findings help explain the enhanced fitness of viral variants of concern and a potential avenue for continued viral selection.

SARS-CoV-2 的进化平衡了 N 蛋白磷酸化的冲突作用。
导致 COVID-19 大流行的冠状病毒 SARS-CoV-2 的所有品系都含有核壳(N)蛋白 199 至 205 氨基酸之间的突变,这些突变与感染力增强有关。这些突变的影响一直难以确定,因为在感染过程中,N 蛋白对病毒复制和病毒粒子组装都有贡献。在这里,我们使用单循环感染和病毒样颗粒试验来证明 N 蛋白磷酸化对病毒组装和基因组复制具有相反的影响。与N蛋白磷酸化程度低的进化变体(如Delta(N:R203M)、Iota(N:S202R)和B.1.2(N:P199L))相比,原始SARS-CoV-2 N蛋白磷酸化程度高,导致基因组复制水平高,但颗粒组装水平低10倍。一个新的开放阅读框编码一种被称为 N* 的截短 N 蛋白,它出现在 B.1.1 系以及随后的 Alpha、Gamma 和 Omicron 变体系中,支持高水平的组装和复制。我们的发现有助于解释令人担忧的病毒变异体的适应性增强以及病毒继续选择的潜在途径。
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来源期刊
PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
自引率
3.00%
发文量
598
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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