Host cell-encoded deaminases act as antiviral restriction factors to impair viral replication and production through introducing mutations in the viral genome. We sought to understand whether deaminases are involved in SARS-CoV-2 mutation and replication, and how the viral factors interact with deaminases to trigger these processes. Here, we show that APOBEC and ADAR deaminases act as the driving forces for SARS-CoV-2 mutagenesis, thereby blocking viral infection and production. Mechanistically, SARS-CoV-2 nucleocapsid (N) protein, which is responsible for packaging viral genomic RNA, interacts with host deaminases and co-localizes with them at stress granules to facilitate viral RNA mutagenesis. N proteins from several coronaviruses interact with host deaminases at RNA granules in a manner dependent on its F17 residue, suggesting a conserved role in modulation of viral mutagenesis in other coronaviruses. Furthermore, mutant N protein bearing a F17A substitution cannot localize to deaminase-containing RNA granules and leads to reduced mutagenesis of viral RNA, providing support for its function in enhancing deaminase-dependent viral RNA editing. Our study thus provides further insight into virus-host cell interactions mediating SARS-CoV-2 evolution.

中文翻译：

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病毒 N 蛋白劫持含脱氨酶的 RNA 颗粒以增强 SARS-CoV-2 诱变。


宿主细胞编码的脱氨酶作为抗病毒限制因子，通过在病毒基因组中引入突变来损害病毒复制和产生。我们试图了解脱氨酶是否参与 SARS-CoV-2 突变和复制，以及病毒因子如何与脱氨酶相互作用以触发这些过程。在这里，我们表明 APOBEC 和 ADAR 脱氨酶是 SARS-CoV-2 诱变的驱动力，从而阻断病毒感染和产生。从机制上讲，负责包装病毒基因组 RNA 的 SARS-CoV-2 核衣壳 （N） 蛋白与宿主脱氨酶相互作用，并在应激颗粒上与它们共定位，以促进病毒 RNA 诱变。来自几种冠状病毒的 N 蛋白以依赖于其 F17 残基的方式与 RNA 颗粒上的宿主脱氨酶相互作用，表明在其他冠状病毒中调节病毒诱变中起着保守作用。此外，带有 F17A 取代的突变 N 蛋白不能定位于含脱氨酶的 RNA 颗粒，并导致病毒 RNA 的诱变减少，为其增强脱氨酶依赖性病毒 RNA 编辑的功能提供支持。因此，我们的研究为介导 SARS-CoV-2 进化的病毒-宿主细胞相互作用提供了进一步的见解。