Viral N protein hijacks deaminase-containing RNA granules to enhance SARS-CoV-2 mutagenesis

作者：Zhean Li, Lingling Luo, Xiaohui Ju, Shisheng Huang, Liqun Lei, Yanying Yu, Jia Liu, Pumin Zhang, Tian Chi, Peixiang Ma, Cheng Huang, Xingxu Huang, Qiang Ding, Yu Zhang · 发表于：The EMBO Journal · 年份：2024 · DOI：10.1038/s44318-024-00314-y · 被引用次数：8 · 研究领域：RNA regulation and disease、RNA Research and Splicing、Viral Infections and Immunology Research

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.