Borgogna Cinzia, Cislaghi Ilaria, Turati Sarah, Mozzi Alessandra, Forni Diego, Cagliani Rachele, Sironi Manuela, Gariglio Marisa
Virology Unit, Department of Translational Medicine, University of Piemonte Orientale, Via Generale Solaroli 17, Novara (NO), 28100, Italy.
Scientific Institute IRCCS E. MEDEA, Department of Computational Biology Unit, Via Don Luigi Monza 20, Bosisio Parini (LC), 23842, Italy.
Virus Evol. 2025 Aug 22;11(1):veaf063. doi: 10.1093/ve/veaf063. eCollection 2025.
Betacoronaviruses (β-CoVs) display divergent mechanisms to evade host antiviral responses, yet the evolutionary origin and functional relevance of their strategies remain unclear. Stress granules (SGs), central to host defenses, are disrupted by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein its interaction with G3BP1 mediated by an ITFG motif. This interaction inhibits SG assembly, enhancing viral replication and immune evasion. Here, we analyzed 179 N protein sequences across β-CoVs subgenera and identified the ITFG motif in sarbecoviruses but not in MERS-CoV or embecoviruses. Among tested CoVs, only SARS-CoV-2 N showed robust G3BP1 binding and in infected cells. Phylogenetic analyses revealed that the ΦxFG motif emerged independently in sarbecoviruses and a bat-infecting merbecovirus clade. The VGTF motif in these merbecoviruses also binds to G3BP1, suggesting convergent evolution in viral evasion strategies. The emergence of this motif was unrelated to 4a protein inactivation, another viral protein that inhibits SG formation.
β冠状病毒（β-CoVs）展现出不同的机制来逃避宿主的抗病毒反应，但其策略的进化起源和功能相关性仍不清楚。应激颗粒（SGs）是宿主防御的核心，却被严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的核衣壳（N）蛋白破坏，该蛋白通过一个ITFG基序与G3BP1相互作用。这种相互作用抑制了应激颗粒的组装，增强了病毒复制和免疫逃逸。在此，我们分析了β冠状病毒亚属中的179个N蛋白序列，在沙贝病毒中鉴定出了ITFG基序，但在中东呼吸综合征冠状病毒（MERS-CoV）或恩贝病毒中未鉴定出。在测试的冠状病毒中，只有SARS-CoV-2的N蛋白在体外和感染细胞中都表现出与G3BP1的强结合。系统发育分析表明，ΦxFG基序在沙贝病毒和一个感染蝙蝠的梅贝病毒分支中独立出现。这些梅贝病毒中的VGTF基序也与G3BP1结合，表明病毒逃逸策略存在趋同进化。该基序的出现与4a蛋白失活无关，4a蛋白是另一种抑制应激颗粒形成的病毒蛋白。
