Brüggemann Yannick, Meister Toni Luise, Heinen Natalie, Richter Emely, Westhoven Saskia, Poppe Michael, Shaban Mohammed Samer, Sirkinti Leyla, Nocke Maximilian, Todt Daniel, Pfaender Stephanie, Kracht Michael, Steinmann Eike
Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.
Institute for Infection Research and Vaccine Development (IIRVD), Centre for Internal Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany.
Npj Viruses. 2025 Sep 18;3(1):69. doi: 10.1038/s44298-025-00152-7.
Identifying common host factors essential for the replication cycles of human coronaviruses (HCoV) could help uncover potential therapeutic targets. Mitogen-activated protein kinases (MAPKs) regulate critical cellular signaling pathways. Among them, c-Jun N-terminal kinases (JNK) are activated in response to diverse environmental stresses, including viral infections. However, the relevance of the JNK pathway for host responses and replication of HCoV infections has remained elusive. Using live-cell microscopy, quantitative immunofluorescence and immunoblotting, we found that JNK is specifically activated in cells infected with HCoV-229E and plays a crucial role in mediating the phosphorylation of the viral nucleocapsid (N) protein, an essential step required during the viral replication cycle. Consequently, pharmacological inhibition of JNK kinase activity impeded HCoV-229E as well as SARS-CoV-2 infection. Given the conservation of phosphorylation sites within the nucleocapsid protein across coronaviruses, inhibitors targeting these N protein kinases, such as JNK, may hold therapeutic promise as broad-spectrum CoV antivirals.
确定人类冠状病毒（HCoV）复制周期所必需的常见宿主因子，有助于发现潜在的治疗靶点。丝裂原活化蛋白激酶（MAPK）调节关键的细胞信号通路。其中，c-Jun氨基末端激酶（JNK）会在包括病毒感染在内的多种环境应激反应中被激活。然而，JNK信号通路与HCoV感染的宿主反应及复制之间的相关性仍不明确。通过活细胞显微镜观察、定量免疫荧光和免疫印迹，我们发现JNK在感染HCoV-229E的细胞中被特异性激活，并在介导病毒核衣壳（N）蛋白磷酸化过程中发挥关键作用，这是病毒复制周期中必需的关键步骤。因此，JNK激酶活性的药理学抑制会阻碍HCoV-229E以及SARS-CoV-2的感染。鉴于冠状病毒核衣壳蛋白内磷酸化位点的保守性，靶向这些N蛋白激酶（如JNK）的抑制剂，可能作为广谱冠状病毒抗病毒药物具有治疗前景。
