SARS-CoV-2 hijacks cellular kinase CDK2 to promote viral RNA synthesis

Signal Transduction and Targeted Therapy

Article

Yan Chang¹  Quanjie Li²  Saisai Guo²  Zixiong Zhang²  Jing Wang²  Xiaoyu Li²  Qian Liu²  Jiwei Ding²  Dongrong Yi²  Yongxin Zhang²  Ling Ma²  Jianyuan Zhao²  Lidan Wang²  Shan Cen³  Chen Liang⁴  Fei Guo⁵  Jianwei Wang⁵  Xiaojing Dong⁵  Xiaobo Lei⁵ 

[1] Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China;Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China;Department of Immunology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China;CAMS Key Laboratory of Antiviral Drug Research, Chinese Academy of Medical Sciences & Peking Union Medical Sciences, Beijing, China;Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada;NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China;

DOI  :  10.1038/s41392-022-01239-w

 received in 2022-05-04, accepted in 2022-10-24,  发布年份 2022

来源: Springer

【 摘 要 】

The coronavirus disease 2019 (COVID-19) pandemic has devastated global health. Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks. Here, we have identified host proteins that associate with nonstructural protein 12 (nsp12), the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 using a mass spectrometry (MS)-based proteomic approach. Among the candidate factors, CDK2 (Cyclin-dependent kinase 2), a member of cyclin-dependent kinases, interacts with nsp12 and causes its phosphorylation at T20, thus facilitating the assembly of the RdRp complex consisting of nsp12, nsp7 and nsp8 and promoting efficient synthesis of viral RNA. The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection. Taken together, we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex, thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

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