Affiliation:
1. Division of Respiratory and Critical Care Medicine, Respiratory Infection and Intervention Laboratory of Frontiers Science Center for Disease‐related Molecular Network, State Key Laboratory of Biotherapy West China Hospital of Sichuan University Chengdu Sichuan China
2. Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ‐CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega‐Science, Kunming Institute of Zoology Chinese Academy of Sciences Kunming China
3. Department of Pathophysiology, Shihezi University School of Medicine the Key Laboratory of Xinjiang Endemic and Ethnic Diseases Shihezi Xinjiang China
Abstract
AbstractThe RNA‐dependent RNA polymerase (RdRp) is a crucial element in the replication and transcription of RNA viruses. Although the RdRps of lethal human coronaviruses severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), SARS‐CoV, and Middle East respiratory syndrome coronavirus (MERS‐CoV) have been extensively studied, the molecular mechanism of the catalytic subunit NSP12, which is involved in pathogenesis, remains unclear. In this study, the biochemical and cell biological results demonstrate the interactions between SARS‐CoV‐2 NSP12 and seven host proteins, including three splicing factors (SLU7, PPIL3, and AKAP8). The entry efficacy of SARS‐CoV‐2 considerably decreased when SLU7 or PPIL3 was knocked out, indicating that abnormal splicing of the host genome was responsible for this occurrence. Furthermore, the polymerase activity and stability of SARS‐CoV‐2 RdRp were affected by the three splicing factors to varying degrees. In addition, NSP12 and its homologues from SARS‐CoV and MERS‐CoV suppressed the alternative splicing of cellular genes, which were influenced by the three splicing factors. Overall, our research illustrates that SARS‐CoV‐2 NSP12 can engage with various splicing factors, thereby impacting virus entry, replication, and gene splicing. This not only improves our understanding of how viruses cause diseases but also lays the foundation for the development of antiviral therapies.