SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication

  • Signal Transduct Target Ther. 2023 May 9;8(1):194. doi: 10.1038/s41392-023-01459-8.
Pan Pan  #  1  2  3 ,  Weiwei Ge  #  4 ,  Zhiwei Lei  #  5 ,  Wei Luo  #  6 ,  Yuqing Liu  5 ,  Zhanwen Guan  6 ,  Lumiao Chen  7 ,  Zhenyang Yu  4 ,  Miaomiao Shen  4 ,  Dingwen Hu  4 ,  Qi Xiang  4 ,  Wenbiao Wang  5 ,  Pin Wan  8 ,  Mingfu Tian  7 ,  Yang Yu  5 ,  Zhen Luo  5 ,  Xulin Chen  5 ,  Heng Xiao  5 ,  Qiwei Zhang  5 ,  Xujing Liang  7 ,  Xin Chen  9 ,  Yongkui Li  10 ,  Jianguo Wu  7  8  5  4
Affiliations
  • 1. The First Affiliated Hospital of Jinan University, 510632, Guangzhou, China. [email protected].
  • 2. Foshan Institute of Medical Microbiology, 528315, Foshan, China. [email protected].
  • 3. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, 510632, Guangzhou, China. [email protected].
  • 4. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, 430072, Wuhan, China.
  • 5. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, 510632, Guangzhou, China.
  • 6. The First People's Hospital of Foshan, 528315, Foshan, China.
  • 7. The First Affiliated Hospital of Jinan University, 510632, Guangzhou, China.
  • 8. Foshan Institute of Medical Microbiology, 528315, Foshan, China.
  • 9. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, 510632, Guangzhou, China. [email protected].
  • 10. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, 510632, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 37160897 DOI: 10.1038/s41392-023-01459-8
Abstract

Viral Infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 Infection increases the complexity and difficulty of viral Infection prevention, and especially the high-frequency asymptomatic Infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its Infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell Apoptosis, but the trVLP lacking N protein didn't. Further study verified that N protein repressed cell Apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein Mcl-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of Mcl-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a Mcl-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with Other viruses. We anticipate that abrogating the N/MCL-1-dominated Apoptosis repression is conducive to the treatments of SARS-CoV-2 Infection as well as coinfections with Other viruses.

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