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

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

Affiliations

  • 1 The First Affiliated Hospital of Jinan University, 510632, Guangzhou, China. panpan@jnu.edu.cn.
  • 2 Foshan Institute of Medical Microbiology, 528315, Foshan, China. panpan@jnu.edu.cn.
  • 3 Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, 510632, Guangzhou, China. panpan@jnu.edu.cn.
  • 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. chenx@jnu.edu.cn.
  • 10 Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, 510632, Guangzhou, China. lyk070@jnu.edu.cn.
  • # Contributed equally.
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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