Volume 8 Issue 6, Jun 2023:
Article
SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication
Pan Pan
ORCID: orcid.org/0000-0002-7214-1393,Weiwei Ge,Zhiwei Lei
ORCID: orcid.org/0000-0002-9406-2127,Wei luo,Yuqing Liu,Zhanwen Guan,Lumiao Chen,Zhenyang Yu,Miaomiao Shen,Dingwen Hu,Qi Xiang,Wenbiao Wang
ORCID: orcid.org/0000-0003-4944-764X,Pin Wan,Mingfu Tian
ORCID: orcid.org/0000-0003-0122-6397,Yang Yu,Zhen Luo
ORCID: orcid.org/0000-0002-1142-2845,Xulin Chen,Heng Xiao,Qiwei Zhang,Xujing Liang,Xin Chen,Yongkui Li
ORCID: orcid.org/0000-0002-1532-4855 &…Jianguo Wu
ORCID: orcid.org/0000-0002-8326-2895
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.
