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

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.