ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may keep patients in a clinically asymptomatic state by blocking cellular innate antiviral immunity, but the molecular mechanism remains unclear. Here, we screened the viral proteins of SARS-CoV-2 and found that the spike (S) protein inhibits the activation of interferon-stimulated genes (ISGs) and even reduces the expression of these genes to below background values. Mechanistically, the S protein interacted with STAT1, STAT2, and IRF9 and impedes the phosphorylation of STAT1/STAT2, thus preventing the formation of the interferon-stimulating gene factor 3 (ISGF3) complex and inhibiting the downstream production of Interferon-stimulated genes (ISGs). Remarkably, we also have found that the inhibitory mechanism of the S protein was conservative among SARS-CoV-2 variants and other human coronaviruses, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Truncation studies indicated that the most conserved S2 domain played a major inhibitory role. Altogether, our findings unveil a new mechanism by which SARS-CoV-2 S protein attenuated the host's antiviral immune response and provide new insights into the pathogenic mechanism of coronavirus.
Subject(s)
Coronavirus Infections , Severe Acute Respiratory SyndromeABSTRACT
Copper death is a newly identified unique form of regulated apoptosis. Studies suggest that it may be the mode of apoptosis in cancer cells. Therefore, copper death-related genes may become therapeutic targets for hepatocellular carcinoma. Also, SARS-CoV-2 is currently the most widely spread virus in the world with no curative drug available. Liver cancer is the most common fatal malignancy in the world. By the time a patient presents to the clinic, liver cancer has progressed to an advanced stage and the prognosis is often poor. In this study, the prognosis of patients with liver cancer when they get SARS-CoV-2 was predicted by examining the relationship between SARS-CoV-2, copper death and liver cancer.