METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection

Summary It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of SARS-CoV-2 gene in regulating host cell innate immune response. Our data show that SARS-CoV-2 virus has m6A modifications which are enriched in the 3'-end of the viral genome. We find that host cell m6A methyltransferase METTL3 depletion decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in severe COVID-19 patients. These findings will aid to understand the COVID-19 pathogenesis and help in designing future studies of regulating innate immunity for COVID-19 treatment.