COVID variants hijack a key cellular control mechanism, study finds
Researchers discovered that SARS-CoV-2 infections strip away m6A methylation, a chemical tag that regulates how cells read their genetic instructions. The finding could explain why different variants trigger varying immune responses and may point toward new therapeutic targets for treating severe COVID and other viral infections.
Originaltitel: Global loss of cellular m<SUP>6</SUP>A RNA methylation following infection with different SARS-CoV-2 variants
ABSTRACT Host-viral interactions during SARS-CoV-2 infection are needed to understand COVID-19 pathogenesis and may help to guide the design of novel antiviral therapeutics. N 6 -methyladenosine modification (m 6 A), one of the most abundant cellular RNA modifications, regulates key processes in RNA metabolism during a stress response. Gene expression profiles observed post-infection with different SARS-CoV-2 variants show changes in the expression of genes related to RNA catabolism, including m 6 A readers and erasers. We found that infection with SARS-CoV-2 variants caused a loss of m 6 A in cellular RNAs, whereas m 6 A was detected abundantly in viral RNA. METTL3, the m 6 A methyltransferase, showed an unusual cytoplasmic localization post-infection. The B.1.351 variant had a less pronounced effect on METTL3 localization and loss of m 6 A than the B.1 and B.1.1.7 variants. We also observed a loss of m 6 A upon SARS-CoV-2 infection in air/liquid interface cultures of human airway epithelia, confirming that m 6 A loss is characteristic of SARS-CoV-2 infected cells. Further, transcripts with m 6 A modification were preferentially down-regulated post-infection. Inhibition of the export protein XPO1 resulted in the restoration of METTL3 localization, recovery of m 6 A on cellular RNA, and increased mRNA expression. Stress granule formation, which was compromised by SARS-CoV-2 infection, was restored by XPO1 inhibition and accompanied by a reduced viral infection in vitro . Together, our study elucidates how SARS-CoV-2 inhibits the stress response and perturbs cellular gene expression in an m 6 A-dependent manner.