Global loss of cellular mA RNA methylation following infection with different SARS-CoV-2 variants.

Insights into host-virus interactions during SARS-CoV-2 infection are needed to understand COVID-19 pathogenesis and may help to guide the design of novel antiviral therapeutics. -Methyladenosine modification (mA), one of the most abundant cellular RNA modifications, regulates key processes in RNA metabolism during stress response. Gene expression profiles observed postinfection with different SARS-CoV-2 variants show changes in the expression of genes related to RNA catabolism, including mA readers and erasers. We found that infection with SARS-CoV-2 variants causes a loss of mA in cellular RNAs, whereas mA is detected abundantly in viral RNA. METTL3, the mA methyltransferase, shows an unusual cytoplasmic localization postinfection. The B.1.351 variant has a less-pronounced effect on METTL3 localization and loss of mA than did the B.1 and B.1.1.7 variants. We also observed a loss of mA upon SARS-CoV-2 infection in air/liquid interface cultures of human airway epithelia, confirming that mA loss is characteristic of SARS-CoV-2-infected cells. Further, transcripts with mA modification are preferentially down-regulated postinfection. Inhibition of the export protein XPO1 results in the restoration of METTL3 localization, recovery of mA on cellular RNA, and increased mRNA expression. Stress granule formation, which is compromised by SARS-CoV-2 infection, is 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 mA-dependent manner.