A metal ion orients SARS-CoV-2 mRNA to ensure accurate 2'-O methylation of its first nucleotide

SARS-CoV-2 nonstructural protein 16 (nsp16) is an mRNA 2'-O methyltransferase targeting its first transcribed nucleotide, usually an adenine. Ablation of its 2'O-methyltransferase activity resulted in a remarkable induction of type I IFN, suggesting that the 2'-O methylation of viral mRNA is involved in the restriction of recognition by cellular sensors for induction of innate immune responses. Structural analyses revealed that a divalent cation is essential for this catalysis. Comparison of amino acid sequence of this enzyme among several variants proposed a mutation in the essential amino acid in the catalytic site. Mutation in this amino acid resulted in a reduced pattern of 2'-O methylation in the nucleotide, indicating that SARS-CoV-2 variant exhibits altered degrees of methylation, which may contribute to the appearance of different magnitude of host immune response during viral infection.