N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting
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The paper investigates how incorporating modified ribonucleotides like N1-methylpseudouridine (1-methylΨ) into mRNA vaccines affects their translation fidelity. They found that 1-methylΨ significantly increases +1 ribosomal frameshifting during mRNA translation, resulting in mistranslated proteins. This was shown using reporter mRNAs in vitro and in cells.
The +1 ribosomal frameshifting is likely caused by ribosome stalling during translation elongation when 1-methylΨ is present. It occurs at specific "slippery sequences" in the mRNA. In mice and humans vaccinated with a 1-methylΨ-containing mRNA vaccine (BNT162b2), T cell responses were detected against +1 frameshifted peptide products. This suggests cellular immunity can develop against mistranslated proteins.
However, altering the slippery sequences in the mRNA through synonymous mutations reduced +1 frameshifting. This demonstrates mRNA sequence optimization could help avoid potential adverse effects from mistranslation. Overall, the study shows 1-methylΨ incorporation impacts mRNA translation fidelity and elicits off-target T cell responses in vivo. Foreshadowing a future where RNA vaccines that contain N1-methylpseudouridine can elicit immune responses in vivo not only to the encoded protein(s) but also to products of frequent mistranslation. It highlights the need to further study and optimize therapeutic mRNA mistranslation and immunogenicity.
https://www.nature.com/articles/s41586-023-06800-3
