Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 37, Pages 13123-13133Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.014260
Keywords
m6A modification; immune evasion; RIG-I sensing; innate immunity; viral immunology; cellular immune response; hepatitis B virus (HBV; Hep B); hepatitis C virus (HCV; Hep C)
Categories
Funding
- National Institutes of Health [AI125350, AI139234, AI085087]
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N-6-Methyladenosine (m(6)A), the methylation of the adenosine base at the nitrogen 6 position, is the most common epitranscriptomic modification of mRNA that affects a wide variety of biological functions. We have previously reported that hepatitis B viral RNAs are m(6)A-modified, displaying a dual functional role in the viral life cycle. Here, we show that cellular m(6)A machinery regulates host innate immunity against hepatitis B and C viral infections by inducing m(6)A modification of viral transcripts. The depletion of the m(6)A writer enzymes (METTL3 and METTL14) leads to an increase in viral RNA recognition by retinoic acid-inducible gene I (RIG-I), thereby stimulating type I interferon production. This is reversed in cells in which m(6)A METTL3 and METTL14 are overexpressed. The m(6)A modification of viral RNAs renders RIG-I signaling less effective, whereas single nucleotide mutation of m(6)A consensus motif of viral RNAs enhances RIG-I sensing activity. Importantly, m(6)A reader proteins (YTHDF2 and YTHDF3) inhibit RIG-I-transduced signaling activated by viral RNAs by occupying m(6)A-modified RNAs and inhibiting RIG-I recognition. Collectively, our results provide new insights into the mechanism of immune evasion via m(6)A modification of viral RNAs.
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