Epitranscriptomic cytidine methylation of the hepatitis B viral RNA is essential for viral reverse transcription and particle production.

Autor:	Su PA; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Chang CH; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Yen SB; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.; Taiwan International Graduate Program, National Yang-Ming Chiao-Tung University and Academia Sinica, Taipei 115, Taiwan., Wu HY; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Tung WJ; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan., Hu YP; Institute of Biomedical Sciences Summer Undergraduate Internship Program, Academia Sinica, Taipei 115, Taiwan., Chen YI; Institute of Biomedical Sciences Summer Undergraduate Internship Program, Academia Sinica, Taipei 115, Taiwan., Lin MH; Department of Microbiology, National Taiwan University College of Medicine, Taipei 100, Taiwan., Shih C; Graduate Institute of Cell Biology, College of Life Sciences, China Medical University, Taichung 404, Taiwan., Chen PJ; National Taiwan University Center for Genomic Medicine, National Taiwan University, Taipei 100, Taiwan.; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan.; Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan., Tsai K; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jun 11; Vol. 121 (24), pp. e2400378121. Date of Electronic Publication: 2024 Jun 03.
DOI:	10.1073/pnas.2400378121
Abstrakt:	Epitranscriptomic RNA modifications have emerged as important regulators of the fate and function of viral RNAs. One prominent modification, the cytidine methylation 5-methylcytidine (m 5 C), is found on the RNA of HIV-1, where m 5 C enhances the translation of HIV-1 RNA. However, whether m 5 C functionally enhances the RNA of other pathogenic viruses remains elusive. Here, we surveyed a panel of commonly found RNA modifications on the RNA of hepatitis B virus (HBV) and found that HBV RNA is enriched with m 5 C as well as ten other modifications, at stoichiometries much higher than host messenger RNA (mRNA). Intriguingly, m 5 C is mostly found on the epsilon hairpin, an RNA element required for viral RNA encapsidation and reverse transcription, with these m 5 C mainly deposited by the cellular methyltransferase NSUN2. Loss of m 5 C from HBV RNA due to NSUN2 depletion resulted in a partial decrease in viral core protein (HBc) production, accompanied by a near-complete loss of the reverse transcribed viral DNA. Similarly, mutations introduced to remove the methylated cytidines resulted in a loss of HBc production and reverse transcription. Furthermore, pharmacological disruption of m 5 C deposition led to a significant decrease in HBV replication. Thus, our data indicate m 5 C methylations as a critical mediator of the epsilon elements' function in HBV virion production and reverse transcription, suggesting the therapeutic potential of targeting the m 5 C methyltransfer process on HBV epsilon as an antiviral strategy. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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