Internal RNA 2'O-methylation in the HIV-1 genome counteracts ISG20 nuclease-mediated antiviral effect.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
11 04 2023
11 04 2023
Historique:
accepted:
19
10
2022
revised:
16
09
2022
received:
30
03
2022
medline:
12
4
2023
pubmed:
11
11
2022
entrez:
10
11
2022
Statut:
ppublish
Résumé
RNA 2'O-methylation is a 'self' epitranscriptomic modification allowing discrimination between host and pathogen. Indeed, human immunodeficiency virus 1 (HIV-1) induces 2'O-methylation of its genome by recruiting the cellular FTSJ3 methyltransferase, thereby impairing detection by RIG-like receptors. Here, we show that RNA 2'O-methylations interfere with the antiviral activity of interferon-stimulated gene 20-kDa protein (ISG20). Biochemical experiments showed that ISG20-mediated degradation of 2'O-methylated RNA pauses two nucleotides upstream of and at the methylated residue. Structure-function analysis indicated that this inhibition is due to steric clash between ISG20 R53 and D90 residues and the 2'O-methylated nucleotide. We confirmed that hypomethylated HIV-1 genomes produced in FTSJ3-KO cells were more prone to in vitro degradation by ISG20 than those produced in cells expressing FTSJ3. Finally, we found that reverse-transcription of hypomethylated HIV-1 was impaired in T cells by interferon-induced ISG20, demonstrating the direct antagonist effect of 2'O-methylation on ISG20-mediated antiviral activity. Despite highly effective antiretroviral therapies, the human immunodeficiency virus (HIV-1) remains a major public health threat. Its pathogenesis depends on its ability to establish a persistent infection in cells of the immune system. Our study highlights a new insight into how HIV-1 evades early restriction by the immune system. We showed that 2′O-methylation marks found inside HIV-1 RNA promote viral evasion from the antiviral action of the interferon-stimulated gene 20-kDa protein (ISG20), an innate immune restriction factor with a nuclease activity. By disrupting the level of 2′O-methylation of the HIV-1 genome, we demonstrated that ISG20 impairs the reverse transcription process of hypomethylated viruses, as a result of viral RNA decay.
Autres résumés
Type: plain-language-summary
(eng)
Despite highly effective antiretroviral therapies, the human immunodeficiency virus (HIV-1) remains a major public health threat. Its pathogenesis depends on its ability to establish a persistent infection in cells of the immune system. Our study highlights a new insight into how HIV-1 evades early restriction by the immune system. We showed that 2′O-methylation marks found inside HIV-1 RNA promote viral evasion from the antiviral action of the interferon-stimulated gene 20-kDa protein (ISG20), an innate immune restriction factor with a nuclease activity. By disrupting the level of 2′O-methylation of the HIV-1 genome, we demonstrated that ISG20 impairs the reverse transcription process of hypomethylated viruses, as a result of viral RNA decay.
Identifiants
pubmed: 36354007
pii: 6819936
doi: 10.1093/nar/gkac996
pmc: PMC10085690
doi:
Substances chimiques
Exoribonucleases
EC 3.1.-
Interferons
9008-11-1
ISG20 protein, human
EC 3.1.-
RNA, Viral
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2501-2515Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
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