Internal RNA 2′O-methylation in the HIV-1 genome counteracts ISG20 nuclease-mediated antiviral effect

Author:

El Kazzi Priscila1ORCID,Rabah Nadia12ORCID,Chamontin Célia3,Poulain Lina1,Ferron François14ORCID,Debart Françoise5,Canard Bruno1ORCID,Missé Dorothée6,Coutard Bruno7,Nisole Sébastien3ORCID,Decroly Etienne1ORCID

Affiliation:

1. AFMB, CNRS, Aix-Marseille University , UMR 7257, Case 925, 163 Avenue de Luminy , 13288 Marseille Cedex 09, France

2. Université de Toulon , 83130 La Garde , France

3. IRIM, CNRS UMR9004, Université de Montpellier , Montpellier , France

4. European Virus Bioinformatics Center , Leutragraben 1, 07743 Jena , Germany

5. IBMM, UMR 5247 CNRS, Université de Montpellier , ENSCM, Montpellier , France

6. MIVEGEC, Univ. Montpellier, CNRS , IRD, Montpellier, France

7. Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207) , Marseille , France

Abstract

Abstract 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.

Funder

Foundation Méditerranée Infection

Agence Nationale de la Recherche

Foundation pour la recherche médicale

Agence Nationale de la Recherche sur le SIDA et les Hépatites virales

Publisher

Oxford University Press (OUP)

Subject

Genetics

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