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Pré-Publication, Document De Travail Année : 2020

An epitranscriptomic switch at the 5´-UTR controls genome selection during HIV-1 genomic RNA packaging

Camila Pereira-Montecinos
  • Fonction : Auteur
Daniela Toro-Ascuy
  • Fonction : Auteur
Cecilia Rojas-Fuentes
  • Fonction : Auteur
Sebastián Riquelme-Barrios
  • Fonction : Auteur
Bárbara Rojas-Araya
  • Fonction : Auteur
Francisco García-De-Gracia
  • Fonction : Auteur
Paulina Aguilera-Cortés
  • Fonction : Auteur
Catarina Ananías-Sáez
  • Fonction : Auteur
Grégoire de Bisschop
  • Fonction : Auteur
Jonás Chaniderman
  • Fonction : Auteur
Mónica Acevedo
  • Fonction : Auteur
Fernando Valiente-Echeverría
  • Fonction : Auteur
Ricardo Soto-Rifo
  • Fonction : Auteur

Résumé

During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA (gRNA). While the simple retrovirus MLV segregates its full-length RNA into two functional populations, the HIV-1 full-length RNA was proposed to exist as a single population used indistinctly for protein synthesis or packaging. However, the mechanisms by which the HIV-1 Gag protein selects the two RNA molecules that will be packaged into nascent virions remain poorly understood. Here, we demonstrate that HIV-1 full-length RNA packaging is regulated through an epitranscriptomic switch requiring demethylation of two conserved adenosine residues present within the 5′-UTR. As such, while m 6 A deposition by METTL3/METTL14 onto the full-length RNA was associated with increased Gag synthesis and reduced packaging, FTO-mediated demethylation was required for the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and drives full-length RNA demethylation. Finally, the specific inhibition of the FTO RNA demethylase activity suppressed HIV-1 full-length RNA packaging. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the full-length RNA molecules that will be used as viral genomes.
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Dates et versions

hal-03020001 , version 1 (11-12-2020)

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Camila Pereira-Montecinos, Daniela Toro-Ascuy, Cecilia Rojas-Fuentes, Sebastián Riquelme-Barrios, Bárbara Rojas-Araya, et al.. An epitranscriptomic switch at the 5´-UTR controls genome selection during HIV-1 genomic RNA packaging. 2020. ⟨hal-03020001⟩
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