RT Journal Article
SR Electronic
T1 An epitranscriptomic switch at the 5′-UTR controls genome selection during HIV-1 genomic RNA packaging
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 676031
DO 10.1101/676031
A1 Camila Pereira-Montecinos
A1 Daniela Toro-Ascuy
A1 Cecilia Rojas-Fuentes
A1 Sebastián Riquelme-Barrios
A1 Bárbara Rojas-Araya
A1 Francisco García-de-Gracia
A1 Paulina Aguilera-Cortés
A1 Catarina Ananías-Sáez
A1 Grégoire de Bisschop
A1 Jonás Chaniderman
A1 Mónica L. Acevedo
A1 Bruno Sargueil
A1 Fernando Valiente-Echeverría
A1 Ricardo Soto-Rifo
YR 2019
UL http://biorxiv.org/content/early/2019/06/19/676031.abstract
AB 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 m6A 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.