Epitranscriptomic regulation of HIV-1 full-length RNA packaging
Autor
Pereira-Montecinos, Camila
Toro-Ascuy, Daniela
Ananias-Saez, Catarina
Gaete-Argel, Aracelly
Rojas-Fuentes, Cecilia
Riquelme-Barrios, Sebastian
Rojas-Araya, Barbara
Garcia-de-Gracia, Francisco
Aguilera-Cortes, Paulina
Chnaiderman, Jonas
Acevedo, Monica L.
Valiente-Echeverria, Fernando
Soto-Rifo, Ricardo
Resumen
During retroviral replication, the full-length RNA serves both as mRNA and genomic RNA. 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 deposition of N-6-methyladenosine (m(6)A) regulates full-length RNA packaging. 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 promoted the incorporation of the full-length RNA into viral particles. Interestingly, HIV-1 Gag associates with the RNA demethylase FTO in the nucleus and contributes to full-length RNA demethylation. We further identified two highly conserved adenosines within the 5 '-UTR that have a crucial functional role in m(6)A methylation and packaging of the full-length RNA. Together, our data propose a novel epitranscriptomic mechanism allowing the selection of the HIV-1 full-length RNA molecules that will be used as viral genomes.
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