A Conserved uORF Regulates APOBEC3G Translation and Is Targeted by HIV-1 Vif Protein to Repress the Antiviral Factor
Camille Libre,
Tanja Seissler,
Santiago Guerrero,
Julien Batisse,
Cédric Verriez,
Benjamin Stupfler,
Orian Gilmer,
Romina Cabrera-Rodriguez,
Melanie M. Weber,
Agustin Valenzuela-Fernandez,
Andrea Cimarelli,
Lucie Etienne,
Roland Marquet,
Jean-Christophe Paillart
Affiliations
Camille Libre
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Tanja Seissler
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Santiago Guerrero
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Julien Batisse
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Cédric Verriez
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Benjamin Stupfler
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Orian Gilmer
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Romina Cabrera-Rodriguez
Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38320 Tenerife, Spain
Melanie M. Weber
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Agustin Valenzuela-Fernandez
Laboratorio de Inmunología Celular y Viral, Unidad de Farmacología, Sección de Medicina, Facultad de Ciencias de la Salud, Universidad de La Laguna, 38320 Tenerife, Spain
Andrea Cimarelli
CIRI-International Center for Infectiology Research, INSERM U1111, Université Claude Bernard de Lyon 1, CNRS, UMR 5308, Ecole Normale de Lyon, Université de Lyon, F-69000 Lyon, France
Lucie Etienne
CIRI-International Center for Infectiology Research, INSERM U1111, Université Claude Bernard de Lyon 1, CNRS, UMR 5308, Ecole Normale de Lyon, Université de Lyon, F-69000 Lyon, France
Roland Marquet
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
Jean-Christophe Paillart
Architecture et Réactivité de l’ARN, UPR 9002, Université de Strasbourg: CNRS, 2 Allée Conrad Roentgen, F-67000 Strasbourg, France
The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular restriction factors APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutation during reverse transcription. Vif counteracts A3G at several levels (transcription, translation, and protein degradation) that altogether reduce the levels of A3G in cells and prevent its incorporation into viral particles. How Vif affects A3G translation remains unclear. Here, we uncovered the importance of a short conserved uORF (upstream ORF) located within two critical stem-loop structures of the 5′ untranslated region (5′-UTR) of A3G mRNA for this process. A3G translation occurs through a combination of leaky scanning and translation re-initiation and the presence of an intact uORF decreases the extent of global A3G translation under normal conditions. Interestingly, the uORF is also absolutely required for Vif-mediated translation inhibition and redirection of A3G mRNA into stress granules. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific feature to repress its translation.