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A conserved uORF impacts APOBEC3G translation and is essential for translational inhibition by the HIV-1 Vif protein

Camille Libre, Tanja Seissler, View ORCID ProfileSantiago Guerrero, View ORCID ProfileJulien Batisse, Cédric Verriez, Benjamin Stupfler, Orian Gilmer, Melanie M. Weber, View ORCID ProfileAndrea Cimarelli, View ORCID ProfileLucie Etienne, View ORCID ProfileRoland Marquet, View ORCID ProfileJean-Christophe Paillart
doi: https://doi.org/10.1101/2021.01.13.426487
Camille Libre
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Tanja Seissler
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Santiago Guerrero
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Julien Batisse
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Cédric Verriez
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Benjamin Stupfler
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Orian Gilmer
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Melanie M. Weber
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Andrea Cimarelli
2CIRI-International Center for Infectiology Research, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, F-69000 Lyon, France
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Lucie Etienne
2CIRI-International Center for Infectiology Research, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, F-69000 Lyon, France
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Roland Marquet
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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Jean-Christophe Paillart
1Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, 2 Allée Conrad Roentgen, F-67084 Strasbourg cedex, France
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  • For correspondence: jc.paillart@ibmc-cnrs.unistra.fr
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ABSTRACT

The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular cytosine deaminases APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutations during reverse transcription. Vif counteracts A3G by several non-redundant mechanisms (transcription, translation and protein degradation) that concur in reducing the levels of A3G in cell and in preventing 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. Extensive mutagenesis of A3G 5′-UTR, combined with an analysis of their translational effect in transfected cells, indicated that the uORF represses A3G translation and that A3G mRNA is translated through a dual leaky-scanning and re-initiation mechanism. Interestingly, the uORF is also mandatory for the Vif-mediated repression of A3G translation. Furthermore, we showed that the redirection of A3G mRNA into stress granules was dependent not only on Vif, but also on the uORF. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific motif to repress its translation.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 13, 2021.
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A conserved uORF impacts APOBEC3G translation and is essential for translational inhibition by the HIV-1 Vif protein
Camille Libre, Tanja Seissler, Santiago Guerrero, Julien Batisse, Cédric Verriez, Benjamin Stupfler, Orian Gilmer, Melanie M. Weber, Andrea Cimarelli, Lucie Etienne, Roland Marquet, Jean-Christophe Paillart
bioRxiv 2021.01.13.426487; doi: https://doi.org/10.1101/2021.01.13.426487
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A conserved uORF impacts APOBEC3G translation and is essential for translational inhibition by the HIV-1 Vif protein
Camille Libre, Tanja Seissler, Santiago Guerrero, Julien Batisse, Cédric Verriez, Benjamin Stupfler, Orian Gilmer, Melanie M. Weber, Andrea Cimarelli, Lucie Etienne, Roland Marquet, Jean-Christophe Paillart
bioRxiv 2021.01.13.426487; doi: https://doi.org/10.1101/2021.01.13.426487

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