In vitro, in cellulo and structural characterizations of the interaction between the integrase of Porcine Endogenous Retrovirus A/C and proteins of the BET family
2019
Gallay, Kathy | Blot, Guillaume | Chahpazoff, Margaux | Yajjou-Hamalian, Halima | Confort, Marie-Pierre | de Boisseson, Claire | Leroux, Aurélie | Luengo, Catherine | Fiorini, Francesca | Lavigne, Marc | Chebloune, Yahia | Gouet, Patrice | Moreau, Karen | Blanchard, Yannick | Ronfort, Corinne | Infections Virales et Pathologie Comparée - UMR 754 (IVPC) ; Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE) ; Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon | Laboratoire de Ploufragan-Plouzané-Niort [ANSES] ; Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES) | Microbiologie moléculaire et biochimie structurale - Molecular Microbiology and Structural Biochemistry (MMSB) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS) | Département de Virologie - Department of Virology ; Institut Pasteur [Paris] (IP) | Institut Cochin (IC UM3 (UMR 8104 / U1016)) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) | Laboratoire Pathogénèse et Vaccination Lentivirales (PAVAL Lab) ; Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]) | French Institute INRA (Institut National de la Recherche Agronomique) ANSES (Agence Nationale securite sanitaire de l'alimentation, de l'environnement et du travail) Centre National de la Recherche Scientifique (CNRS)Rhone-Alpes-Auvergne region 18003930 ARC Health 2016
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Показать больше [+] Меньше [-]Английский. Retroviral integrase (IN) proteins catalyze the permanent integration of the viral genome into host DNA. They can productively recruit cellular proteins, and the human Bromodomain and Extra-Terminal domain (hBET) proteins have been shown to be co-factors for integration of gamma-retroviruses such as Murine Leukemia Virus (MLV) into human cells. By using two-hybrid, co-immunoprecipitation and in vitro interaction assays, we showed that IN of the gamma- Porcine Endogenous Retrovirus-A/C (PERV IN) interacts through its C-terminal domain (CTD) with hBET proteins. We observed that PERV IN interacts with the BRD2, BRD3 and BRD4 proteins in vitro and that the BRD2 protein specifically binds and co-localizes with PERV IN protein in the nucleus of cells. We further mapped the interaction sites to the conserved Extra-Terminal (ET) domain of the hBET proteins and to several amino acids of the of the C-terminal tail of the PERV IN CTD. Finally, we determined the first experimental structure of an IN CTD - BET ET complex from small-angle X-ray scattering data (SAXS). We showed that the two factors assemble as two distinct modules linked by a short loop which confers partial flexibility. The SAXS-restrained model is structurally compatible with the binding of the PERV intasome to BRD2. Altogether, these data confirm the important role of host BET proteins in the gamma-retroviruses' targeting site and efficiency of integration.
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