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Impact of HIV-1 Vpr manipulation of the DNA repair enzyme UNG2 on B lymphocyte class switch recombination.
Eldin, Patrick; Péron, Sophie; Galashevskaya, Anastasia; Denis-Lagache, Nicolas; Cogné, Michel; Slupphaug, Geir; Briant, Laurence.
Afiliación
  • Eldin P; Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, UMR 9004, Université de Montpellier, 1919 Route de Mende, 34293, Montpellier Cedex 5, France. patrick.eldin@irim.cnrs.fr.
  • Péron S; Contrôle de la Réponse Immune B et des Lymphoproliférations (CBRIL), UMR CNRS 7276 INSERM 1262, Centre de Biologie et de Recherche en Santé (CBRS), Faculté de Limoges, 2 rue du Dr. Marcland, 87000, Limoges, France.
  • Galashevskaya A; Proteomics and Modomics Experimental Core (PROMEC), Department of Cancer Research and Molecular Medicine, Laboratory Centre, Norwegian University of Science and Technology (NTNU), 5th Floor. Erling Skjalgssons gt. 1, 7491, Trondheim, Norway.
  • Denis-Lagache N; Contrôle de la Réponse Immune B et des Lymphoproliférations (CBRIL), UMR CNRS 7276 INSERM 1262, Centre de Biologie et de Recherche en Santé (CBRS), Faculté de Limoges, 2 rue du Dr. Marcland, 87000, Limoges, France.
  • Cogné M; Contrôle de la Réponse Immune B et des Lymphoproliférations (CBRIL), UMR CNRS 7276 INSERM 1262, Centre de Biologie et de Recherche en Santé (CBRS), Faculté de Limoges, 2 rue du Dr. Marcland, 87000, Limoges, France.
  • Slupphaug G; Proteomics and Modomics Experimental Core (PROMEC), Department of Cancer Research and Molecular Medicine, Laboratory Centre, Norwegian University of Science and Technology (NTNU), 5th Floor. Erling Skjalgssons gt. 1, 7491, Trondheim, Norway.
  • Briant L; Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, UMR 9004, Université de Montpellier, 1919 Route de Mende, 34293, Montpellier Cedex 5, France.
J Transl Med ; 18(1): 310, 2020 08 10.
Article en En | MEDLINE | ID: mdl-32778120
ABSTRACT

BACKGROUND:

HIV-1 Vpr encodes a 14 kDa protein that has been implicated in viral pathogenesis through modulation of several host cell functions. In addition to pro-apoptotic and cytostatic properties, Vpr can redirect cellular E3 ubiquitin ligases (such as DCAF1-Cul4A E3 ligase complex) to target many host proteins and interfere with their functions. Among them, Vpr binds the uracil DNA glycosylase UNG2, which controls genome uracilation, and induces its specific degradation leading to loss of uracil removal activity in infected cells. Considering the essential role of UNG2 in antibody diversification in B-cells, we evaluated the impact of Vpr on UNG2 fate in B lymphocytes and examined the functional consequences of UNG2 modulations on class switch recombination (CSR).

METHODS:

The impact of Vpr-induced UNG2 deregulation on CSR proficiency was evaluated by using virus-like particles able to deliver Vpr protein to target cells including the murine model CSR B cell line CH12F3 and mouse primary B-cells. Co-culture experiments were used to re-examine the ability of Vpr to be released by HIV-1 infected cells and to effectively accumulate in bystander B-cells. Vpr-mediated UNG2 modulations were monitored by following UNG2 protein abundance and uracil removal enzymatic activity.

RESULTS:

In this study we report the ability of Vpr to reduce immunoglobulin class switch recombination (CSR) in immortalized and primary mouse B-cells through the degradation of UNG2. We also emphasize that Vpr is released by producing cells and penetrates bystander B lymphocytes.

CONCLUSIONS:

This work therefore opens up new perspectives to study alterations of the B-cell response by using Vpr as a specific CSR blocking tool. Moreover, our results raise the question of whether extracellular HIV-1 Vpr detected in some patients may manipulate the antibody diversification process that engineers an adapted response against pathogenic intruders and thereby contribute to the intrinsic B-cell humoral defect reported in infected patients.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: VIH-1 Límite: Animals / Humans Idioma: En Revista: J Transl Med Año: 2020 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: VIH-1 Límite: Animals / Humans Idioma: En Revista: J Transl Med Año: 2020 Tipo del documento: Article País de afiliación: Francia