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J. Biol. Chem., Vol. 283, Issue 31, 21686-21692, August 1, 2008

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Assembly with the Cul4A-DDB1^DCAF1 Ubiquitin Ligase Protects HIV-1 Vpr from Proteasomal Degradation^*

Erwann Le Rouzic¹, Marina Morel², Diana Ayinde³, Nadia Belaïdouni⁴, Justine Letienne, Catherine Transy⁵, and Florence Margottin-Goguet⁶

From the Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris 75014, France and INSERM, U567, Paris 75014, France

Many viruses subvert the host ubiquitin-proteasome system to optimize their life cycle. We recently documented such a mechanism for the human immunodeficiency virus type 1 Vpr protein, which promotes cell cycle arrest by recruiting the DCAF1 adaptor of the Cul4A-DDB1 ubiquitin ligase, a finding now confirmed by several groups. Here we examined the impact of Cul4A-DDB1^DCAF1 on Vpr stability. We show that the Vpr(Q65R) mutant, which is defective in DCAF1 binding, undergoes proteasome-mediated degradation at a higher rate than wild-type Vpr. DCAF1 overexpression stabilizes wild-type Vpr and leads to its cytoplasmic accumulation, whereas it has no effect on the Vpr(Q65R) mutant. Conversely, small interfering RNA-mediated silencing of DCAF1 decreases the steady state amount of the viral protein. Stabilization by DCAF1, which is conserved by Vpr species from human immunodeficiency virus type 2 and the SIVmac strain, results in increased G₂ arrest and requires the presence of DDB1, indicating that it occurs through assembly of Vpr with a functional Cul4A-DDB1^DCAF1 complex. Furthermore, in human immunodeficiency virus type 1-infected cells, the Vpr protein, issued from the incoming viral particle, is destabilized under DCAF1 or DDB1 silencing. Together with our previous findings, our data suggest that Cul4A-DDB1^DCAF1 acts at a dual level by providing Vpr with the equipment for the degradation of specific host proteins and by counter-acting its proteasome targeting by another cellular E3 ubiquitin ligase. This protection mechanism may represent an efficient way to optimize the activity of Vpr molecules that are delivered by the incoming virus before neosynthesis takes place. Targeting the Vpr-DCAF1 interaction might therefore present therapeutic interest.

Received for publication, December 18, 2007 , and in revised form, June 3, 2008.

^* This work was supported by grants from Mairie de Paris, Agence national de recherches sur le SIDA et les hépatites virales, Sidaction, and Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by INSERM.

² Supported by Sidaction and Fondation de France.

³ Supported by the French ministry of education.

⁴ Supported by Mairie de Paris.

⁵ To whom correspondence may be addressed: Institut Cochin, Département Maladies Infectieuses, bâtiment Gustave Roussy, 27, rue du faubourg Saint Jacques, 75014 Paris, France. Tel.: 33-1-40-51-66-16; Fax: 33-1-40-51-65-70; E-mail: margottin-goguet{at}cochin.inserm.fr.

⁶ To whom correspondence may be addressed: Institut Cochin, Département Maladies Infectieuses, bâtiment Gustave Roussy, 27, rue du faubourg Saint Jacques, 75014 Paris, France. Tel.: 33-1-40-51-66-16; Fax: 33-1-40-51-65-70; E-mail: transy{at}cochin.inserm.fr.

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				A. Bergamaschi, D. Ayinde, A. David, E. Le Rouzic, M. Morel, G. Collin, D. Descamps, F. Damond, F. Brun-Vezinet, S. Nisole, et al. The Human Immunodeficiency Virus Type 2 Vpx Protein Usurps the CUL4A-DDB1DCAF1 Ubiquitin Ligase To Overcome a Postentry Block in Macrophage Infection J. Virol., May 15, 2009; 83(10): 4854 - 4860. [Abstract] [Full Text] [PDF]