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J. Biol. Chem., Vol. 279, Issue 1, 788-795, January 2, 2004

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HIV-1 Vpu Sequesters -Transducin Repeat-containing Protein (TrCP) in the Cytoplasm and Provokes the Accumulation of -Catenin and Other SCF^TrCP Substrates^*

Corinne Besnard-Guerin, Nadia Belaïdouni, Irina Lassot¶, Emmanuel Segeral||, Aude Jobart, Christelle Marchal, and Richard Benarous**

From the Institut Cochin, Department of Infectious Diseases, INSERM U567, CNRS UMR 8104, Université R. Descartes Paris V, 27 Rue du Faubourg St. Jacques, 75014 Paris, France

The human immunodeficiency virus type 1 Vpu protein acts as an adaptor for the proteasomal degradation of CD4 by recruiting CD4 and -transducin repeat-containing protein (TrCP), the receptor component of the multisubunit SCF-TrCP E3 ubiquitin ligase complex. We showed that the expression of a Vpu-green fluorescent fusion protein prevented the proteosomal degradation of TrCP substrates such as -catenin, IB, and ATF4, which are normally directly targeted to the proteasome for degradation. -Catenin was translocated into the nucleus, whereas the tumor necrosis factor-induced nuclear translocation of NFB was impaired. -Catenin was also up-regulated in cells producing Vpu+ human immunodeficiency virus type 1 but not in cells producing Vpu-deficient viruses. The overexpression of ATF4 also provoked accumulation of -catenin, but to a lower level than that resulting from the expression of Vpu. Finally, the expression of Vpu induces the exclusion of TrCP from the nucleus. These data suggest that Vpu is a strong competitive inhibitor of TrCP that impairs the degradation of SCF^TrCP substrates as long as Vpu has an intact phosphorylation motif and can bind to TrCP.

Received for publication, July 24, 2003 , and in revised form, October 1, 2003.

^* This work was supported in part by grants from the Agence Nationale de Recherches sur le Sida, SIDACTION, the French Ministry of Research and Industry, Association pour la Recherche sur le Cancer, and Ligue Nationale Contre le Cancer. 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.

Supported by Sidaction.

^¶ Supported by La Ligue Nationale Contre le cancer.

^|| Supported by Association pour la Recherche sur le Cancer.

Supported by INSERM. To whom correspondence may be addressed. Tel.: 33-1-40-51-65-77; Fax: 33-1-40-51-65-70; E-mail: besnardguerin{at}cochin.inserm.fr.

^** To whom correspondence may be addressed. Tel.: 33-1-40-51-65-71; Fax: 33-1-40-51-65-70; E-mail: benarous{at}cochin.inserm.fr.

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