HIV-1 Vpu sequesters beta-transducin repeat-containing protein (betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin and other SCFbetaTrCP substrates.
The human immunodeficiency virus type 1 Vpu protein acts as an adaptor for the proteasomal degradation of CD4 by recruiting CD4 and beta-transducin repeat-containing protein (betaTrCP), the receptor component of the multisubunit SCF-betaTrCP E3 ubiquitin ligase complex. We showed that the expression of a Vpu-green fluorescent fusion protein prevented the proteosomal degradation of betaTrCP substrates such as beta-catenin, IkappaBalpha, and ATF4, which are normally directly targeted to the proteasome for degradation. Beta-catenin was translocated into the nucleus, whereas the tumor necrosis factor-induced nuclear translocation of NFkappaB was impaired. Beta-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 beta-catenin, but to a lower level than that resulting from the expression of Vpu. Finally, the expression of Vpu induces the exclusion of betaTrCP from the nucleus. These data suggest that Vpu is a strong competitive inhibitor of betaTrCP that impairs the degradation of SCFbetaTrCP substrates as long as Vpu has an intact phosphorylation motif and can bind to betaTrCP.
Besnard-Guerin
Corinne
C
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. besnard-guerin@cochin.inserm.fr
Belaïdouni
Nadia
N
Lassot
Irina
I
Segeral
Emmanuel
E
Jobart
Aude
A
Marchal
Christelle
C
Benarous
Richard
R
D001665:Binding Sites; D002460:Cell Line; D003593:Cytoplasm / Q000502:physiology / Q000821:virology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D007700:Kinetics; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins / Q000502:physiology*; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics* / Q000378:metabolism*; D000086082:Viroporin Proteins
D003598:Cytoskeletal Proteins; D054298:Human Immunodeficiency Virus Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; C471644:BTRC protein, human; C495270:CTNNB1 protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins