HIV-1 Vpu Sequesters β-Transducin Repeat-containing Protein (βTrCP) in the Cytoplasm and Provokes the Accumulation of β-Catenin and Other SCFβTrCP Substrates

Abstract

The human immunodeficiency virus type 1 Vpu protein acts as an adaptor for the proteasomal degradation of CD4 by recruiting CD4 and β-transducin repeat-containing protein (βTrCP), the receptor component of the multisubunit SCF-βTrCP E3 ubiquitin ligase complex. We showed that the expression of a Vpu-green fluorescent fusion protein prevented the proteosomal degradation of βTrCP substrates such as β-catenin, IκBα, and ATF4, which are normally directly targeted to the proteasome for degradation. β-Catenin was translocated into the nucleus, whereas the tumor necrosis factor-induced nuclear translocation of NF-κB was impaired. β-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 β-catenin, but to a lower level than that resulting from the expression of Vpu. Finally, the expression of Vpu induces the exclusion of βTrCP from the nucleus. These data suggest that Vpu is a strong competitive inhibitor of βTrCP that impairs the degradation of SCFβTrCP substrates as long as Vpu has an intact phosphorylation motif and can bind to βTrCP.