Modulation of -Catenin and E-Cadherin Interaction by Vpu Increases HIV-1 Particle Release

Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri

^* To whom correspondence should be addressed. Email: LRATNER{at}IM.WUSTL.EDU.

	Abstract

Viral protein U (Vpu) is a 17 kd HIV-1 accessory protein, that enhances the release of particles from the surface of infected cells. Vpu recruits beta-transducin repeat-containing protein (-TrCP), and mediates proteasomal degradation of CD4. By sequestering -TrCP away from other cellular substrates, Vpu leads to the stabilization of -TrCP substrates such as -catenin, IKB, ATF4 and Cdc25A, but not other substrates such as Emi1. This study shows that in addition to stabilizing -catenin, Vpu leads to depression of both total and -catenin associated E-cadherin levels through a -TrCP dependent stabilization of the transcriptional repressor Snail. We show that both downregulation of overall E-cadherin levels and dissociation of E-cadherin from -catenin results in enhanced viral release. In contrast, overexpression of E-cadherin or prevention of dissociation of E-cadherin from -catenin results in depressed virus release. Since E-cadherin is expressed only in dendritic cells and macrophages, and not in T cells, our data suggests that the HIV-1 vpu gene may have evolved to counteract different restrictions to assembly in different cells.