Modulation of beta-catenin and E-cadherin interaction by Vpu increases human immunodeficiency virus type 1 particle release.
Vpu (viral protein U) is a 17-kDa human immunodeficiency virus type 1 (HIV-1) accessory protein that enhances the release of particles from the surfaces of infected cells. Vpu recruits beta-transducin repeat-containing protein (beta-TrCP) and mediates proteasomal degradation of CD4. By sequestering beta-TrCP away from other cellular substrates, Vpu leads to the stabilization of beta-TrCP substrates such as beta-catenin, IkappaBalpha, ATF4, and Cdc25A, but not of other substrates such as Emi1. This study shows that in addition to stabilizing beta-catenin, Vpu leads to the depression of both total and beta-catenin-associated E-cadherin levels through beta-TrCP-dependent stabilization of the transcriptional repressor Snail. We showed that both downregulation of overall E-cadherin levels and dissociation of E-cadherin from beta-catenin result in enhanced viral release. By contrast, the overexpression of E-cadherin or the prevention of the dissociation of E-cadherin from beta-catenin results in depressed levels of virus release. Since E-cadherin is expressed only in dendritic cells and macrophages, and not in T cells, our data suggest that the HIV-1 vpu gene may have evolved to counteract different restrictions to assembly in different cells.
Salim
Aneeza
A
Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Ratner
Lee
L
D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D015497:HIV-1 / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D014779:Virus Replication; D051176:beta Catenin / Q000378:metabolism*; D000086082:Viroporin Proteins
D015820:Cadherins; D054298:Human Immunodeficiency Virus Proteins; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins