Salim Aneeza, Ratner Lee
Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
J Virol. 2008 Apr;82(8):3932-8. doi: 10.1128/JVI.00430-07. Epub 2008 Feb 6.
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.
Vpu（病毒蛋白U）是一种17千道尔顿的1型人类免疫缺陷病毒（HIV-1）辅助蛋白，可增强感染细胞表面病毒颗粒的释放。Vpu招募含β-转导蛋白重复序列的蛋白（β-TrCP）并介导CD4的蛋白酶体降解。通过将β-TrCP与其他细胞底物隔离，Vpu导致β-TrCP底物如β-连环蛋白、IκBα、ATF4和Cdc25A的稳定，但不会导致其他底物如Emi1的稳定。本研究表明，除了稳定β-连环蛋白外，Vpu还通过转录抑制因子Snail的β-TrCP依赖性稳定作用导致总E-钙黏蛋白水平和与β-连环蛋白相关的E-钙黏蛋白水平降低。我们发现，整体E-钙黏蛋白水平的下调以及E-钙黏蛋白与β-连环蛋白的解离均导致病毒释放增加。相比之下，E-钙黏蛋白的过表达或E-钙黏蛋白与β-连环蛋白解离的预防导致病毒释放水平降低。由于E-钙黏蛋白仅在树突状细胞和巨噬细胞中表达，而不在T细胞中表达，我们的数据表明，HIV-1 vpu基因可能已经进化以应对不同细胞中组装的不同限制。
