β -TrCP Dependency of HIV-1 Vpu-Induced Downregulation of CD4 and BST-2/Tetherin

Fabien      P. Blanchet; J.      P. Mitchell; Vincent      Piguet

Abstract

During evolution, pathogens have evolved strategies to counteract key cellular restriction mechanisms in order to efficiently invade target cells and fulfill essential steps of their replication cycle. Human Immunodeficiency Virus-1 and some Simian counterparts express a small multifunctional protein, Vpu, which influences viral replication. By acting as a multifunctional adapter, Vpu enhances viral particle release and infectivity. Therefore Vpu, an accessory protein, contributes to pathogenesis while avoiding superinfection. These effects rely mainly on the ability of Vpu to target the host proteins CD4 and BST-2/tetherin. Indeed, Vpu downregulates the cell surface expression of these receptors and subsequently induces their proteolysis via a mechanism involving a β -TrCP-containing E3 ubiquitin ligase complex. In this review, we will detail recent research aimed at elucidating the mechanism of Vpu-mediated CD4 and BST-2/tetherin downregulation and degradation as well as their subsequent consequences on viral pathogenesis.

Keywords: BST-2/tetherin, CD4, Human Immunodeficiency Virus-1 (HIV-1), lysosome, proteasome, SCFbTrCP E3 ubiquitin ligase, Ubiquitination, Viral Protein U (Vpu), degradation, proteolysis