The human immunodeficiency virus type I (HIV-1) Vpu protein binds to the CD4 receptor and targets it to the proteasome for degradation. This process requires the recruitment of human beta TrCP, a component of the Skp1-Cullin-F box (SCF) ubiquitin ligase complex, that interacts with phosphorylated Vpu molecules. Vpu, unlike other ligands of PTrCP, has never been reported to be degraded. We provide evidence that Vpu, itself, is ubiquitinated and targeted for degradation by the proteasome. We demonstrate that the mutant Vpu2.6, which cannot interact with PTrCP, is stable and, unlike wild-type Vpu, is not polyubiquitinated. These results suggest that PTrCP is involved in Vpu polyubiquitination. (c) 2007 Elsevier Inc. All rights reserved.