Figure 2

Model of Vpu-mediated CD4 degradation. First, Vpu retains CD4 in the ER through TM domains interactions; formation of Env/CD4 complexes could contribute to this retention. In addition, CD4 and Vpu also interact through their cytosolic domains. The minimal region of the CD4 cytoplasmic tail conferring Vpu sensitivity was mapped to the region 414-LSEKKT-419. Recruitment of the SCF^β-TrCP E3 ubiquitin ligase complex by Vpu is mediated by interactions of phosphoserines in Vpu and the WD boxes of β-TrCP. Interactions between Vpu and CD4 result in the trans-ubiquination of the cytosolic tail of CD4 on lysine, serine and threonine residues. These ubiquitination events might further contribute to CD4 retention in the ER but, importantly, target CD4 for degradation by the cytosolic proteasome. This targeting involves a dislocation step mediated by the p97-UFD1L-NPL4 complex, a critical component of ERAD. This complex recognizes K48-linked polyubiquitinated chains on the cytosolic tail of CD4 through the UFD1L co-factor. The p97 protein via its ATPase activity subsequently directs the dislocation of CD4 across the ER membrane where the receptor becomes readily accessible for proteasomal degradation.