A NOVEL HUMAN WD PROTEIN, H-BETA-TRCP, THAT INTERACTS WITH HIV-1 VPU CONNECTS CD4 TO THE ER DEGRADATION PATHWAY THROUGH AN F-BOX MOTIF

HIV-1 Vpu interacts with CD4 in the endoplasmic reticulum and triggers CD4 degradation, presumably by proteasomes. Human beta TrCP identifie d by interaction with Vpu connects CD4 to this proteolytic machinery, and CD4-Vpu-beta TrCP ternary complexes have been detected by coimmuno precipitation. beta TrCP binding to Vpu and its recruitment to membran es require two phosphoserine residues in Vpu essential for CD4 degrada tion. In beta TrCP, WD repeats at the C terminus mediate binding to Vp u, and an F box near the N terminus is involved in interaction with Sk p1p, a targeting factor for ubiquitin-mediated proteolysis. An F-box d eletion mutant of beta TrCP had a dominant-negative effect on Vpu-medi ated CD4 degradation. These data suggest that beta TrCP and Skp1p repr esent components of a novel ER-associated protein degradation pathway that mediates CD4 proteolysis.