Nef-induced CD4 degradation: A diacidic-based motif in Nef functions as a lysosomal targeting signal through the binding of beta-COP in endosomes

The Nef protein of primate lentiviruses downregulates the cell surface expr ession of CD4 through a two-step process. First, Nef connects the cytoplasm ic tail of CD4 with adaptor protein complexes (AP), thereby inducing the fo rmation of CD4-specific clathrin-coated pits that rapidly endocytose the vi ral receptor. Second; Nef targets internalized CD4 molecules for degradatio n. Here we show that Nef accomplishes this second task by acting as a conne ctor between CD4 and the beta subunit of COPI coatomers in endosomes. A seq uence encompassing a critical acidic dipeptide, located nearby but distinct from the AP-binding determinant of HIV-1 Nef, is responsible for beta-COP recruitment and for routing to lysosomes. A novel class of endosomal sortin g motif, based on acidic residues, is thus revealed, and beta-COP is identi fied as its downstream partner.