Mechanism of Nef-induced CD4 endocytosis: Nef connects CD4 with the chain of adaptor complexes

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Abstract
The Nef protein of primate lentiviruses down‐regulates the cell surface expression of CD4 and probably MHC I by connecting these receptors with the endocytic machinery. Here, we reveal that Nef interacts with the μ chains of adaptor complexes, key components of clathrin‐coated pits. For human immunodeficiency virus type 2 (HIV‐2) and simian immunodeficiency virus (SIV) Nef, this interaction occurs via tyrosine‐based motifs reminiscent of endocytosis signals. Mutating these motifs prevents the binding of SIV Nef to the μ chain of plasma membrane adaptor complexes, abrogates its ability to induce CD4 internalization, suppresses the accelerated endocytosis of a chimeric integral membrane protein harboring Nef as its cytoplasmic domain and confers a dominant‐negative phenotype to the viral protein. Taken together, these data identify μ adaptins as downstream mediators of the down‐modulation of CD4, and possibly MHC I, by Nef.