Interaction of endocytic signals from the HIV-1 envelope glycoprotein complex with members of the adaptor medium chain family

Abstract

The envelope glycoprotein (Env) complex of HIV-1 undergoes rapid internalization from the plasma membrane of human cells by virtue of a tyrosine-based endocytic signal (RQGYSPL, residues 704-710) in the cytosolic tall of the protein (J. F. Rowell et al., J, Immunol. 155, 473-488, 1995). Here we demonstrate that this tyrosine-based signal interacts with the μ2 (medium) chain of the AP-2 clathrin-associated adaptor, a protein complex involved in endocytosis of cell surface receptors. The same signal is also capable of interacting with two other members of the adaptor medium chain family, μ1 and μ3A, which are components of the AP-1 and AP-3 adaptor complexes, respectively. Interactions with μ1 and μ3A might be responsible for the targeting of the internalized envelope glycoprotein to lysosomes or to the basolateral plasma membrane of polarized epithelial cells. A second potential tyrosine-based signal (LFSYHRL, residues 760-766) also interacts with μ1, μ2, and μ3A, although it is less important for internalization in vivo probably due to its position within the cytosolic tail. Overexpression of chimeric proteins having the HIV-1 Env cytosolic tail increases expression of the transferrin receptor on the cell surface, probably due to saturation of the cellular pool of μ2 by the overexpressed proteins. These observations suggest that HIV-1 Env utilizes the protein sorting machinery of the host cells for internalization and sorting at various steps of the endocytic and biosynthetic pathways.