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Vol. 18, Issue 2, 414-425, February 2007

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A Conserved Dileucine Motif Mediates Clathrin and AP-2–dependent Endocytosis of the HIV-1 Envelope Protein

Rahel Byland^*, Patricia J. Vance, James A. Hoxie, and Mark Marsh^*

*Cell Biology Unit, MRC-Laboratory for Molecular Cell Biology and Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom; and Hematology-Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104

Submitted June 19, 2006; Revised November 3, 2006; Accepted November 6, 2006
Monitoring Editor: Jean Gruenberg

During the assembly of enveloped viruses viral and cellular components essential for infectious particles must colocalize at specific membrane locations. For the human and simian immunodeficiency viruses (HIV and SIV), sorting of the viral envelope proteins (Env) to assembly sites is directed by trafficking signals located in the cytoplasmic domain of the transmembrane protein gp41 (TM). A membrane proximal conserved GYxxØ motif mediates endocytosis through interaction with the clathrin adaptor AP-2. However, experiments with SIV_mac239 Env indicate the presence of additional signals. Here we show that a conserved C-terminal dileucine in HIV_HxB2 also mediates endocytosis. Biochemical and morphological assays demonstrate that the C-terminal dileucine motif mediates internalization as efficiently as the GYxxØ motif and that both must be removed to prevent Env internalization. RNAi experiments show that depletion of the clathrin adaptor AP-2 leads to increased plasma membrane expression of HIV Env and that this adaptor is required for efficient internalization mediated by both signals. The redundancy of conserved endocytosis signals and the role of the SIV_mac239 Env GYxxØ motif in SIV pathogenesis, suggest that these motifs have functions in addition to endocytosis, possibly related to Env delivery to the site of viral assembly and/or incorporation into budding virions.

Address correspondence to: Mark Marsh (m.marsh{at}ucl.ac.uk)

Abbreviations used: Env, envelope glycoprotein; gp, glycoprotein; HIV, human immunodeficiency virus; SIV, simian immunodeficiency virus; SU, surface subunit of the viral envelope glycoprotein; TM, transmembrane subunit of the viral envelope glycoprotein.

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