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Journal of Virology, March 2001, p. 2982-2992, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2982-2992.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Highly Conserved C-Terminal Dileucine Motif in the Cytosolic Domain of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Is Critical for Its Association with the AP-1 Clathrin Adapter

Stéphanie Wyss,1,dagger Clarisse Berlioz-Torrent,2 Michael Boge,1 Guillaume Blot,2 Stefan Höning,3 Richard Benarous,2,* and Markus Thali1,4,*

Institute of Microbiology, University of Lausanne, CH-1011 Lausanne, Switzerland1; CJF 97/03 INSERM, Institut Cochin de Génétique Moléculaire, 75014 Paris, France2; Biochemistry II, University of Goettingen, 37073 Goettingen, Germany3; and Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 054054

Received 8 November 2000/Accepted 13 December 2000

Short amino acid sequences in the cytosolic domains of transmembrane proteins are recognized by specialized adapter proteins which are part of coated vesicles utilized to transport membrane proteins between the trans-Golgi network (TGN) and the plasma membrane (forward and backward). Previously, we and others reported that the membrane-proximal tyrosine residues Y712 (human immunodeficiency virus [HIV]) and Y721 (simian immunodeficiency virus [SIV]) in the envelope glycoprotein (Env) of the primate lentiviruses are crucial for the association of Env with clathrin-associated adapter complex AP-2. The same tyrosine-based endocytosis motifs in the cytosolic domains (EnvCD) of transmembrane gp41 of HIV type 1 (HIV-1) and SIV, respectively, were also shown to modulate the interaction with TGN- and endosome-based clathrin-associated complex AP-1. Our findings suggested that EnvCD binding to AP-1, unlike the association of EnvCD with AP-2, is dependent largely on residues other than Y712 and Y721. Here, we tested if motifs downstream of Y712 affect HIV-1 EnvCD-AP-1 binding and Env trafficking. Mutational analysis revealed that the C-terminal leucine-based motif in Env was crucial for the recruitment of AP-1 in vitro and in Env-expressing cells. In addition to affecting Env-AP-1 association, mutations at the C terminus of Env also altered the subcellular localization of Env, suggesting that proper post-Golgi routing of Env depends on its recruitment of AP-1. Finally, the C-terminal dileucine was shown to assist the membrane-proximal Y712 motif in restricting the cell surface expression of Env.

* Corresponding author. Mailing address for Richard Benarous: INSERM Unit 529, Interactions Moléculaires Hôte-Pathogène, Institut Cochin de Génétique Moléculaire, 24 Rue du Fg. St-Jaques, 75014 Paris, France. Phone: 33 1 44 41 25 65. Fax: 33 1 44 41 23 99. E-mail: benarous{at}icgm.cochin.inserm.fr. Mailing address for Markus Thali: University of Vermont, Department of Microbiology and Molecular Genetics, 320 Stafford Hall, Burlington, VT 05405. Phone: (802) 656-1056. Fax: (802) 656-8749. E-mail: markus.thali{at}uvm.edu.

dagger Present address: University of Pennsylvania, Department of Hematology-Oncology, Philadelphia, PA 19104.

Journal of Virology, March 2001, p. 2982-2992, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2982-2992.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.