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First published online July 30, 2004
doi: 10.1242/10.1242/jcs.01266

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Human Dlg protein binds to the envelope glycoproteins of human T-cell leukemia virus type 1 and regulates envelope mediated cell-cell fusion in T lymphocytes

¹ Département Biologie Cellulaire, CNRS UMR 8104 and INSERM U567, Institut Cochin, 22 rue Méchain, 75014 Paris, France
² Département Maladies Infectieuses, CNRS UMR 8104 and INSERM U567, Institut Cochin, 22 rue Méchain, 75014 Paris, France
³ Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif CEDEX, France
⁴ Department of Pharmacology and Cancer Center, University of Illinois College of Medicine, Chicago, IL 60607, USA
⁵ CNRS UPR 9051, Hôpital St.-Louis, 75475 Paris CEDEX 10, France

^* Authors for correspondence (e-mail: vblot{at}cochin.inserm.fr; pique{at}chu-stlouis.fr)

Accepted 13 April 2004

Human homologue of the Drosophila Dlg tumor suppressor (hDlg) is a widely expressed scaffold protein implicated in the organization of multi-protein complexes at cell adhesion sites such as the neuronal synapse. hDlg contains three PDZ domains that mediate its binding to the consensus motifs present at the C-termini of various cell surface proteins, thus inducing their clustering and/or stabilization at the plasma membrane. Using a yeast two-hybrid screen, we identified hDlg as a cellular binding partner of a viral membrane integral protein, the envelope glycoprotein (Env) of human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 is a human retrovirus that infects CD4+ T lymphocytes and is preferentially transmitted via direct contacts between infected and target cells, through a structure referred to as the virological synapse. Here, we demonstrate that hDlg interacts with a classical PDZ domain-binding motif present at the C-terminus of the cytoplasmic domain of HTLV-1 Env and conserved in the related HTLV-2 virus. We further document that, in HTLV-1 infected primary T cells, hDlg and Env are concentrated in restricted areas of the plasma membrane, enriched in molecules involved in T-cell contacts. The presence of Gag proteins responsible for viral assembly and budding in these areas indicated that they constitute platforms for viral assembly and transmission. Finally, a mutant virus unable to bind hDlg exhibited a decreased ability to trigger Env mediated cell fusion between T lymphocytes. We thus propose that hDlg stabilizes HTLV-1 envelope glycoproteins at the virological synapse formed between infected and target cells, hence assisting the cell-to-cell transmission of the virus.

Key words: hDlg, Retrovirus, Envelope, Cell-to-cell transmission, Virological synapse

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