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J. Biol. Chem., Vol. 283, Issue 35, 23903-23913, August 29, 2008

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An Interaction between the Human T Cell Leukemia Virus Type 1 Basic Leucine Zipper Factor (HBZ) and the KIX Domain of p300/CBP Contributes to the Down-regulation of Tax-dependent Viral Transcription by HBZ^*

Isabelle Clerc^¶12, Nicholas Polakowski^||2, Charlotte André-Arpin^¶, Pamela Cook^||, Benoit Barbeau^**, Jean-Michel Mesnard^¶3, and Isabelle Lemasson^||4

From the Université Montpellier 1 and CNRS, UM5236, Centre d'Études d'Agents Pathogènes et Biotechnologies pour la Santé (CPBS), Montpellier F-34965, France, ^¶Université Montpellier 2, CPBS, Montpellier F-34095, France, the ^||Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, and the ^**Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Québec H2X 3X8, Canada

Activation of human T cell leukemia virus type 1 (HTLV-1) transcription is established through the formation of protein complexes on the viral promoter that are essentially composed of the cellular basic leucine zipper (bZIP) transcription factor cAMP-response element-binding protein (CREB (or certain other members of the ATF/CREB family), the HTLV-1-encoded transactivator Tax, and the pleiotropic cellular coactivators p300/CBP. HTLV-1 bZIP factor (HBZ) is a protein encoded by HTLV-1 that contains a bZIP domain and functions to repress HTLV-1 transcription. HBZ has been shown to repress viral transcription by dimerizing with CREB, which occurs specifically through the bZIP domain in each protein, and preventing CREB from binding to the DNA. However, we previously found that HBZ causes only partial removal of CREB from a chromosomally integrated viral promoter, and more importantly, an HBZ mutant lacking the COOH-terminal bZIP domain retains the ability to repress viral transcription. These results suggest that an additional mechanism contributes to HBZ-mediated repression of HTLV-1 transcription. In this study, we show that HBZ binds directly to the p300 and CBP coactivators. Two LXXLL-like motifs located within the NH₂-terminal region of HBZ are important for this interaction and specifically mediate binding to the KIX domain of p300/CBP. We provide evidence that this interaction interferes with the ability of Tax to bind p300/CBP and thereby inhibits the association of the coactivators with the viral promoter. Our findings demonstrate that HBZ utilizes a bipartite mechanism to repress viral transcription.

Received for publication, April 23, 2008 , and in revised form, July 2, 2008.

^* This work was supported by a Research Development Grant Program Award from East Carolina University (to I. C.) and by institutional grants from CNRS and the Université Montpellier 1 (UM 1) and grants from the Association pour la Recherche sur le Cancer (Grant 3606), the Fondation Recherche Médicale (Comité Languedoc), and the Ligue Contre le Cancer (Comitéde l'Hérault) (to J. M. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the Agence Nationale de Recherche sur le SIDA (ANRS).

² These authors contributed equally to this work.

³ To whom correspondence may be addressed: CS 69033, Institut de Biologie, CPBS, 4 Bd. Henri IV, 34965 Montpellier Cedex 2, France. Tel.: 33-467-608-660; Fax: 33-467-604-420; E-mail: jean-michel.mesnard{at}univ-montp1.fr ⁴ To whom correspondence may be addressed: Dept. of Microbiology and Immunology, Brody School of Medicine, East Carolina University, 600 Moye Blvd., Greenville, NC 27834. Tel.: 252-744-2706; Fax: 252-744-3104; E-mail: lemassoni{at}ecu.edu.

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