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J. Biol. Chem., Vol. 282, Issue 45, 33132-33141, November 9, 2007

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The PDZ Domain-binding Motif of the Human T Cell Leukemia Virus Type 1 Tax Protein Induces Mislocalization of the Tumor Suppressor hScrib in T cells^*

From the Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Centre National de la Recherche Scientifique/UM 1/UM 2 UMR 5236/IFR 122, Institut de Biologie, 34965 Montpellier, France

Interactions with cellular PDZ domain-containing proteins obviously contribute to the tumorigenic potential of several viral oncoproteins. In this regard, the oncogenic potential of the human T cell leukemia virus type 1 Tax protein correlates with its binding capacity to the tumor suppressor hDlg. Recent results show that hDlg in T cells is associated to a network of scaffolding proteins including another PDZ domain-containing protein termed hScrib. Interestingly, previous studies have revealed complementary activities of both proteins in the control of epithelial cell polarity. Here, we demonstrate that Tax can bind to hScrib and that the resulting Tax/hScrib complex is present in human T cell leukemia virus type 1-infected T cells. By confocal microscopy, we show that Tax modifies the localization of hScrib in transfected COS cells as well as in infected T cell lines and targets hScrib to particular spots exhibiting a granular distribution, mainly distributed in the cytoplasm. Given that Tax sequesters hScrib to these particular structures, we postulate that Tax might inhibit hScrib activity. Providing further support to this idea, we find that transient overexpression of hScrib attenuates T cell receptor-induced NFAT activity but that the presence of Tax counteracts this negative effect on the NFAT pathway. The fact that hDlg and hScrib are both targeted by Tax underlies their importance in T cell function.

Received for publication, March 15, 2007 , and in revised form, August 3, 2007.

^* This work was supported by institutional grants from the Centre National de la Recherche Scientifique and the Université Montpellier 1 and Association pour la Recherche sur le Cancer Grant 3606 (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 To whom correspondence should be addressed: Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, UMR 5236, Institut de Biologie, CS 69033, 4 Bd Henri IV, 34965 Montpellier Cedex 2, France. Tel.: 33-467-600-349; Fax: 33-467-604-420; E-mail: jean-michel.mesnard{at}univ-montp1.fr.

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				I. Clerc, N. Polakowski, C. Andre-Arpin, P. Cook, B. Barbeau, J.-M. Mesnard, and I. Lemasson 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 J. Biol. Chem., August 29, 2008; 283(35): 23903 - 23913. [Abstract] [Full Text] [PDF]