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J. Biol. Chem., Vol. 279, Issue 41, 43307-43320, October 8, 2004

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A 10-Amino Acid Domain within Human T-cell Leukemia Virus Type 1 and Type 2 Tax Protein Sequences Is Responsible for Their Divergent Subcellular Distribution^*

Laurent Meertens¶, Sébastien Chevalier, Robert Weil||, Antoine Gessain, and Renaud Mahieux**

From the Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur and ^||Unité de Biologie Moléculaire de l'Expression Génique, FRE 2364 CNRS, Institut Pasteur, 75724 Paris Cedex 15, France

Human T-cell leukemia virus type 1 and type 2 (HTLV-1/2) are related retroviruses that infect T-lymphocytes. Whereas HTLV-1 infection can cause leukemia, HTLV-2 has not been demonstrated to be the agent of a hematological malignant disease. Nevertheless, the virally encoded Tax-1 and Tax-2 transactivators display a high percentage of similarity. Tax-1 is a shuttling protein that contains a noncanonical nuclear localization signal as well as a nuclear export signal. The presence of the nuclear localization signal and the nuclear export signal domains in the Tax-2 sequence has not been determined. The distribution of Tax-2 in infected cells is not known but has been assumed to be similar to that of Tax-1. By using a Tax-2-specific antibody, we report here that Tax-2 is located predominantly in the cytoplasm of the HTLV-2 immortalized or transformed infected T-cells. These results were confirmed after transient transfection of untagged Tax-1 and Tax-2 constructs, histidine tag Tax1/Tax2, GFP-Tax, and Tax-GFP fusion constructs in several cell lines. We show that this unanticipated localization is not due to a default in the Tax-2 nuclear localization signal functions nor to major differences in Tax-2 versus Tax-1 binding to the IKK/NEMO protein. In addition, we demonstrate that inhibiting the proteasome results in a relocalization of Tax-1 in the cytoplasm, similar to that of Tax-2. By using a series of Tax-1/Tax-2 chimeras, we determined that the minimal domain that is necessary for Tax-2 peculiar distribution encompasses amino acids 90-100. Finally, we show a high correlation between intracellular localization of Tax and their NF-B or CREB transactivating ability.

Received for publication, January 16, 2004 , and in revised form, July 1, 2004.

^* This work was supported in part by l'Association de Recherche sur le Cancer Grant 4781 and ARECA (to R. M.) and le Ministère de la Recherche (to L. M. and S. C.), CANAM, and Pasteur Weizmann fellowships (to L. 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. 9.

Both authors contributed equally to this work.

^¶ To whom correspondence may be addressed: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel.: 33-1-45-68-89-06; Fax: 33-1-40-61-34-65; E-mail: meertens{at}pasteur.fr.

^** Supported by INSERM. To whom correspondence may be addressed: Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France. Tel.: 33-1-45-68-89-06; Fax: 33-1-40-61-34-65; E-mail: rmahieux{at}pasteur.fr.

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