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J. Biol. Chem., Vol. 283, Issue 22, 15127-15133, May 30, 2008

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In Vitro Activation of the IB Kinase Complex by Human T-cell Leukemia Virus Type-1 Tax^*

Sohini Mukherjee¹, Veera S. Negi¹, Gladys Keitany, Yuetsu Tanaka^¶, and Kim Orth, A Beckman Young Investigator, Burroughs Wellcome Investigator, and C. C. Caruth Biomedical Scholar²

From the Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, University of Washington School of Public Health, Seattle, Washington 98195, and ^¶Department of Immunology, University of the Ryukyus, Uehara 207, Nishihara-cho, Nakagami-gun, Okinawa 903-0215, Japan

Human T-cell leukemia virus type-I expresses Tax, a 40-kDa oncoprotein that activates IB kinase (IKK), resulting in constitutive activation of NFB. Herein, we have developed an in vitro signaling assay to analyze IKK complex activation by recombinant Tax. Using this assay in combination with reporter assays, we demonstrate that Tax-mediated activation of IKK is independent of phosphatases. We show that sustained activation of the Tax-mediated activation of the NFB pathway is dependent on an intact Hsp90-IKK complex. By acetylating and thereby preventing activation of the IKK complex by the Yersinia effector YopJ, we demonstrate that Tax-mediated activation of the IKK complex requires a phosphorylation step. Our characterization of an in vitro signaling assay system for the mechanism of Tax-mediated activation of the IKK complex with a variety of mutants and inhibitors results in a working model for the biochemical mechanism of Tax-induced activation.

Received for publication, June 12, 2007 , and in revised form, January 25, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01-AI056404 and R21-DK072134 from NIAID. This work was also supported by the Welch Research Foundation (I-1561). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148. Tel.: 214-648-1685; Fax: 214-648-1488; E-mail: Kim.Orth{at}utsouthwestern.edu.

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