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Originally published In Press as doi:10.1074/jbc.C000777200 on April 26, 2001

J. Biol. Chem., Vol. 276, Issue 27, 24445-24448, July 6, 2001
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ACCELERATED PUBLICATION
Persistent Activation of NF-kappa B by the Tax Transforming Protein Involves Chronic Phosphorylation of Ikappa B Kinase Subunits IKKbeta and IKKgamma *

Robert S. Carter, Brian C. Geyer, Minhui Xie, Carlos A. Acevedo-Suárez, and Dean W. BallardDagger

From the Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0295

The Tax transforming protein encoded by human T-cell leukemia virus type 1 (HTLV1) persistently activates transcription factor NF-kappa B and deregulates the expression of downstream genes that mediate cell cycle entry. We recently found that Tax binds to and chronically stimulates the catalytic function of Ikappa B kinase (IKK), a cellular enzyme complex that phosphorylates and inactivates the Ikappa B inhibitory subunit of NF-kappa B. We now demonstrate that the IKKbeta catalytic subunit and IKKgamma regulatory subunit of IKK are chronically phosphorylated in HTLV1-infected and Tax-transfected cells. Alanine substitutions at Ser-177 and Ser-181 in the T loop of IKKbeta protect both of these IKK subunits from Tax-directed phosphorylation and prevent the induction of Ikappa B kinase activity. Each of these inhibitory effects is recapitulated in Tax transfectants expressing the bacterial protein YopJ, a potent in vivo agonist of T loop phosphorylation. Moreover, ectopically expressed forms of IKKbeta that contain glutamic acid substitutions at Ser-177 and Ser-181 have the capacity to phosphorylate a recombinant IKKgamma substrate in vitro. We conclude that Tax-induced phosphorylation of IKKbeta is required for IKKbeta activation, phosphoryl group transfer to IKKgamma , and acquisition of the deregulated IKK phenotype.

* This study was supported by National Institutes of Health Grant RO1 CA82556 (to D. W. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Vanderbilt University School of Medicine, A4301 Medical Center N., Nashville, TN 37232-0295. Tel.: 615-343-1548; Fax: 615-343-5743; E-mail: dean.ballard@mcmail.vanderbilt.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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