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Molecular and Cellular Biology, September 1998, p. 5157-5165, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Human T-Cell Leukemia Virus Type 1 Tax Induction of NF-kappa B Involves Activation of the Ikappa B Kinase alpha  (IKKalpha ) and IKKbeta Cellular Kinases

Romas Geleziunas,1,* Sharon Ferrell,1 Xin Lin,1 Yajun Mu,1 Emmett T. Cunningham Jr.,1 Mark Grant,2 Margery A. Connelly,3 John E. Hambor,2 Kenneth B. Marcu,3 and Warner C. Greene1,4

Gladstone Institute of Virology and Immunology1 and Departments of Medicine, Microbiology, and Immunology4 University of California, San Francisco, San Francisco, California 94141-9100; Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, Stony Brook, New York 11794-52153; and Central Research Division, Pfizer Inc., Groton, Connecticut 063402

Received 20 January 1998/Returned for modification 7 March 1998/Accepted 2 June 1998

Tax corresponds to a 40-kDa transforming protein from the pathogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1) that activates nuclear expression of the NF-kappa B/Rel family of transcription factors by an unknown mechanism. Tax expression promotes N-terminal phosphorylation and degradation of Ikappa Balpha , a principal cytoplasmic inhibitor of NF-kappa B. Our studies now demonstrate that HTLV-1 Tax activates the recently identified cellular kinases Ikappa B kinase alpha  (IKKalpha ) and IKKbeta , which normally phosphorylate Ikappa Balpha on both of its N-terminal regulatory serines in response to tumor necrosis factor alpha (TNF-alpha ) and interleukin-1 (IL-1) stimulation. In contrast, a mutant of Tax termed M22, which does not induce NF-kappa B, fails to activate either IKKalpha or IKKbeta . Furthermore, endogenous IKK enzymatic activity was significantly elevated in HTLV-1-infected and Tax-expressing T-cell lines. Transfection of kinase-deficient mutants of IKKalpha and IKKbeta into either human Jurkat T or 293 cells also inhibits NF-kappa B-dependent reporter gene expression induced by Tax. Similarly, a kinase-deficient mutant of NIK (NF-kappa B-inducing kinase), which represents an upstream kinase in the TNF-alpha and IL-1 signaling pathways leading to IKKalpha and IKKbeta activation, blocks Tax induction of NF-kappa B. However, plasma membrane-proximal elements in these proinflammatory cytokine pathways are apparently not involved since dominant negative mutants of the TRAF2 and TRAF6 adaptors, which effectively block signaling through the cytoplasmic tails of the TNF-alpha and IL-1 receptors, respectively, do not inhibit Tax induction of NF-kappa B. Together, these studies demonstrate that HTLV-1 Tax exploits a distal part of the proinflammatory cytokine signaling cascade leading to induction of NF-kappa B. The pathological alteration of this cytokine pathway leading to NF-kappa B activation by Tax may play a central role in HTLV-1-mediated transformation of human T cells, clinically manifested as the adult T-cell leukemia.

* Corresponding author: Mailing address: Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 695-3825. Fax: (415) 826-1514. E-mail: Romas_Geleziunas{at}quickmail.ucsf.edu.

Molecular and Cellular Biology, September 1998, p. 5157-5165, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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