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Journal of Virology, May 2006, p. 4227-4241, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4227-4241.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

An Alternative Splice Product of I{kappa}B Kinase (IKK{gamma}), IKK{gamma}-{Delta}, Differentially Mediates Cytokine and Human T-Cell Leukemia Virus Type 1 Tax-Induced NF-{kappa}B Activation

Tao Hai,1 Man-Lung Yeung,2 Thomas G. Wood,3 Yuanfen Wei,3 Shoji Yamaoka,4 Zoran Gatalica,5 Kuan-Teh Jeang,2 and Allan R. Brasier1,3*

Department of Internal Medicine,1 Sealy Center for Molecular Sciences, University of Texas Medical Branch, Galveston, Texas 77555-1060,3 Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0460,2 Department of Microbiology, Tokyo Medical and Dental University, School of Medicine, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan,4 Department of Pathology, Creighton University, Omaha, Nebraska 681315

Received 28 November 2005/ Accepted 8 February 2006

NF-{kappa}B is an inducible transcription factor mediating innate immune responses whose activity is controlled by the multiprotein I{kappa}B kinase (IKK) "signalsome". The core IKK consists of two catalytic serine kinases, IKK{alpha} and IKKß, and a noncatalytic subunit, IKK{gamma}. IKK{gamma} is required for IKK activity by mediating kinase oligomerization and serving to couple the core catalytic subunits to upstream mitogen-activated protein 3-kinase cascades. We have discovered an alternatively spliced IKK{gamma} mRNA isoform, encoding an in-frame deletion of exon 5, termed IKK{gamma}-{Delta}. Using a specific reverse transcription-PCR assay, we find that IKK{gamma}-{Delta} is widely expressed in cultured human cells and normal human tissues. Because IKK{gamma}-{Delta} protein is lacking a critical coiled-coil domain important in protein-protein interactions, we sought to determine its signaling properties by examining its ability to self associate, couple to activators of the canonical pathway, and mediate human T-cell leukemia virus type 1 (HTLV-1) Tax-induced NF-{kappa}B activity. Coimmunoprecipitation and confocal colocalization assays indicate IKK{gamma}-{Delta} has strong homo- and heterotypic association with wild-type (WT) IKK{gamma} and, like IKK{gamma} WT, associates with the IKKß kinase. Similarly, IKK{gamma}-{Delta} mediates IKK kinase activity and downstream NF-{kappa}B-dependent transcription in response to tumor necrosis factor (TNF) and the NF-{kappa}B-inducing kinase-IKK{alpha} signaling pathway. Surprisingly, however, in contrast to IKK{gamma} WT, IKK{gamma}-{Delta} is not able to mediate HTLV-1 Tax-induced NF-{kappa}B-dependent transcription, even though IKK{gamma}-{Delta} binds and colocalizes with Tax. These observations suggest that IKK{gamma}-{Delta} is a functionally distinct alternatively spliced mRNA product differentially mediating TNF-induced, but not Tax-induced, signals converging on the IKK signalsome. Differing levels of IKK{gamma}-{Delta} expression, therefore, may affect signal transduction cascades coupling to IKK.

* Corresponding author. Mailing address: Division of Endocrinology, MRB 8.138, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1060. Phone: (409) 772-2824. Fax: (409) 772-8709. E-mail: arbrasie{at}utmb.edu.

Journal of Virology, May 2006, p. 4227-4241, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4227-4241.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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