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Journal of Virology, December 2007, p. 13735-13742, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01790-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-{kappa}B Activation{triangledown}

Noula Shembade,1 Nicole S. Harhaj,1 Masahiro Yamamoto,2 Shizuo Akira,2 and Edward W. Harhaj1*

Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, the University of Miami, Miller School of Medicine, Miami, Florida 33136,1 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan2

Received 27 July 2007/ Accepted 2 October 2007

Ubiquitination of the human T-cell leukemia virus 1 Tax oncoprotein provides an important regulatory mechanism that promotes the Tax-mediated activation of NF-{kappa}B. However, the type of polyubiquitin chain linkages and the host factors that are required for Tax ubiquitination have not been identified. Here, we demonstrate that Tax polyubiquitin chains are composed predominantly of lysine 63-linked chains. Furthermore, the ubiquitination of Tax is critically dependent on the E2 ubiquitin-conjugating enzyme Ubc13. Tax interacts with Ubc13, and small interfering RNA-mediated knockdown of Ubc13 expression abrogates Tax ubiquitination and the activation of NF-{kappa}B. Mouse fibroblasts lacking Ubc13 exhibit impaired Tax activation of NF-{kappa}B despite normal tumor necrosis factor- and interleukin-1-mediated NF-{kappa}B activation. Finally, the interaction of Tax with NEMO is disrupted in the absence of Tax ubiquitination and Ubc13 expression, suggesting that Tax ubiquitination is critical for NEMO binding. Collectively, our results reveal that Ubc13 is essential for Tax ubiquitination, its interaction with NEMO, and Tax-mediated NF-{kappa}B activation.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, the University of Miami, Miller School of Medicine, 1550 NW 10 Avenue, Miami, FL 33136. Phone: (305) 243-7893. Fax: (305) 243-6410. E-mail: eharhaj{at}med.miami.edu

{triangledown} Published ahead of print on 17 October 2007.

Journal of Virology, December 2007, p. 13735-13742, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01790-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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