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J. Biol. Chem., Vol. 282, Issue 16, 12119-12126, April 20, 2007

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Heptad Repeats Regulate Protein Phosphatase 2A Recruitment to I-B Kinase /NF-B Essential Modulator and Are Targeted by Human T-lymphotropic Virus Type 1 Tax^*

Sohee Hong, Ling-Chi Wang¹, Xiang Gao, Yu-Liang Kuo, Baoying Liu, Randall Merling, Hsing-Jien Kung^¶, Hsiu-Ming Shih¹, and Chou-Zen Giam²

From the Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, the Division of Molecular and Genomic Medicine, National Health Research Institutes, 128, Sec 2, Yen-Chiu-Yuan Road, Taipei 115, Taiwan, and the ^¶University of California Davis Cancer Center, Sacramento, California 95817

The switching on-and-off of I-B kinase (IKK) and NF-B occurs rapidly after signaling. How activated IKK becomes down-regulated is not well understood. Here we show that following tumor necrosis factor- stimulation, protein phosphatase 2A (PP2A) association with IKK is increased. A heptad repeat in IKK, helix 2 (HLX2), mediates PP2A recruitment. Two other heptad repeats downstream of HLX2, termed coiled-coil region 2 (CCR2) and leucine zipper (LZ), bind HLX2 and negatively regulate HLX2 interaction with PP2A. HTLV-1 transactivator Tax also binds HLX2, and this interaction is enhanced by CCR2 but reduced by LZ. In the presence of Tax, PP2A-IKK binding is greatly strengthened. Interestingly, peptides spanning CCR2 and/or LZ disrupt IKK-Tax and IKK-PP2A interactions and potently inhibit NF-B activation by Tax and tumor necrosis factor-. We propose that when IKK is resting, HLX2, CCR2, and LZ form a helical bundle in which HLX2 is sequestered. The HLX2-CCR2-LZ bundle becomes unfolded by signal-induced modifications of IKK or after Tax binding. In this conformation, IKK becomes activated. IKK then recruits PP2A via the exposed HLX2 domain for rapid down-regulation of IKK. Tax-PP2A interaction, however, renders PP2A inactive, thus maintaining Tax-PP2A-IKK in an active state. Finally, CCR2 and LZ possibly inhibit IKK activation by stabilizing the HLX2-CCR2-LZ bundle.

Received for publication, November 7, 2006 , and in revised form, January 16, 2007.

^* This work was supported by grants from the National Institutes of Health and a grant from the United States Military Cancer Institute (to C.-Z. G.). 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 Present address: Institute of Biomedical Sciences, Academia Sinica, 128, Sec 2, Yen-Chiu-Yuan Road, Taipei 115, Taiwan.

² To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Tel.: 301-295-9624; Fax: 301-295-1545; E-mail: cgiam{at}usuhs.mil.

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