Heptad repeats regulate protein phosphatase 2A recruitment to I-κB kinase γ/NF-κB essential modulator and are targeted by human T-lymphotropic virus type 1 tax

Sohee Hong, Ling Chi Wang, Xiang Gao, Yu Liang Kuo, Baoying Liu, Randall Merling, Hsing Jien Kung, Hsiu Ming Shih, Chou Zen Giam

研究成果: 雜誌貢獻文章同行評審

24 引文 斯高帕斯(Scopus)

摘要

The switching on-and-off of I-κB kinase (IKK) and NF-κB occurs rapidly after signaling. How activated IKK becomes down-regulated is not well understood. Here we show that following tumor necrosis factor-α stimulation, protein phosphatase 2A (PP2A) association with IKK is increased. A heptad repeat in IKKγ, 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-IKKγ binding is greatly strengthened. Interestingly, peptides spanning CCR2 and/or LZ disrupt IKKγ-Tax and IKKγ-PP2A interactions and potently inhibit NF-κB activation by Tax and tumor necrosis factor-α. 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 IKKγ or after Tax binding. In this conformation, IKK becomes activated. IKKγ 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.
原文英語
頁(從 - 到)12119-12126
頁數8
期刊Journal of Biological Chemistry
282
發行號16
DOIs
出版狀態已發佈 - 四月 20 2007
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 分子生物學
  • 細胞生物學

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