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

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)12119-12126
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number16
DOIs
Publication statusPublished - Apr 20 2007
Externally publishedYes

Fingerprint

Protein Phosphatase 2
Human T-lymphotropic virus 1
Taxation
Leucine Zippers
Viruses
Modulators
Phosphotransferases
tax Gene Products
Tumor Necrosis Factor-alpha
Chemical activation
Trans-Activators
Conformations
Down-Regulation
Association reactions
Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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

In: Journal of Biological Chemistry, Vol. 282, No. 16, 20.04.2007, p. 12119-12126.

Research output: Contribution to journalArticle

Hong, Sohee ; Wang, Ling Chi ; Gao, Xiang ; Kuo, Yu Liang ; Liu, Baoying ; Merling, Randall ; Kung, Hsing Jien ; Shih, Hsiu Ming ; Giam, Chou Zen. / 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. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 16. pp. 12119-12126.
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T1 - 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

AU - Hong, Sohee

AU - Wang, Ling Chi

AU - Gao, Xiang

AU - Kuo, Yu Liang

AU - Liu, Baoying

AU - Merling, Randall

AU - Kung, Hsing Jien

AU - Shih, Hsiu Ming

AU - Giam, Chou Zen

PY - 2007/4/20

Y1 - 2007/4/20

N2 - 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.

AB - 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.

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