Article

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

University of California, Davis, Davis, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2007; 282(16):12119-26. DOI: 10.1074/jbc.M610392200
Source: PubMed

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.

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    • "Tax binds IKKγ in a region two heptads downstream of HLX2 termed coiled-coil region 2 (CCR2). When Tax binds this region, it exposes the HLX2 domain for PP2A binding and simultaneously inactivates PP2A, preventing it from dissociating, resulting in IKK being constitutively active[158,159]. Tax also has the ability to form complexes with NF-κB monomers in the cytoplasm. "
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    • "While HIV-1 Vpr, Adenovirus E4orf, and hepatitis C virus NS5A proteins induce cell cycle arrest and apoptosis by binding PP2A (Georgopoulou et al., 2006; Li et al., 2009; Godet et al., 2010), PP2A inactivation by Epstein-Barr virus EBNA-LP protects against apoptosis (Garibal et al., 2007). HTLV-I Tax and HPV E7 protein also binds and inactivates PP2A, but the biological consequences for the viral life cycle remain unknown (Pim et al., 2005; Hong et al., 2007). "
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    • "Conflicting data about the contribution of PP2A in modulating NFκB activity exist, while most of the reports connect inhibition of PP2A to NFκB activation [10,28-32]. Less evidence exists suggesting IKK-PP2A complex formation to be a prerequisite for TNF-induced phosphorylation of IKKβ and degradation of IκBα [33]. "
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