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
The switching on-and-off of I-kappaB kinase (IKK) and NF-kappaB occurs rapidly after signaling. How activated IKK becomes down-regulated is not well understood. Here we show that following tumor necrosis factor-alpha stimulation, protein phosphatase 2A (PP2A) association with IKK is increased. A heptad repeat in IKKgamma, 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-IKKgamma binding is greatly strengthened. Interestingly, peptides spanning CCR2 and/or LZ disrupt IKKgamma-Tax and IKKgamma-PP2A interactions and potently inhibit NF-kappaB activation by Tax and tumor necrosis factor-alpha. 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 IKKgamma or after Tax binding. In this conformation, IKK becomes activated. IKKgamma 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.
Available from: Ugo Moens
- "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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ABSTRACT: Polyomaviruses are naked viruses with an icosahedral capsid that surrounds a circular double-stranded DNA molecule of about 5000 base-pairs. Their genome encodes at least five proteins: large and small tumor antigens and the capsid proteins VP1, VP2 and VP3. The tumor antigens are expressed during early stages of the viral life cycle and are implicated in the regulation of viral transcription and DNA replication, while the capsid proteins are produced later during infection. Members of the Polyomaviridae family have been isolated in birds (Avipolyomavirus) and mammals (Orthopolyomavirus and Wukipolyomavirus). Some mammalian polyomaviruses encode an additional protein, referred to as agnoprotein, which is a relatively small polypeptide that exerts multiple functions. This review discusses the structure, post-translational modifications, and functions of agnoprotein, and speculates why not all polyomaviruses express this protein.
Virology 06/2012; 432(2):316-26. DOI:10.1016/j.virol.2012.05.024 · 3.32 Impact Factor
Available from: Thomas Sauter
- "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 . "
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ABSTRACT: Biological effects of nuclear factor-kappaB (NF kappaB) can differ tremendously depending on the cellular context. For example, NF kappaB induced by interleukin-1 (IL-1) is converted from an inhibitor of death receptor induced apoptosis into a promoter of ultraviolet-B radiation (UVB)-induced apoptosis. This conversion requires prolonged NF kappaB activation and is facilitated by IL-1 + UVB-induced abrogation of the negative feedback loop for NF kappaB, involving a lack of inhibitor of kappaB (I kappaB alpha) protein reappearance. Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha.
To investigate the mechanism underlying the general PP2A-mediated tuning of IKK beta phosphorylation upon IL-1 stimulation, we have developed a strictly reduced mathematical model based on ordinary differential equations which includes the essential processes concerning the IL-1 receptor, IKK beta and PP2A. Combining experimental and modelling approaches we demonstrate that constitutively active, but not post-stimulation activated PP2A, tunes out IKK beta phosphorylation thus allowing for I kappaB alpha resynthesis in response to IL-1. Identifiability analysis and determination of confidence intervals reveal that the model allows reliable predictions regarding the dynamics of PP2A deactivation and IKK beta phosphorylation. Additionally, scenario analysis is used to scrutinize several hypotheses regarding the mode of UVB-induced PP2Ac inhibition. The model suggests that down regulation of PP2Ac activity, which results in prevention of I kappaB alpha reappearance, is not a direct UVB action but requires instrumentality.
The model developed here can be used as a reliable building block of larger NF kappa B models and offers comprehensive simplification potential for future modeling of NF kappa B signaling. It gives more insight into the newly discovered mechanisms for IKK deactivation and allows for substantiated predictions and investigation of different hypotheses. The evidence of constitutive activity of PP2Ac at the IKK complex provides new insights into the feedback regulation of NF kappa B, which is crucial for the development of new anti-cancer strategies.
BMC Systems Biology 08/2009; 3(1):71. DOI:10.1186/1752-0509-3-71 · 2.44 Impact Factor
Available from: yu-liang Kuo
- "HTLV-1 encodes a 40 kDa trans-activator, Tax, which plays a crucial role in viral replication and cell transformation [1-3]. Tax activates the expression of viral and cellular genes by interacting with a variety of host cell factors [4,5] including transcription factors CREB/ATF [6-9], transcriptional co-activators CBP/p300 [10-14], and the regulatory subunit of the I-κB kinase, IKKγ [15-20]. "
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ABSTRACT: HTLV-1 Tax can induce senescence by up-regulating the levels of cyclin-dependent kinase inhibitors p21(CIP1/WAF1) and p27(KIP1). Tax increases p27(KIP1) protein stability by activating the anaphase promoting complex/cyclosome (APC/C) precociously, causing degradation of Skp2 and inactivation of SCF(Skp2), the E3 ligase that targets p27(KIP1). The rate of p21(CIP1/WAF1) protein turnover, however, is unaffected by Tax. Rather, the mRNA of p21(CIP1/WAF1) is greatly up-regulated. Here we show that Tax increases p21 mRNA expression by transcriptional activation and mRNA stabilization. Transcriptional activation of p21(CIP1/WAF1) by Tax occurs in a p53-independent manner and requires two tumor growth factor-beta-inducible Sp1 binding sites in the -84 to -60 region of the p21(CIP1/WAF1) promoter. Tax binds Sp1 directly, and the CBP/p300-binding activity of Tax is required for p21(CIP1/WAF1) trans-activation. Tax also increases the stability of p21(CIP1/WAF1) transcript. Several Tax mutants trans-activated the p21 promoter, but were attenuated in stabilizing p21(CIP1/WAF1) mRNA, and were less proficient in increasing p21(CIP1/WAF1) expression. The possible involvement of Tax-mediated APC/C activation in p21(CIP1/WAF1) mRNA stabilization is discussed.
Retrovirology 05/2009; 6(1):35. DOI:10.1186/1742-4690-6-35 · 4.19 Impact Factor
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