Heptad repeats regulate protein phosphatase 2A recruitment to I-kappa B kinase gamma/NF-kappa B essential modulator and are targeted by human T-lymphotropic virus type 1 tax
ABSTRACT 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.
- SourceAvailable from: Ugo Moens
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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). "
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 · 3.28 Impact Factor
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- "Other viral oncoproteins, including E7 from HPV-16, E1A from adenovirus-5, HBx from Hepatitis-B and Tax from HTLV-1, also induce supernumerary centrosomes (De Luca et al., 2003; Duensing and Munger, 2003; Fujii et al., 2006; Nitta et al., 2006). As E7, E1A and Tax bind to PP2A and affect its phosphatase activity (Liao and Hung, 2004; Pim et al., 2005; Hong et al., 2007), PP2A disruption may represent a shared mechanism for deregulating centrosome replication by viral oncoproteins. "
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- "Following stimulation by either endogenous or viral stimuli, IKKg would unfold into an open conformation representing the activated form in which the previously sequestered groups become accessible. These hypotheses are entirely consistent with the conformation of IKKg that we observe, leading us to propose a mechanism for ks-vFLIP-induced NF-kB constitutive activation comparable to that put forward for Tax (Hong et al., 2007). In our model (Figures 6C–6E), IKKg in an inactive, helical bundle conformation (that may or may not be further stabilized by "
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