NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation.
Torres, Alice A
Proceedings of the National Academy of Sciences of the United States of America
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Neidel, S., Ren, H., Torres, A. A., & Smith, G. (2019). NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation.. Proceedings of the National Academy of Sciences of the United States of America, 116 (12), 5699-5704. https://doi.org/10.1073/pnas.1813504116
Vaccinia virus protein A49 inhibits NF-κB activation by molecular mimicry and has a motif close to the N terminus that is conserved in IκBα, β-catenin, HIV vpu and other proteins. This motif contains 2 conserved serines and, for IκBα and β-catenin, phosphorylation of these serines enables recognition by the E3 ubiquitin ligase β-TrCP. Binding of IκBα and β-catenin to β-TrCP leads to their ubiquitylation at upstream lysines and thereafter proteasomemediated degradation. In contrast, HIV vpu and VACV A49 lack these lysines and so are not degraded. This report demonstrates that A49 is phosphorylated at serine 7, but not serine 12, and that this is necessary and sufficient for binding β-TrCP and antagonism of NF-κB activation. Phosphorylation of A49 S7 occurs when NF- κB signaling is activated by addition of IL-1β, or overexpression of TRAF6 or IKKβ, the kinase needed for IκBα phosphorylation and activation of NF-κB signaling. Thus A49 shows beautiful biological regulation for it becomes an NF-κB antagonist upon activation of NF-κB signaling. The virulence of viruses expressing mutant A49 proteins, or lacking A49 (vΔA49), were tested. vΔA49 was attenuated compared to wild type, as reported previously, but viruses expressing A49 that cannot bind β-TrCP, or that binds β-TrCP constitutively, each had intermediate virulence. Therefore, A49 promotes virulence by inhibiting NF-κB activation and by another unknown mechanism independent of S7 phosphorylation and NF- κB antagonism. Lastly, a virus lacking A49 was a more potent vaccine than wild type virus.
Humans, Vaccinia virus, Ubiquitin-Protein Ligases, beta-Transducin Repeat-Containing Proteins, NF-kappa B, Phosphoproteins, Viral Proteins, Virulence, Signal Transduction, Molecular Mimicry, Phosphorylation, I-kappa B Proteins, I-kappa B Kinase, Ubiquitination, Feedback, Physiological
Wellcome Trust (090315/B/09/Z)
External DOI: https://doi.org/10.1073/pnas.1813504116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289404