Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry: a mechanism to inhibit NF-κB activation and promote immune evasion and virulence

Daniel S. Mansur, Carlos Maluquer de Motes, Leonie Unterholzner, Rebecca P. Sumner, Brian J. Ferguson, Hongwei Ren, Pavla Strnadova, Andrew G. Bowie, Geoffrey L. Smith

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    Abstract

    The transcription factor NF-?B is essential for immune responses against pathogens and its activation requires the phosphorylation, ubiquitination and proteasomal degradation of I?Ba. Here we describe an inhibitor of NF-?B from vaccinia virus that has a closely related counterpart in variola virus, the cause of smallpox, and mechanistic similarity with the HIV protein Vpu. Protein A49 blocks NF-?B activation by molecular mimicry and contains a motif conserved in I?Ba which, in I?Ba, is phosphorylated by IKKß causing ubiquitination and degradation. Like I?Ba, A49 binds the E3 ligase ß-TrCP, thereby preventing ubiquitination and degradation of I?Ba. Consequently, A49 stabilised phosphorylated I?Ba (p-I?Ba) and its interaction with p65, so preventing p65 nuclear translocation. Serine-to-alanine mutagenesis within the I?Ba-like motif of A49 abolished ß-TrCP binding, stabilisation of p-I?Ba and inhibition of NF-?B activation. Remarkably, despite encoding nine other inhibitors of NF-?B, a VACV lacking A49 showed reduced virulence in vivo.
    Original languageEnglish
    Article numbere1003183
    JournalPLoS Pathogens
    Volume9
    Issue number2
    DOIs
    Publication statusPublished - 28 Feb 2013

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    Mansur, D. S., Maluquer de Motes, C., Unterholzner, L., Sumner, R. P., Ferguson, B. J., Ren, H., Strnadova, P., Bowie, A. G., & Smith, G. L. (2013). Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry: a mechanism to inhibit NF-κB activation and promote immune evasion and virulence. PLoS Pathogens, 9(2), [e1003183]. https://doi.org/10.1371/journal.ppat.1003183