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

Research output: Contribution to Journal/MagazineJournal articlepeer-review

  • 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
Article numbere1003183
<mark>Journal publication date</mark>02/2013
<mark>Journal</mark>PLoS Pathogens
Issue number2
Publication StatusPublished
<mark>Original language</mark>English


The transcription factor NF-κB is essential for immune responses against pathogens and its activation requires the phosphorylation, ubiquitination and proteasomal degradation of IκBα. Here we describe an inhibitor of NF-κB 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-κB activation by molecular mimicry and contains a motif conserved in IκBα which, in IκBα, is phosphorylated by IKKβ causing ubiquitination and degradation. Like IκBα, A49 binds the E3 ligase β-TrCP, thereby preventing ubiquitination and degradation of IκBα. Consequently, A49 stabilised phosphorylated IκBα (p-IκBα) and its interaction with p65, so preventing p65 nuclear translocation. Serine-to-alanine mutagenesis within the IκBα-like motif of A49 abolished β-TrCP binding, stabilisation of p-IκBα and inhibition of NF-κB activation. Remarkably, despite encoding nine other inhibitors of NF-κB, a VACV lacking A49 showed reduced virulence in vivo.