title: Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry: a mechanism to inhibit NF-κB activation and promote immune evasion and virulence.
abstract: 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.
authors.affiliation: Department of Virology, Faculty of Medicine, Imperial College London, St Mary's Campus, London, United Kingdom.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Mansur
authors.forename: Carlos
authors.initials: C
authors.lastname: Maluquer de Motes
authors.forename: Leonie
authors.initials: L
authors.lastname: Unterholzner
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Sumner
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Ferguson
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ren
authors.forename: Pavla
authors.initials: P
authors.lastname: Strnadova
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bowie
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
mesh_terms: D000818:Animals; D002460:Cell Line; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D057131:Immune Evasion; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D012901:Variola virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D014774:Virulence; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase