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

Mansur, Daniel S. and Maluquer de Motes, Carlos and Unterholzner, Leonie and Sumner, Rebecca P. and Ferguson, Brian J. and Ren, Hongwei and Strnadova, Pavla and Bowie, Andrew G. and Smith, Geoffrey 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. ISSN 1553-7366

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.