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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

Mansur, DS, Maluquer de Motes, C, Unterholzner, L, Sumner, RP, Ferguson, BJ, Ren, H, Strnadova, P, Bowie, AG and Smith, GL (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 Pathog, 9 (2).

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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.

Item Type: Article
Authors :
NameEmailORCID
Mansur, DSUNSPECIFIEDUNSPECIFIED
Maluquer de Motes, Cc.maluquerdemotes@surrey.ac.ukUNSPECIFIED
Unterholzner, LUNSPECIFIEDUNSPECIFIED
Sumner, RPUNSPECIFIEDUNSPECIFIED
Ferguson, BJUNSPECIFIEDUNSPECIFIED
Ren, HUNSPECIFIEDUNSPECIFIED
Strnadova, PUNSPECIFIEDUNSPECIFIED
Bowie, AGUNSPECIFIEDUNSPECIFIED
Smith, GLUNSPECIFIEDUNSPECIFIED
Date : February 2013
Identification Number : https://doi.org/10.1371/journal.ppat.1003183
Uncontrolled Keywords : Animals, Cell Line, I-kappa B Kinase, Immune Evasion, Mice, Mice, Inbred BALB C, Molecular Mimicry, Mutagenesis, Site-Directed, NF-kappa B, Phosphorylation, Protein Binding, Ubiquitin-Protein Ligases, Vaccinia virus, Variola virus, Virulence, beta-Transducin Repeat-Containing Proteins
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:01
Last Modified : 17 May 2017 14:46
URI: http://epubs.surrey.ac.uk/id/eprint/826040

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