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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, Smith GL - PLoS Pathog. (2013)

Bottom Line: 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.Remarkably, despite encoding nine other inhibitors of NF-κB, a VACV lacking A49 showed reduced virulence in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Faculty of Medicine, Imperial College London, St Mary's Campus, London, United Kingdom.

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.

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Related in: MedlinePlus

Inhibition of NF-κB activation by A49.Model depicting how poxvirus protein A49 interferes with activation of the transcription factor NF-κB by targeting the E3 ligase β-TrCP and thus preventing the degradation of IκBα.
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ppat-1003183-g008: Inhibition of NF-κB activation by A49.Model depicting how poxvirus protein A49 interferes with activation of the transcription factor NF-κB by targeting the E3 ligase β-TrCP and thus preventing the degradation of IκBα.

Mentions: Here, the VACV WR A49 protein is shown to be an inhibitor of innate immune signalling by blocking NF-κB activation. A49 was identified as an inhibitor of IFNβ expression in a screen of VACV proteins encoded near the genome termini, and dissection of the mechanism by which A49 inhibited IFNβ activation showed that A49 blocked NF-κB activation by binding to the WD40 domain of the E3 ubiquitin ligase β-TrCP (Figure 4 and 5). Thus, even though IκBα was phosphorylated by upstream kinases, β-TrCP-mediated ubiquitination of p-IκBα was reduced, p-IκBα was stabilised in complex with NF-κB and so NF-κB was retained in the cytosol (Figure 8).


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, Smith GL - PLoS Pathog. (2013)

Inhibition of NF-κB activation by A49.Model depicting how poxvirus protein A49 interferes with activation of the transcription factor NF-κB by targeting the E3 ligase β-TrCP and thus preventing the degradation of IκBα.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585151&req=5

ppat-1003183-g008: Inhibition of NF-κB activation by A49.Model depicting how poxvirus protein A49 interferes with activation of the transcription factor NF-κB by targeting the E3 ligase β-TrCP and thus preventing the degradation of IκBα.
Mentions: Here, the VACV WR A49 protein is shown to be an inhibitor of innate immune signalling by blocking NF-κB activation. A49 was identified as an inhibitor of IFNβ expression in a screen of VACV proteins encoded near the genome termini, and dissection of the mechanism by which A49 inhibited IFNβ activation showed that A49 blocked NF-κB activation by binding to the WD40 domain of the E3 ubiquitin ligase β-TrCP (Figure 4 and 5). Thus, even though IκBα was phosphorylated by upstream kinases, β-TrCP-mediated ubiquitination of p-IκBα was reduced, p-IκBα was stabilised in complex with NF-κB and so NF-κB was retained in the cytosol (Figure 8).

Bottom Line: 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.Remarkably, despite encoding nine other inhibitors of NF-κB, a VACV lacking A49 showed reduced virulence in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology, Faculty of Medicine, Imperial College London, St Mary's Campus, London, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus