Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry
T2 - a mechanism to inhibit NF-κB activation and promote immune evasion and virulence
AU - Mansur, Daniel S.
AU - Maluquer de Motes, Carlos
AU - Unterholzner, Leonie
AU - Sumner, Rebecca P.
AU - Ferguson, Brian J.
AU - Ren, Hongwei
AU - Strnadova, Pavla
AU - Bowie, Andrew G.
AU - Smith, Geoffrey L.
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Line
KW - I-kappa B Kinase
KW - Immune Evasion
KW - Mice
KW - Mice, Inbred BALB C
KW - Molecular Mimicry
KW - Mutagenesis, Site-Directed
KW - NF-kappa B
KW - Phosphorylation
KW - Protein Binding
KW - Ubiquitin-Protein Ligases
KW - Vaccinia virus
KW - Variola virus
KW - Virulence
KW - beta-Transducin Repeat-Containing Proteins
U2 - 10.1371/journal.ppat.1003183
DO - 10.1371/journal.ppat.1003183
M3 - Journal article
C2 - 23468625
VL - 9
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 2
M1 - e1003183
ER -