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

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 - 2013/2/28

Y1 - 2013/2/28

N2 - The transcription factor NF-?B is essential for immune responses against pathogens and its activation requires the phosphorylation, ubiquitination and proteasomal degradation of I?Ba. Here we describe an inhibitor of NF-?B 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-?B activation by molecular mimicry and contains a motif conserved in I?Ba which, in I?Ba, is phosphorylated by IKKß causing ubiquitination and degradation. Like I?Ba, A49 binds the E3 ligase ß-TrCP, thereby preventing ubiquitination and degradation of I?Ba. Consequently, A49 stabilised phosphorylated I?Ba (p-I?Ba) and its interaction with p65, so preventing p65 nuclear translocation. Serine-to-alanine mutagenesis within the I?Ba-like motif of A49 abolished ß-TrCP binding, stabilisation of p-I?Ba and inhibition of NF-?B activation. Remarkably, despite encoding nine other inhibitors of NF-?B, a VACV lacking A49 showed reduced virulence in vivo.

AB - The transcription factor NF-?B is essential for immune responses against pathogens and its activation requires the phosphorylation, ubiquitination and proteasomal degradation of I?Ba. Here we describe an inhibitor of NF-?B 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-?B activation by molecular mimicry and contains a motif conserved in I?Ba which, in I?Ba, is phosphorylated by IKKß causing ubiquitination and degradation. Like I?Ba, A49 binds the E3 ligase ß-TrCP, thereby preventing ubiquitination and degradation of I?Ba. Consequently, A49 stabilised phosphorylated I?Ba (p-I?Ba) and its interaction with p65, so preventing p65 nuclear translocation. Serine-to-alanine mutagenesis within the I?Ba-like motif of A49 abolished ß-TrCP binding, stabilisation of p-I?Ba and inhibition of NF-?B activation. Remarkably, despite encoding nine other inhibitors of NF-?B, a VACV lacking A49 showed reduced virulence in vivo.

U2 - 10.1371/journal.ppat.1003183

DO - 10.1371/journal.ppat.1003183

M3 - Article

C2 - 23468625

SN - 1553-7366

VL - 9

JO - PLoS Pathogens

JF - PLoS Pathogens

IS - 2

M1 - e1003183

ER -