Poxvirus Targeting of E3 Ligase β-TrCP by Molecular Mimicry: A Mechanism to Inhibit NF-ĸB Activation and Promote Immune Evasion and Virulence

Daniel S. Mansur, Carlos Maluquer de Motes, Leonie Unterholzne1r, Rebecca P. SumnerBrian J. Ferguson, Hongwei Ren, Pavla Strnadova, Andrew G. Bowie, Geoffrey L. Smith

PLoS Pathog (2013) 9: e1003183

Speaker: Yi-Sheng Kao (高宜聲)                               Time: 13:10~14:00, Apr.23, 2014

Commentator: Dr. Pin Ling (凌斌 老師)               Place: Room 601

Abstract:

  The nuclear factor kappa B (NF-κB) signaling pathway is an important host immune response to defense pathogen infections. In unstimulated cells, the NF-κB heterodimer p65/p50, is found as an inactive form bound to the inhibitor of κB (IκBα) in the cytoplasm. Upon stimulation, signaling cascades will lead to the phosphorylation of the IκBα by the IκB kinase (IKK) complex. Subsequently, p-IκBα is polyubiquitinated by the E3 ligase β-TrCP and degraded via proteasomes. (1) Then, NF-κB can finally translocate to the nucleus and active responsible genes for host defense. However, viruses have developed various mechanisms to suppress NF-κB mediated host immune responses. For example, the prototypic member of the poxvirus family, vaccinia virus (VACV) (2), expressing many proteins as inhibitors of NF-κB has been reported. Nevertheless, previous study revealed that there are additional VACV proteins as potential NF-κB inhibitor. In this study, the authors found that VACV protein A49 which inhibits the induction of IFNβ promoter can suppress NF-κB activation. They proved that A49 has a mimic motif of IκBα to interact with WD40 domain of E3 ligase β-TrCP. This interaction prevents IκBα from ubiquitination and degradation. Hence, NF-κB retains as inactivate form in the cytoplasm, which reduces host responses to infection. Moreover, VACV lacking A49 shows less virulent than wild type viruses. In conclusion, VACV A49 which is highly conserved in variola virus (3) increases viral virulence by suppressing immune activation.

References:

1.  Hayden, M. et al. (2008) Shared principles in NF-kappaB signaling. Cell 132:344-362.

2.  Gubser C, et al. (2004) Poxvirus genomes: a phylogenetic analysis. J Gen Virol 85: 105–117.

3.  Esposito JJ, et al. (2006) Genome sequence diversity and clues to the evolution of variola virus. Science 313: 807–812.