Dr Zihang Zhu

Postgraduate Research Student
+44 (0)1483 686568
33 BC 02

Academic and research departments


Pallett Mitchell A., Ren Hongwei, Zhang Rui-Yao, Scutts Simon R., Gonzalez Laura, Zhu Zihang, Maluquer de Motes Carlos, Smith Geoffrey L., Shisler Joanna L. (2019) Vaccinia Virus BBK E3 Ligase Adaptor A55 Targets Importin-Dependent NF-ºB Activation and Inhibits CD8+ T-Cell Memory,Journal of Virology93(10) American Society for Microbiology
Viral infection of cells is sensed by pathogen recognition receptors that trigger an antiviral innate immune response, and consequently viruses have evolved countermeasures. Vaccinia virus (VACV) evades the host immune response by expressing scores of immunomodulatory proteins. One family of VACV proteins are the BTB-BACK (broad-complex, tram-trac, and bric-a-brac [BTB] and C-terminal Kelch [BACK]) domain-containing, Kelch-like (BBK) family of predicted cullin-3 E3 ligase adaptors: A55, C2, and F3. Previous studies demonstrated that gene A55R encodes a protein that is nonessential for VACV replication yet affects viral virulence in vivo. Here, we report that A55 is an NF-ºB inhibitor acting downstream of IºB± degradation, preventing gene transcription and cytokine secretion in response to cytokine stimulation. A55 targets the host importin ±1 (KPNA2), acting to reduce p65 binding and its nuclear translocation. Interestingly, while A55 was confirmed to coprecipitate with cullin-3 in a BTB-dependent manner, its NF-ºB inhibitory activity mapped to the Kelch domain, which alone is sufficient to coprecipitate with KPNA2 and inhibit NF-ºB signaling. Intradermal infection of mice with a virus lacking A55R (v”A55) increased VACV-specific CD8+ T-cell proliferation, activation, and cytotoxicity in comparison to levels of the wild-type (WT) virus. Furthermore, immunization with v”A55 induced increased protection to intranasal VACV challenge compared to the level with control viruses. In summary, this report describes the first target of a poxvirus-encoded BBK protein and a novel mechanism for DNA virus immune evasion, resulting in increased CD8+ T-cell memory and a more immunogenic vaccine.