Vaccinia Virus BBK E3 Ligase Adaptor A55 Targets Importin-Dependent NF-κB Activation and Inhibits CD8+ T-Cell Memory.
Scutts, Simon R
Journal of virology
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Pallett, M. A., Ren, H., Zhang, R., Scutts, S. R., Gonzalez, L., Zhu, Z., Maluquer de Motes, C., & et al. (2019). Vaccinia Virus BBK E3 Ligase Adaptor A55 Targets Importin-Dependent NF-κB Activation and Inhibits CD8+ T-Cell Memory.. Journal of virology, 93 (10)https://doi.org/10.1128/jvi.00051-19
Viral infection of cells is sensed by pathogen recognition receptors that trigger an anti-viral 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 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 non-essential for VACV replication yet affects viral virulence in vivo. Here we report that A55 is an NF-κB inhibitor acting downstream of IκBα degradation, preventing gene transcription and cytokine secretion in response to cytokine stimulation. A55 targets the host importin α1 (KPNA2), acting to reduce p65 binding and its nuclear translocation. Interestingly, whilst A55 was confirmed to co-precipitate with cullin-3 in a BTB-dependent manner, its NF-κB inhibitory activity mapped to the Kelch domain, which alone is sufficient to co-precipitate with KPNA2 and inhibit NF-κB signalling. Intradermal infection of mice with a virus lacking A55R (vΔA55) increased VACV-specific CD8+ T-cell proliferation, activation, and cytotoxicity in comparison to the WT virus. Furthermore, immunisation with vΔA55 induced increased protection to intranasal VACV challenge compared to 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.
T-Lymphocytes, Cell Line, Animals, Mice, Inbred C57BL, Humans, Mice, Poxviridae, Vaccinia virus, Vaccinia, Ubiquitin-Protein Ligases, Cullin Proteins, Karyopherins, alpha Karyopherins, NF-kappa B, Viral Proteins, Virus Replication, Virulence, Signal Transduction, Female, Immunity, Innate, Immune Evasion, HEK293 Cells, BTB-POZ Domain, Kelch Repeat
Wellcome Trust (090315/B/09/Z)
External DOI: https://doi.org/10.1128/jvi.00051-19
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289689