Vaccinia Virus BBK E3 Ligase Adaptor A55 Targets Importin-Dependent NF-κB Activation and Inhibits CD8+ T-Cell Memory.

Journal of Virology
Mitchell A PallettGeoffrey L Smith

Abstract

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-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, while A55 was confirmed to coprecipitate with cullin-3 in a BTB-dependent manner, its NF-κB inhibitory activity mapped to the Kelch domain, which alone is sufficient to coprecipitate with KPNA2 and inhibit NF-κB signaling. Intradermal infection of mice with a virus lacking A55R (vΔA55) increased VACV-specifi...Continue Reading

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Citations

Apr 17, 2020·Expert Opinion on Biological Therapy·Adrian PelinRagunath Singaravelu
Feb 27, 2020·The Journal of General Virology·Sarah NeidelGeoffrey L Smith
Oct 30, 2020·Frontiers in Immunology·Misbah El-JesrCarlos Maluquer de Motes
Dec 3, 2020·Pathogens·Justyna Struzik, Lidia Szulc-Dąbrowska
Jun 8, 2021·The Journal of Biological Chemistry·Qingtang ShenAlexander F Palazzo
Aug 29, 2021·Pathogens·Sian Lant, Carlos Maluquer de Motes

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Methods Mentioned

BETA
acetylation
enzyme-linked immunosorbent assay
ELISA
PMA
nuclear translocation
immunoprecipitation
transfection
co-IP
fluorescence-activated cell sorting
tandem

Software Mentioned

FlowJo
Odyssey
Zeiss Zen
GraphPad Prism
ImageJ

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