Mechanism of vaccinia viral protein B14-mediated inhibition of IκB kinase β activation

The Journal of Biological Chemistry
Qingyu TangGuozhou Xu

Abstract

Activation of IκB kinase β (IKKβ) is a central event in the NF-κB-mediated canonical pro-inflammatory pathway. Numerous studies have reported that oligomerization-mediated trans autophosphorylation of IKKβ is indispensable for its phosphorylation, leading to its activation and IKKβ-mediated phosphorylation of substrates such as IκB proteins. Moreover, IKKβ's interaction with the NF-κB essential modifier (NEMO) is necessary for IKKβ activation. Interestingly, some viruses encode virulence factors that target IKKβ to inhibit NF-κB-mediated antiviral immune responses. One of these factors is the vaccinia viral protein B14, which directly interacts with and inhibits IKKβ. Here we mapped the interaction interface on the B14 and IKKβ proteins. We observed that B14 binds to the junction of the kinase domain (KD) and scaffold and dimerization domain (SDD) of IKKβ. Molecular docking analyses identified key interface residues in both IKKβ and B14 that were further confirmed by mutational studies to promote binding of the two proteins. During trans autophosphorylation of protein kinases in the IKK complex, the activation segments of neighboring kinases need to transiently interact with each other's active sites, and we found that the B14-...Continue Reading

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Citations

Aug 8, 2018·Viruses·Liyao DengXiaoyue Chen
Apr 17, 2020·Expert Opinion on Biological Therapy·Adrian PelinRagunath Singaravelu
Oct 30, 2020·Frontiers in Immunology·Misbah El-JesrCarlos Maluquer de Motes
Dec 31, 2020·Pathogens·Chathura D SuraweeraMarc Kvansakul
Sep 16, 2021·Journal of Virology·Benjamin E Nilsson-PayantBenjamin R tenOever

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Methods Mentioned

BETA
ubiquitination
transfection
immunoprecipitation
pull down
pulldown
size
light scattering
X-ray
gel filtration
PCR

Software Mentioned

ROSETTA
Cluspro
FRODOCK

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