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

Journal of Biological Chemistry(2018)

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摘要
Activation of IB kinase (IKK) is a central event in the NF-B-mediated canonical pro-inflammatory pathway. Numerous studies have reported that oligomerization-mediated trans autophosphorylation of IKK is indispensable for its phosphorylation, leading to its activation and IKK-mediated phosphorylation of substrates such as IB proteins. Moreover, IKK's interaction with the NF-B essential modifier (NEMO) is necessary for IKK activation. Interestingly, some viruses encode virulence factors that target IKK to inhibit NF-B-mediated antiviral immune responses. One of these factors is the vaccinia viral protein B14, which directly interacts with and inhibits IKK. Here we mapped the interaction interface on the B14 and IKK proteins. We observed that B14 binds to the junction of the kinase domain (KD) and scaffold and dimerization domain (SDD) of IKK. Molecular docking analyses identified key interface residues in both IKK 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-IKK interaction sterically hinders direct contact between the kinase domains of IKK in the IKK complex, containing IKK, IKK, and NEMO in human cells. We conclude that binding of B14 to IKK prevents IKK trans autophosphorylation and activation, thereby inhibiting NF-B signaling. Our study provides critical structural and mechanistic information for the design of potential therapeutic agents to target IKK activation for the management of inflammatory disorders.
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关键词
molecular docking,autophosphorylation,protein kinase,virus,inhibition mechanism,B14,IKKβ, protein kinase,trans autophosphorylation,vaccinia virus
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