Qian Li, Zhenhua Zheng, Yan Liu, Zhenfeng Zhang, Qingshi Liu, Jin Meng, Xianliang Ke, Qinxue Hu and Hanzhong Wang
J Virol. 2016 Apr 29;90(10):5141-51. doi: 10.1128/JVI.03021-15. Print 2016 May 15.
The NF-κB signaling network, which is an ancient signaling pathway, plays a pivotal role in innate immunity that constitutes a first line of defense against invading pathogens including viruses. However, numerous viruses possess evolved strategies to antagonize the activation of NF-κB signaling pathway. Our previous study demonstrated that the nonstructural protein 2C of enterovirus 71 (EV71), which is the major pathogen of hand-foot-and-mouth disease, inhibits TNFα-mediated activation of NF-κB by suppressing IκB kinase β (IKKβ) phosphorylation. Nevertheless, the mechanism underlying the inhibition of IKKβ phosphorylation by EV71 2C remains largely elusive. We demonstrated that EV71 2C interacts with all isoforms of protein phosphatase 1 (PP1) catalytic subunit (PP1α, PP1β and PP1γ) through PP1 docking motifs. EV71 2C has no influences on subcellular localization of PP1. In addition, the PP1-binding-deficient EV71 2C mutant 3E3L nearly completely lose the ability to suppress IKKβ phosphorylation and markedly restore NF-κB activation, thereby indicating that PP1-binding is efficient for EV71 2C-mediated inhibition of IKKβ phosphorylation and NF-κB activation. We further demonstrated that 2C forms a complex with PP1 and IKKβ to dephosphorylate IKKβ. Notably, we revealed that other human enteroviruses including poliovirus (PV), Coxsackie A virus 16 (CVA16), and Coxsackie B virus 3 (CVB3), use 2C proteins to recruit PP1, leading to the inhibition of IKKβ phosphorylation. Our findings indicate that enteroviruses exploit a novel mechanism to inhibit IKKβ phosphorylation by recruiting PP1 and IKKβ to form a complex through 2C proteins, which ultimately results in the inhibition of NF-κB signaling pathway.