The NF-κB signaling network， which is an ancient signaling pathway， plays a pivotal role in innate immunity and constitutes a first line of defense against invading pathogens， including viruses. However， numerous viruses possess evolved strategies to antagonize the activation of the 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 tumor necrosis factor alpha (TNF-α)-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 ... More
The NF-κB signaling network， which is an ancient signaling pathway， plays a pivotal role in innate immunity and constitutes a first line of defense against invading pathogens， including viruses. However， numerous viruses possess evolved strategies to antagonize the activation of the 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 tumor necrosis factor alpha (TNF-α)-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 demonstrate that EV71 2C interacts with all isoforms of the protein phosphatase 1 (PP1) catalytic subunit (the PP1α， PP1β， and PP1γ isoforms) through PP1-docking motifs. EV71 2C has no influence on the subcellular localization of PP1. In addition， the PP1-binding-deficient EV71 2C mutant 3E3L nearly completely lost the ability to suppress IKKβ phosphorylation and NF-κB activation was markedly restored in the mutant， thereby indicating that PP1 binding is efficient for EV71 2C-mediated inhibition of IKKβ phosphorylation and NF-κB activation. We further demonstrate that 2C forms a complex with PP1 and IKKβ to dephosphorylate IKKβ. Notably， we reveal 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 the NF-κB signaling pathway.
