201: Casine kinase II is a novel regulator of TBK1/IRF3 and type I interferon induction by various innate receptors

Abstract

Upon sensing the presence of viral nucleic acids, multiple pattern recognition receptors (PRRs) can trigger the activation of TBK1 and IRF3, eliciting the induction of type I interferon, whereby initiate host defense mechanisms against invading viruses. To better understand the molecular mechanisms underlying the activation of TBK1 and IRF3 by PRR signals, we sought to identify novel protein kinases involved in type I interferon induction. By screening libraries of small molecular inhibitors and shRNAs targeting protein kinases, we identified serine/threonine kinase CK2 as a novel regulator of type I interferon induction in various PRR signals. Inhibition of CK2 activity or knocking-down of CK2 expression resulted in hyperactivation of TBK1 and IRF3 upon the activation of TLR3/4 as well as cytosolic RNA and DNA sensors by their synthetic ligands or RNA/DNA viruses. Moreover, overexpression of the wild-type but not the kinase-inactive mutant of CK2 attenuated type I interferon induction upon viral infection, further indicating that its kinase activity is required for tamping IFNs induction. Strikingly, blockade of CK2 activity alone was sufficient to activate TBK1 and IRF3, resulting in type I IFN induction in the absence of PRR stimuli. More importantly, blocking CK2 activity was able to efficiently suppress the infection and replication of VSV and HCV, suggesting a new strategy to overcome viral immune evasion mechanisms which target signal molecules upstream of TBK1. Mechanistically, CK2 regulates the activation of TBK1 and IRF3 through its substrate protein phosphatase PP2A. Indeed, PP2A, but not CK2 forms complexes with TBK1 and IRF3, and was also able to diminish TBK1- and IRF3-induced IFN exprssion. Taken together, our results not only identify CK2 as a novel regulator of TBK1 and IRF3 in PRR signals, but also reveal a new strategy to contain viruses which are capable of interfering type I interferon induction by PRRs.