The Ret finger protein inhibits signaling mediated by the noncanonical and canonical IκB kinase family members

IFN regulatory factor-3 is a transcription factor that is required for the rapid induction of type I IFNs in the innate antiviral response. Two noncanonical I kappa B kinase (IKK) family members, IKK epsilon and TRAF family-associated NF-kappa B activator-binding kinase-1, have been shown to phosphorylate IFN regulatory factor-3 and are critically involved in virus-triggered and TLR3-mediated signaling leading to induction of type I IFNs. In yeast two-hybrid screens for potential IKK epsilon-interacting proteins, we identified Ret finger protein (RFP) as an IKK epsilon-interacting protein. Coimmunoprecipitation experiments indicated that RFP interacted with IKK epsilon and TRAF family-associated NF-kappa B activator-binding kinase-1 as well as the two canonical IKK family members, IKK beta and IKK alpha. RFP inhibited activation of the IFN-stimulated response element and/or NF-kappa B mediated by the IKK family members and triggered by TNF, IL-1, polyinosinic-polycytidylic acid (ligand for TLR3), and viral infection. Moreover, knockdown of RFP expression by RNA interference-enhanced activation of IFN-stimulated response element and/or NF-kappa B triggered by polyinosinic-polycytidylic acid, TNF, and IL-1. Taken together, our findings suggest that RFP negatively regulates signaling involved in the antiviral response and inflammation by targeting the IKKs.