Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection

This chapter opens with a brief overview of the toll-like receptor (TLR)-dependent and -independent pathways of activation. It then focuses on the activation of transcription factors interferon regulatory factors (IRFs) IRF3 and IRF7 by the atypical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1), and IKK-e and their role in the induction of type I interferons (IFNs). The majority of IRFs are involved in distinct aspects of the antiviral response, while two members—IRF4 and IRF8—function mainly as regulators of hematopoiesis in concert with the Ets transcription factor. Importantly, expression of the IKK-related kinases is essential to initiate IRF signaling in response to de novo Sendai virus (SeV), vesicular stomatitis virus (VSV), or measles virus infection, and treatment with RNA interference directed against either IKK-e or TBK1 reduces VSV-inducible IRF3 phosphorylation and IRF-dependent gene expression in human cells. Inhibition of Hsp90 expression by small interfering RNA (siRNA) resulted in an impaired activation of IRF3 following SeV infection. This study proposes that Hsp90 participates in the formation of a complex containing TBK1 and IRF3. In addition to linking TBK1 to the exocyst pathway and Ras-induced transformation, the study demonstrated that the host defense response requires the RalB/Sec5/TBK1 complex following double-stranded RNA (dsRNA) treatment or SeV infection.