Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-κB Activation through TBK1

Abstract

The IKK complex, which is composed of two catalytic subunits, IKKα and IKKβ, has been suggested to be essential for the activation of canonical NF-κB signaling in response to various stimuli, including cytokines (e.g., interleukin-1α [IL-1α] and tumor necrosis factor alpha [TNF-α]), Toll-like receptor (TLR) ligands (e.g., lipopolysaccharide [LPS]), and dsRNAs derived from viruses, or a synthetic analog. STING has been identified as a critical signaling molecule required for the detection of cytosolic dsDNAs derived from pathogens and viruses. However, little is known about how cytosolic dsDNA triggers NF-κB signaling. In the present study, we demonstrate that TBK1, identified as an IKK-related kinase, may predominantly control the activation of NF-κB in response to dsDNA signaling via STING through the IKKαβ activation loop. Thus, our results establish TBK1 as a downstream kinase controlling dsDNA-mediated IRF3 and NF-κB signaling dependent on STING.