NF-κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase

Abstract

The activation of NF‐κB by receptors in the tumor necrosis factor (TNF) receptor and Toll/interleukin‐1 (IL‐1) receptor families requires the TRAF family of adaptor proteins. Receptor oligomerization causes the recruitment of TRAFs to the receptor complex, followed by the activation of a kinase cascade that results in the phosphorylation of IκB. TANK is a TRAF‐binding protein that can inhibit the binding of TRAFs to receptor tails and can also inhibit NF‐κB activation by these receptors. However, TANK also displays the ability to stimulate TRAF‐mediated NF‐κB activation. In this report, we investigate the mechanism of the stimulatory activity of TANK. We find that TANK interacts with TBK1 (TANK‐binding kinase 1), a novel IKK‐related kinase that can activate NF‐κB in a kinase‐dependent manner. TBK1, TANK and TRAF2 can form a ternary complex, and complex formation appears to be required for TBK1 activity. Kinase‐inactive TBK1 inhibits TANK‐mediated NF‐κB activation but does not block the activation mediated by TNF‐α, IL‐1 or CD40. The TBK1–TANK–TRAF2 signaling complex functions upstream of NIK and the IKK complex and represents an alternative to the receptor signaling complex for TRAF‐mediated activation of NF‐κB.