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

The activation of NF-kappa B by receptors in the tumor necrosis factor (TNF ) receptor and Toll/interleukin-1 (IL-1) receptor families requires the TRA F family of adaptor proteins. Receptor oligomerization causes the recruitme nt of TRAFs to the receptor complex, followed by the activation of a kinase cascade that results in the phosphorylation of I kappa B. TANK is a TRAF-b inding protein that can inhibit the binding of TRAFs to receptor tails and can also inhibit NF-kappa B activation by these receptors, However, TANK al so displays the ability to stimulate TRAF-mediated NF-kappa B activation, I n this report, we investigate the mechanism of the stimulatory activity of TANK, We find that TANK interacts with TBK1 (TANK-binding kinase 1), a nove l IKK-related kinase that can activate NF-kappa B in a kinase-dependent man ner. TBK1, TANK and TRAF2 can form a ternary complex, and complex formation appears to be required for TBK1 activity. Kinase-inactive TBK1 inhibits TA NK-mediated NF-kappa B activation but does not block the activation mediate d by TNF-alpha, IL-1 or CD40. The TBK1-TANK-TRAF2 signaling complex functio ns upstream of NIK and the IKK complex and represents an alternative to the receptor signaling complex for TRAF-mediated activation of NF-kappa B.