FAF1 Suppresses IκB Kinase (IKK) Activation by Disrupting the IKK Complex Assembly

Abstract

This study presents a molecular inhibitory mechanism by Fas-associated factor 1 (FAF1) on IκB kinase (IKK) activation, where divergent NF-κB-activating stimuli converge. FAF1 interacts with IKKβ in response to proinflammatory stimuli (such as tumor necrosis factor-α, interleukin-1β, and lipopolysaccharide) and suppresses IKK activation. Interaction of the leucine-zipper domain of IKKβ with FAF1 affected the IKK heterocomplex (IKKα/β) and homocomplex (IKKα/α, IKKβ/β) formations and attenuated IKKγ recruitment to IKKβ. Overexpression of FAF1 reduced the level of IKKβ activity, whereas FAF1 depletion increased the activity. These results indicate that FAF1 inhibits IKK activation and its downstream signaling by interrupting the IKK complex assembly through physical interaction with IKKβ. Taken together, FAF1 robustly suppresses NF-κB activation through the inhibition of IKK activation in combination with previously reported cytoplasmic retention of NF-κB p65 (Park, M. Y., Jang, H. D., Lee, S. Y., Lee, K. J., and Kim, E. (2004) J. Biol. Chem. 279, 2544–2549). Such redundant suppression would prevent inadvertent activation of the NF-κB pathway.