NEMO Ensures Signaling Specificity of the Pleiotropic IKKβ by Directing Its Kinase Activity toward IκBα

Besides activating NF kappa B by phosphorylating I icBs, IKK alpha/IKK beta kinases are also involved in regulating metabolic insulin signaling, the mTOR pathway, Wnt signaling, and autophagy. How IKK beta enzymatic activity is targeted to stimulus-specific substrates has remained unclear. We show here that NEMO, known to be essential for IKK beta activation by inflammatory stimuli, is also a specificity factor that directs IKK beta activity toward I kappa B alpha. Physical interaction and functional competition studies with mutant NEMO and I kappa B proteins indicate that NEMO functions as a scaffold to recruit I alpha lElot to IKK beta Interestingly, expression of NEMO mutants that allow for IKK beta activation by the cytokine IL-1, but fail to recruit I kappa Bs, results in hyperphosphorylation of alternative IKK beta substrates. Furthermore IKK's function in autophagy, which is independent of NF kappa B, is significantly enhanced without NEMO as I kappa B scaffold. Our work establishes a role for scaffolds such as NEMO in determining stimulus-specific signal transduction via the pleiotropic signaling hub IKK.