NEMO ensures signaling specificity of the pleiotropic IKKß by directing its kinase activity toward IκBα.

ABSTRACT

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