NEMO ensures signaling specificity of the pleiotropic IKK? by directing its kinase activity toward I?B?.

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

SUBMITTER: Schrofelbauer B 

PROVIDER: S-EPMC3398199 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature