Severe liver degeneration and lack of NF-κB activation in NEMO/IKKγ-deficient mice

Phosphorylation of I kappa B, an inhibitor of NF-kappa B, is an important step in the activation of the transcription factor NF-kappa B. Phosphorylation is mediated by the I kappa B kinase (IKK) complex, known to contain two catalytic subunits: IKK alpha and IKK beta. A novel, noncatalytic component of this kinase complex called NEMO (NF-kappa B essential modulator)/IKK gamma was identified recently. We have generated NEMO/IKK gamma-deficient mice by gene targeting. Mutant embryos die at E12.5-E13.0 from severe liver damage due to apoptosis. NEMO/ IKK gamma-deficient primary murine embryonic fibroblasts (MEFs) lack detectable NF-kappa B DNA-binding activity in response to TNF alpha, IL-1, LPS, and Poly(IC) and do not show stimulus-dependent I kappa B kinase activity, which correlates with a lack of phosphorylation and degradation of I kappa B alpha. Consistent with these data, mutant MEFs show increased sensitivity to TNF alpha-induced apoptosis. Our data provide in vivo evidence that NEMO/IKK gamma is the first essential, noncatalytic component of the IKK complex.