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

Abstract

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