IKK gamma (NEMO) is involved in the coordination of the AP-1 and NF-kappa B pathways

Tumor necrosis factor alpha (TNF alpha) activates the nuclear factor-kappaB (NF-kappa B) pathway in various cell types, leading to expression of cell survival and inflammatory proteins. One mechanism of cell survival brought about by NF-kappa B is the inhibition of Activator Protein-1 (AP-1), which when activated, could lead to cell death. However, TNFalpha can also induce the AP-1 pathway, and the mechanisms by which these two pathways are regulated in response to TNF alpha are poorly understood. We proposed that Inhibitor of kappa B Kinase gamma (IKK gamma) (which is also known as NF-kappa B essential modulator, NEMO) plays a key role in integrating and coordinating these two pathways. Our results showed that IKK gamma activates the AP-1 pathway, via a mechanism that is dependent on the first leucine zipper (LZ) domain of IKK gamma, by interacting with two proteins of the AP-1 complex, c-Jun and c-Fos, and changing the phosphorylation status of c-Jun. Even though IKK gamma is required for the activation of NF-kappa B, we found that it reduced the activity of NF-kappa B when it was overexpressed. In summary, we demonstrated that transfected IKK gamma, while inhibiting the NF-kappa B pathway, directly interacts with the AP-1 proteins and activates the AP-1 pathway independent of its effects on NF-kappa B. Our results indicate that IKK gamma regulates TNF alpha signaling by coordinating cell responses mediated by the AP-1 and NF-kappa B pathways.