The zinc finger domain of IKK (NEMO) protein in health and disease

Inhibitor of B kinase (IKK) gamma (IKK), also known as nuclear factor B (NF-B) essential modulator (NEMO), is a component of the IKK complex that is essential for the activation of the NF-B pathway. The NF-B pathway plays a major role in the regulation of the expres-sion of genes that are involved in immune response, inflammation, cell adhesion, cell survival and development. As part of the IKK com-plex, IKK plays a regulatory role by linking the complex to upstream signalling molecules. IKK contains two coiled-coil regions, a leucine zipper domain and a highly conserved zinc finger domain. Mutations affecting IKK have been associated with X-linked hypohidrotic ecto-dermal dysplasia with immune deficiency (HED-ID), with the majority of these mutations affecting the C-terminal region of the protein where the zinc finger is located. The zinc finger of IKK is needed for NF-B activation in a cell- and stimulus-specific manner. The major mechanism by which the zinc finger plays this role appears to be the recognition of polyubiquitinated upstream signalling intermediates. This assertion reinforces the current notion that ubiquitination plays a major role in mediating protein–protein interactions in the NF-B signalling pathway. Because the zinc finger domain of IKK is very likely involved in mediating interactions with ubiquitinated proteins, investigations that look for upstream activators or inhibitors of the IKK complex that bind to and interact with the zinc finger of IKK are required to gain a better insight into the exact roles of this domain and into the pathogenesis of HED-ID