Transcription factor NF-kB is activated by proinflammatory stimuli (IL-1, TNF, LPS, bacterial and viral infections) and, in turn, induces transcription of genes coding for mediators of immune and inflammatory responses. NF-kB is regulated by binding to the IkBs, inhibitors that retain it in the cytoplasm of non-stimulated cells. In response to proinflammatory stimuli, the IkBs are rapidly phosphorylated and degraded allowing NF-kB to translocate to the nucleus and induce gene transcription. The investigator has purified a large (900 kDa) protein kinase complex, IKK(IkB kinase), which mediated IkB phosphorylation and NF-kB activation in response to TNF and IL-1. Two of the IKK subunits were molecularly cloned. These proteins, IKKa and IKKb, are serine kinases that interact through leucine zippers and contact important regulatory subunits through helix-loop-helix (HLH) motifs. To complete the characterization of IKK and understand how it functions, he will purify and clone the remaining subunits, which will be expressed, purified and used to reconstitute the entire complex. He will study which IKK components are involved in activation and regulation of its IkB kinase activity and how they interact with IkBa. Using gene targeting techniques, he will generate mutant mice that are deficient either in expression of IKKa and IKKb or in their catalytic functions. He will use these mice to study the physiological functions of IKKa and IKKb, whether they mediate NF-kB activation in response to all known proinflammatory stimuli and whether they are responsible for phosphorylation of all IkB types. The phenotypes of these mice will also indicate whether IKKa and IKKb always function together and whether they regulate targets other than NF-kB. The investigator will also create mice with activating mutations in IKKa or IKKb, which may be prone to development of autoimmune and inflammatory disorders and thus provide useful disease models. He will study the role of protein phosphorylation in IKK activation and identify IKK kinases. He will investigate the signaling pathways leading from the IL-1 and TNF receptors to IKK by focusing on events occurring downstream to the recruitment of TRAF signal transducers.
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