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In this study, Tegethoff et al. (2003) investigated the role of IkB kinase gamma (IKKgamma), also known as NEMO, in the activation of the IKK complex and NF-kB signaling. They showed that IKKgamma forms a tetramer in vivo and in vitro, and that this tetrameric structure is essential for the interaction with IKKalpha and IKKbeta subunits, as well as for the phosphorylation and activation of the IKK complex. They also demonstrated that mutations or deletions that disrupt the tetramerization of IKKgamma impair the NF-kB response to various stimuli, such as TNF-alpha, IL-1beta, and LPS. Their findings suggest that IKKgamma acts as a scaffold protein that mediates the assembly and activation of the IKK complex, which in turn regulates the nuclear translocation and transcriptional activity of NF-kB.
The IKK complex consists of two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma. The IKK complex is responsible for the phosphorylation and degradation of IkB proteins, which are inhibitors of NF-kB. NF-kB is a transcription factor that regulates the expression of genes involved in inflammation, immunity, cell survival, and oncogenesis. The activation of NF-kB is tightly controlled by various extracellular and intracellular signals, such as cytokines, pathogens, oxidative stress, and DNA damage.
Previous studies have shown that IKKgamma is indispensable for the activation of the IKK complex and NF-kB in response to most stimuli. However, the molecular mechanism by which IKKgamma regulates the IKK complex activity and NF-kB signaling was unclear. Tegethoff et al. (2003) used biochemical and genetic approaches to elucidate the role of IKKgamma in the formation and function of the IKK complex. They found that IKKgamma contains a coiled-coil domain that mediates its tetramerization through intermolecular disulfide bonds. They also identified several amino acid residues that are critical for the tetramerization of IKKgamma and its interaction with IKKalpha and IKKbeta.
By using site-directed mutagenesis and gene knock-in techniques, Tegethoff et al. (2003) generated several mutant forms of IKKgamma that were defective in tetramerization or binding to IKKalpha and IKKbeta. They expressed these mutants in mouse embryonic fibroblasts (MEFs) that lacked endogenous IKKgamma and examined their effects on the IKK complex activity and NF-kB activation. They found that all mutants that disrupted the tetramerization of IKKgamma failed to restore the IKK complex activity and NF-kB response in IKKgamma-deficient MEFs. Moreover, some mutants that impaired the binding of IKKgamma to IKKalpha or IKKbeta also showed reduced or abolished IKK complex activity and NF-kB activation. These results indicate that the tetrameric oligomerization of IKKgamma is a prerequisite for its interaction with IKKalpha and IKKbeta, and that these interactions are essential for the phosphorylation and activation of the IKK complex and NF-kB. 061ffe29dd