Kinetic Control of NF-κB

Science Signaling  23 Jun 2009:
Vol. 2, Issue 76, pp. ec207
DOI: 10.1126/scisignal.276ec207

Nuclear factor κB (NF-κB) is a transcription factor composed of two subunits that interact with each other through the Rel-homology domain (RHD). The mammalian NF-κB family includes five genes encoding NF-κB1 (p50 and its precursor p105), NF-κB2 (p52 and its precursor p100), c-Rel, RelA (p65), and RelB; active transcription complexes include either p50 or p52 and one of c-Rel, RelA, or RelB. Two articles by Hoffmann and colleagues describe regulation of NF-κB activity through the p100 and p105 proteins, which serve the dual roles of inhibitor of κB (IκB) proteins and of precursors for p52 and p50. Savinova et al. used biochemical experiments of cellular or recombinant proteins (with or without various mutations) to determine that p100 and p105 were present in high-molecular-weight complexes, whereas other IκB proteins (IκBα, IκBβ, IκBε) were present in low-molecular-weight complexes. The p100 and p105 high-molecular-weight complexes also included p50, p52, RelA, c-Rel, and RelB. p100 and p105 proteins have both the RHD and an ankyrin repeat domain (ANK), and Savinova et al. found that both of these domains were involved in complex formation. They propose a model whereby p100 or p105 is synthesized and dimerizes through the RHD with either itself (complex I) or another NF-κB molecule (complex II), depending on synthesis rates and abundance of the various subunits. Either of these complexes may then bind preformed NF-κB dimers and inhibit their activity or may be processed to form the transcription factor subunit p52 or p50. The authors propose that the kinetics of the interactions between the RHDs and ANKs controls the availability of NF-κB transcriptional dimers both through regulation of precursor processing and through the action of p100 and p105 as IκBs. By mathematically modeling the activation of NF-κB under conditions lacking either IκBα or the IκB activity of p100 (which they refer to as IκBδ in this context), Shih et al. found that loss of IκBα caused misregulation in response to transient stimuli and that loss of IκBδ caused misregulation of NF-κB in response to prolonged stimuli. These predictions were verified by analyzing the responses of wild-type or IκBδ-deficient or IκBα-deficient cells (in which the RelA/p50 dimer predominates) to either cytokines (trigger a transient NF-κB response) or pathogens (trigger a prolonged NF-κB response). The response to cytokines was enhanced by loss of IκBα, whereas the response to pathogens was enhanced by loss of IκBδ. Additional experiments in which sequential stimuli were applied suggested that IκBδ was necessary for the attenuation of NF-κB signaling to a second stimulus in primed cells (first exposed to a prolonged initial stimulus followed by a rest period, and then subsequently exposed to a second stimulus). Together these two articles provide a framework for understanding the kinetics of NF-κB responses and the molecular mechanisms that produce the temporal regulation.

O. V. Savinova, A. Hoffmann, G. Ghosh, The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol. Cell 34, 591-602 (2009). [PubMed]

V. F.-S. Shih, J. D. Kearns, S. Basak, O. V. Savinova, G. Ghosh, A. Hoffmann, Kinetic control of negative feedback regulators of NF-κB/RelA determines their pathogen- and cytokine-receptor signaling specificity. Proc. Natl. Acad. Sci. U.S.A. 106, 9619-9624 (2009). [Abstract] [Full Text]