Substrate complex competition – a regulatory motif that allows NFkB RelA to license but not amplify NFkB RelB

Mitchell, Simon and Hoffmann, Alexander (2019) Substrate complex competition – a regulatory motif that allows NFkB RelA to license but not amplify NFkB RelB. Proceedings of the National Academy of Sciences, 116 (21). pp. 10592-10597. ISSN 1091-6490

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Signaling pathways often share molecular components, tying the activity of one pathway to the functioning of another. In the NFκB signaling system, distinct kinases mediate inflammatory and developmental signaling via RelA and RelB, respectively. Although the substrates of the developmental, so-called noncanonical, pathway are induced by inflammatory/canonical signaling, crosstalk is limited. Through dynamical systems modeling, we identified the underlying regulatory mechanism. We found that as the substrate of the noncanonical kinase NIK, the nfkb2 gene product p100, transitions from a monomer to a multimeric complex, it may compete with and inhibit p100 processing to the active p52. Although multimeric complexes of p100 (IκBδ) are known to inhibit preexisting RelA:p50 through sequestration, here we report that p100 complexes can inhibit the enzymatic formation of RelB:p52. We show that the dose–response systems properties of this complex substrate competition motif are poorly accounted for by standard Michaelis–Menten kinetics, but require more detailed mass action formulations. In sum, although tonic inflammatory signaling is required for adequate expression of the noncanonical pathway precursors, the substrate complex competition motif identified here can prevent amplification of the active RelB:p52 dimer in elevated inflammatory conditions to ensure reliable RelB-dependent developmental signaling independent of inflammatory context.

Item Type: Article
Keywords: FkB canonical pathway, NFkB non-canonical pathway, inflammation, 2 immune development, crosstalk, math model, substrate competition, Michaelis-Menten, 3 mass action, systems biology.
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: R Medicine
Depositing User: Gemma Hamilton
Date Deposited: 17 Jun 2019 11:09
Last Modified: 02 Nov 2019 02:00

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