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Substrate complex competition – a regulatory motif that allows NFkB RelA to license but not amplify NFkB RelB.pdf (1.69 MB)

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

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posted on 2023-06-09, 18:05 authored by Simon MitchellSimon Mitchell, Alexander Hoffmann
Signaling pathways often share molecular components, tying the activity of one pathway to the functioning of another. In the NF?B 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 (I?Bd) 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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Proceedings of the National Academy of Sciences

ISSN

1091-6490

Publisher

National Academy of Sciences

Issue

21

Volume

116

Page range

10592-10597

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-06-17

First Open Access (FOA) Date

2019-11-02

First Compliant Deposit (FCD) Date

2019-06-17

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