Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB.
Substrate complex competition is a regulatory motif that allows NFκB RelA to license but not amplify NFκB RelB.
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底物复合物竞争是一种监管主题，允许 NFκB RelA 许可但不能放大 NFκB RelB。
DOI：
10.1073/pnas.1816000116
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发表时间：
2019
影响因子：
11.1
通讯作者：
Hoffmann,Alexander
中科院分区：
文献类型：
--
作者：
Mitchell,Simon;Hoffmann,Alexander
信号通路通常共享分子组成部分，将一个通路的活性与另一个通路的功能联系起来。在NFκB信号系统中，不同的激酶分别通过RelA和RelB介导炎症和发育信号。虽然基板的发展，所谓的非经典，途径是由炎症/经典信号，串扰是有限的。通过动力学系统建模，我们确定了潜在的调控机制。我们发现，作为非经典激酶NIK的底物，nfkb 2基因产物p100从单体转变为多聚体复合物，它可能与p100竞争并抑制p52加工成活性p52。尽管已知p100的多聚体复合物（IκBδ）通过螯合作用抑制预先存在的RelA：p50，但在此我们报告p100复合物可以抑制RelB：p52的酶促形成。我们发现，这个复杂的底物竞争基序的剂量-反应系统的属性是不好占标准的米氏动力学，但需要更详细的质量行动配方。总之，尽管紧张性炎症信号传导是非经典途径前体充分表达所必需的，但本文鉴定的底物复合物竞争基序可以防止活性RelB：p52二聚体在升高的炎症条件下扩增，以确保可靠的RelB依赖性发育信号传导独立于炎症环境。
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.