A Protein Turnover Signaling Motif Controls the Stimulus-Sensitivity of Stress Response Pathways

Stimulus-induced perturbations from the steady state are a hallmark of signal transduction. In some signaling modules, the steady state is characterized by rapid synthesis and degradation of signaling proteins. Conspicuous among these are the p53 tumor suppressor, its negative regulator Mdm2, and the negative feedback regulator of NFκB, IκBα. We investigated the physiological importance of this turnover, or flux, using a computational method that allows flux to be systematically altered independently of the steady state protein abundances. Applying our method to a prototypical signaling module, we show that flux can precisely control the dynamic response to perturbation. Next, we applied our method to experimentally validated models of p53 and NFκB signaling. We find that high p53 flux is required for oscillations in response to a saturating dose of ionizing radiation (IR). In contrast, high flux of Mdm2 is not required for oscillations but preserves p53 sensitivity to sub-saturating doses of IR. In the NFκB system, degradation of NFκB-bound IκB by the IκB kinase (IKK) is required for activation in response to TNF, while high IKK-independent degradation prevents spurious activation in response to metabolic stress or low doses of TNF. Our work identifies flux pairs with opposing functional effects as a signaling motif that controls the stimulus-sensitivity of the p53 and NFκB stress-response pathways, and may constitute a general design principle in signaling pathways.

由刺激引发的稳态偏移是信号转导过程的标志性特征。在部分信号转导模块中，稳态以信号蛋白的快速合成与降解为典型特征。其中较为突出的包括p53肿瘤抑制蛋白、其负调控因子Mdm2，以及NFκB的负反馈调控因子IκBα。本研究采用一种可独立于稳态蛋白丰度、对通量（flux）进行系统性调控的计算方法，探究了此类蛋白周转的生理学意义。将该方法应用于典型信号转导模块后，我们证实通量可精准调控扰动后的动态响应过程。随后，我们将该方法应用于经实验验证的p53与NFκB信号转导模型。研究发现，当受到饱和剂量电离辐射（IR）刺激时，高p53通量是产生振荡响应的必要条件。与之相反，Mdm2的高通量并非振荡产生的必要条件，但可维持p53对亚饱和剂量电离辐射的敏感性。在NFκB信号系统中，IκB激酶（IKK）介导的NFκB结合型IκB降解，是响应肿瘤坏死因子（TNF）激活的必要条件；而不依赖IKK的高降解通量，则可避免代谢应激或低剂量TNF刺激下的假性激活。本研究揭示了功能效应相反的通量对作为一类信号基序，可调控p53与NFκB应激反应通路的刺激敏感性，或可成为信号转导通路中普遍存在的设计原则。