Innate immune responses, such as cell death and inflammatory signaling, are typically switch-like in nature. They also involve "prion-like" self-templating polymerization of one or more signaling proteins into massive macromolecular assemblies known as signalosomes. Despite the wealth of atomic-resolution structural information on signalosomes, how the constituent polymers nucleate, and whether the switch-like nature of that event at the molecular scale relates to the digital nature of innate immune signaling at the cellular scale, remains unknown. In this perspective, we review current knowledge of innate immune signalosome assembly, with an emphasis on structural constraints that allow the proteins to accumulate in inactive soluble forms poised for abrupt polymerization. We propose that structurally encoded nucleation barriers to protein polymerization kinetically regulate the corresponding pathways, which allows for extremely sensitive, rapid, and decisive signaling upon pathogen detection. We discuss how nucleation barriers satisfy the rigorous on-demand functions of the innate immune system, but also predispose the system to precocious activation that may contribute to progressive age-associated inflammation.

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分子捕鼠器的力学——成核限制的先天免疫信号

先天免疫反应，例如细胞死亡和炎症信号，在本质上通常是类似开关的。它们还涉及将一种或多种信号蛋白“类朊病毒”自模板聚合成称为信号体的大量大分子组装体。尽管关于信号体的原子分辨率结构信息丰富，但组成聚合物如何成核，以及该事件在分子尺度上的开关样性质是否与细胞尺度上先天免疫信号的数字性质有关，仍然未知。从这个角度来看，我们回顾了先天免疫信号体组装的当前知识，重点是结构限制，这些限制允许蛋白质以非活性可溶形式积累，准备突然聚合。我们建议蛋白质聚合的结构编码成核屏障动力学调节相应的途径，这允许在病原体检测时极其敏感、快速和决定性的信号传导。我们讨论了成核屏障如何满足先天免疫系统严格的按需功能，但也使该系统易于发生早熟激活，这可能导致进行性与年龄相关的炎症。