A recurring feature of innate immune receptor signaling is the self-assembly of signaling proteins into oligomeric complexes. The Myddosome is an oligomeric complex that is required to transmit inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for how Myddosome proteins self-assemble and regulate intracellular signaling remains poorly understood. Here, we developed a novel assay to analyze the spatiotemporal dynamics of IL1R and Myddosome signaling in live cells. We found that MyD88 oligomerization is inducible and initially reversible. Moreover, the formation of larger, stable oligomers consisting of more than four MyD88s triggers the sequential recruitment of IRAK4 and IRAK1. Notably, genetic knockout of IRAK4 enhanced MyD88 oligomerization, indicating that IRAK4 controls MyD88 oligomer size and growth. MyD88 oligomer size thus functions as a physical threshold to trigger downstream signaling. These results provide a mechanistic basis for how protein oligomerization might function in cell signaling pathways.

中文翻译：

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MyD88低聚物大小用作触发IL1R Myddosome信号传导的物理阈值。

先天性免疫受体信号转导的重复特征是信号蛋白自组装成寡聚复合物。Myddosome是一种寡聚复合物，是传输TLR / IL1Rs发炎信号所需的寡聚复合物，由MyD88和IRAK家族激酶组成。但是，关于Myddosome蛋白如何自组装和调节细胞内信号转导的分子基础仍然知之甚少。在这里，我们开发了一种新颖的分析方法来分析活细胞中IL1R和Myddosome信号传导的时空动态。我们发现，MyD88寡聚是可诱导的，最初是可逆的。此外，由四个以上MyD88组成的更大，稳定的寡聚物的形成会触发IRAK4和IRAK1的顺序募集。值得注意的是，IRAK4的基因敲除增强了MyD88的寡聚，表明IRAK4控制MyD88低聚物的大小和生长。MyD88寡聚体大小因此充当触发下游信号传导的物理阈值。这些结果为蛋白质寡聚化如何在细胞信号通路中发挥作用提供了机械基础。