Max Planck Institute for Infection Biology, Berlin, Germany.
J Cell Biol. 2021 Jul 5;220(7). doi: 10.1083/jcb.202012071. Epub 2021 May 6.
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.
天然免疫受体信号传递的一个反复出现的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，是从 TLR/IL1Rs 传递炎症信号所必需的，由 MyD88 和 IRAK 家族激酶组成。然而，Myddosome 蛋白如何自组装和调节细胞内信号的分子基础仍知之甚少。在这里，我们开发了一种新的测定法来分析活细胞中 IL1R 和 Myddosome 信号的时空动力学。我们发现 MyD88 寡聚化是可诱导的，最初是可逆的。此外，由超过四个 MyD88 组成的更大、更稳定的寡聚体的形成触发 IRAK4 和 IRAK1 的顺序招募。值得注意的是，IRAK4 的基因敲除增强了 MyD88 寡聚化，表明 IRAK4 控制 MyD88 寡聚体大小和生长。因此，MyD88 寡聚体大小作为触发下游信号的物理阈值。这些结果为蛋白寡聚体如何在细胞信号通路中发挥作用提供了机制基础。
