MyD88 oligomer size functions as a physical threshold to trigger IL1R Myddosome signaling.

Rafael Deliz-Aguirre, Fakun Cao, Fenja H U Gerpott, Nichanok Auevechanichkul, Mariam Chupanova, YeVin Mun, Elke Ziska, Marcus J Taylor

The Journal of cell biology 2021 Jul 05

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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. © 2021 Deliz-Aguirre et al.

Citation

Rafael Deliz-Aguirre, Fakun Cao, Fenja H U Gerpott, Nichanok Auevechanichkul, Mariam Chupanova, YeVin Mun, Elke Ziska, Marcus J Taylor. MyD88 oligomer size functions as a physical threshold to trigger IL1R Myddosome signaling. The Journal of cell biology. 2021 Jul 05;220(7)