Molecular definition of the endogenous Toll-like receptor signalling pathways

Daniel Fisch, Tian Zhang, He Sun, Weiyi Ma, Yunhao Tan, Steven P. Gygi, Darren E. Higgins and Jonathan C. Kagan ()
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Daniel Fisch: Boston Children’s Hospital and Harvard Medical School
Tian Zhang: Harvard Medical School
He Sun: Blavatnik Institute, Harvard Medical School
Weiyi Ma: Boston Children’s Hospital and Harvard Medical School
Yunhao Tan: Boston Children’s Hospital and Harvard Medical School
Steven P. Gygi: Harvard Medical School
Darren E. Higgins: Blavatnik Institute, Harvard Medical School
Jonathan C. Kagan: Boston Children’s Hospital and Harvard Medical School

Nature, 2024, vol. 631, issue 8021, 635-644

Abstract: Abstract Innate immune pattern recognition receptors, such as the Toll-like receptors (TLRs), are key mediators of the immune response to infection and central to our understanding of health and disease1. After microbial detection, these receptors activate inflammatory signal transduction pathways that involve IκB kinases, mitogen-activated protein kinases, ubiquitin ligases and other adaptor proteins. The mechanisms that connect the proteins in the TLR pathways are poorly defined. To delineate TLR pathway activities, we engineered macrophages to enable microscopy and proteomic analysis of the endogenous myddosome constituent MyD88. We found that myddosomes form transient contacts with activated TLRs and that TLR-free myddosomes are dynamic in size, number and composition over the course of 24 h. Analysis using super-resolution microscopy revealed that, within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. Proteomic analysis demonstrated that myddosomes contain proteins that act at all stages and regulate all effector responses of the TLR pathways, and genetic analysis defined the epistatic relationship between these effector modules. Myddosome assembly was evident in cells infected with Listeria monocytogenes, but these bacteria evaded myddosome assembly and TLR signalling during cell-to-cell spread. On the basis of these findings, we propose that the entire TLR signalling pathway is executed from within the myddosome.

Date: 2024
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DOI: 10.1038/s41586-024-07614-7

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