MOLECULAR DEFINITION OF THE ENDOGENOUS TOLL-LIKE RECEPTOR SIGNALING PATHWAY скачать в хорошем качестве

MOLECULAR DEFINITION OF THE ENDOGENOUS TOLL-LIKE RECEPTOR SIGNALING PATHWAY

Talk by Daniel FISCH, Boston Children's Hospital, Harvard Medical School, USA, at the 24th HFSP Awardees Meeting (9-11 July 2025, Melbourne, Australia) Abstract: Toll-like Receptors (TLRs) are key mediators of the immune response to infection. Upon detection of microbes, these prototypical pattern recognition receptors activate inflammatory signal transduction pathways that involve IκB kinases (IKKs), mitogen activated protein kinases (MAPKs), ubiquitin ligases (e.g. TRAF6) and other adaptor and signaling proteins. Current models suggest these signaling proteins operate within functionally distinct multiprotein complexes, which are activated by a receptor-linked adaptor complex known as the myddosome. The mechanisms that connect the protein complexes in the TLR pathways are undefined. To delineate TLR pathway activities, we genetically engineered human and mouse macrophages to add a novel epitope tag to the endogenous myddosome constituent MyD88 which enabled live cell imaging and proteomic analysis. We found that MyD88 forms transient contacts with activated TLRs and that myddosomes dissociate from their seeding TLRs. Cytosolic, TLR-free myddosomes are dynamic in size, number, and composition. Microscopy revealed that MyD88 forms a scaffold for effector protein recruitment, proteomics demonstrated that myddosomes contain proteins that act at all stages and regulate all effector responses of the TLR signaling pathways, and genetics defined the epistatic relationship between these effector modules. Based on these findings, we propose that the entire TLR signaling pathway is executed from within the myddosome.