Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub
- University of Cambridge, United Kingdom
- University of Oxford, United Kingdom
- Bioinformatics Institute, Singapore
Abstract
Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-kB signalling.
Data availability
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Research data supporting Lipopolysaccharide-induced NF-kB nuclear translocation is primarily dependent on MyD88, but TNFα expression requires TRIF and MyD88Available at Apollo - University of Cambridge Repository under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license.
Article and author information
Author details
Funding
Medical Research Council (G1000133)
- Nicholas J Gay
Wellcome (WT100321/z/12/Z)
- Nicholas J Gay
Wellcome (WT108045AIA)
- Clare E Bryant
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Michael L Dustin, University of Oxford, United Kingdom
Version history
- Received: August 20, 2017
- Accepted: January 22, 2018
- Accepted Manuscript published: January 24, 2018 (version 1)
- Version of Record published: February 23, 2018 (version 2)
- Version of Record updated: March 12, 2018 (version 3)
- Version of Record updated: June 26, 2018 (version 4)
Copyright
© 2018, Latty et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub
eLife 7:e31377.
https://doi.org/10.7554/eLife.31377
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