1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub

  1. Sarah Latty
  2. Jiro Sakai
  3. Lee Hopkins
  4. Brett Verstak
  5. Teresa Paramo
  6. Nils A Berglund
  7. Nicholas J Gay
  8. Peter J Bond
  9. David Klenerman
  10. Clare E Bryant  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Oxford, United Kingdom
  3. Bioinformatics Institute, Singapore
https://doi.org/10.7554/eLife.31377
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Cite this article
  1. Sarah Latty
  2. Jiro Sakai
  3. Lee Hopkins
  4. Brett Verstak
  5. Teresa Paramo
  6. Nils A Berglund
  7. Nicholas J Gay
  8. Peter J Bond
  9. David Klenerman
  10. Clare E Bryant
(2018)
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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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

The following previously published data sets were used
    1. Latty S
    2. Sakai J
    3. Cammarota E
    4. Wright J
    5. Cicuta P
    6. Gottschalk R
    (2016) Research data supporting Lipopolysaccharide-induced NF-kB nuclear translocation is primarily dependent on MyD88, but TNFα expression requires TRIF and MyD88
    Available at Apollo - University of Cambridge Repository under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International license.
    https://doi.org/10.17863/CAM.6018

Article and author information

Author details

  1. Sarah Latty

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Jiro Sakai

    Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2526-2766

  3. Lee Hopkins

    Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Brett Verstak

    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Teresa Paramo

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Nils A Berglund

    Bioinformatics Institute, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.

  7. Nicholas J Gay

    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2782-7169

  8. Peter J Bond

    Bioinformatics Institute, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.

  9. David Klenerman

    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7116-6954

  10. Clare E Bryant

    Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    ceb27@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2924-0038

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

  1. Michael L Dustin, University of Oxford, United Kingdom

Version history

  1. Received: August 20, 2017
  2. Accepted: January 22, 2018
  3. Accepted Manuscript published: January 24, 2018 (version 1)
  4. Version of Record published: February 23, 2018 (version 2)
  5. Version of Record updated: March 12, 2018 (version 3)
  6. 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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  1. Sarah Latty
  2. Jiro Sakai
  3. Lee Hopkins
  4. Brett Verstak
  5. Teresa Paramo
  6. Nils A Berglund
  7. Nicholas J Gay
  8. Peter J Bond
  9. David Klenerman
  10. Clare E Bryant
(2018)
Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub
eLife 7:e31377.
https://doi.org/10.7554/eLife.31377

Share this article

https://doi.org/10.7554/eLife.31377

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