1. Immunology and Inflammation
  2. Microbiology and Infectious Disease
Download icon

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
Research Article
  • Cited 7
  • Views 1,767
  • Annotations
Cite this article as: eLife 2018;7:e31377 doi: 10.7554/eLife.31377

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.

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

Publication 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.

Metrics

  • 1,767
    Page views
  • 387
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    Florin Tudor Ilca et al.
    Research Article
    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Damián Pérez-Mazliah et al.
    Research Article Updated