Repository logo
 

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

Published version
Peer-reviewed

Change log

Authors

Latty, Sarah Louise 
Hopkins, Lee 
Verstak, Brett 
Paramo, Teresa 

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-κB signalling.

Description

Keywords

MyD88, TLR signalling, Toll-like receptors, immunology, infectious disease, inflammation, microbiology, none, single molecule fluorescence, Animals, Lymphocyte Antigen 96, Mice, Protein Multimerization, RAW 264.7 Cells, Signal Transduction, Single Molecule Imaging, Toll-Like Receptor 4

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

7

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/H021930/1)
Medical Research Council (G1000133)
Wellcome Trust (100321/Z/12/Z)
Wellcome Trust (108045/Z/15/Z)