The Gay Group have published a paper in Science Advances on “Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome”, together with colleagues from the Departments of Chemistry and Veterinary Medicine and from Berlin and Charlottesville.
Toll-like receptors (TLRs) drive innate immunity via assembly of macromolecular signal transduction platforms [supramolecular organizing centers (SMOCs)] coordinated by adaptor proteins such as Toll/interleukin-1 receptor (IL-1R) domain–containing adaptor-inducing interferon-β (TRIF), but whether oligomeric TRIFosomes form is unknown.
They used cryo–electron microscopy and biophysical characterization of full-length TRIF in vitro to show that it forms filamentous oligomers, which associate with the TRIF signaling partners receptor interacting protein 1 (RIP1) and RIP3 kinases, suggesting that oligomeric TRIFosomes could form. The paper reveals the TRIFosome macromolecular platform formation and unexpectedly shows that TLR signaling can be SMOC-independent in addition to being SMOC-dependent.
The paper concludes:
“Collectively, our data support a concept whereby TLR-driven signaling occurs in a modular fashion with the rapid formation of previously unknown SMOC-independent antipathogen signaling complexes followed by progression to stable SMOC signalling platforms. Determining the structure-function consequences of these diverse signaling responses offers the exciting possibility that could allow uncoupling of protective antipathogen responses from severe inflammatory responses to generate therapeutic targets for chronic inflammatory disease.”