Structural Insights into the Assembly of Large Oligomeric Signalosomes in the Toll-Like Receptor-Interleukin-1 Receptor Superfamily

The Toll-like receptor (TLR)-interleukin 1 receptor (IL-1R) superfamily plays fundamentally important roles in innate immune and inflammatory responses. Structural studies have begun to show that upon ligand stimulation, TLRs and IL-1Rs assemble large oligomeric intracellular signaling complexes, or signalosomes, to induce the activation of kinases and E3 ubiquitin ligases, leading eventually to the activation of the transcription factors that are responsible for the expression of genes whose products mediate immune and infl ammatory responses. The different scaffolds identified by these structural studies provide a molecular foundation for understanding the formation of microscopically visible signaling clusters that have long been known to cell biologists. Here, we illustrate the potential mechanisms of step-by-step assembly from the membrane-proximal interactions to the more downstream events. Formation of large oligomeric signalosomes may help to establish a digital threshold response in TLR and IL-1R signaling.