Cell https://doi.org/10.1016/j.cell.2019.01.039 (2019)

The detection of microbes by Toll-like receptors (TLRs) engages either a large oligomeric protein complex dependent on the adaptor MyD88 (myddosome) that activates the inflammatory transcription factors NF-κB and AP-1 or a complex dependent on the TLR adaptor TRIF that activates the kinase TBK1 to induce type I interferons. In Cell, Tan and Kagan show that TBK1 is a component of the myddosome and is required for the induction of aerobic glycolysis. TLR ligands induce glycolysis in macrophages independently of transcription and with dependence on MyD88 and TBK1. TBK1 is recruited to the myddosome by the adaptor TRAF6 independently of TRIF. Proving the modular nature of the myddosome, MyD88–RIP3 chimeric molecules can induce necroptosis, and MyD88–NpLxIS, which contains an IRF3-activation motif, can activate type I interferons, while a synthetic construct that can oligomerize and contains the NpLxIS motif also activates type I interferons. This indicates that supramolecular organizing centers, such as the myddosome and the inflammasome, are modular machines made of two functional units: an oligomerization platform and an effector domain.