Location, location, location: identifying the neighborhoods of LPS signaling

摘要

Toll-like receptors (TLRs) are transmem-brane proteins that, after microbial ligand-induced formation of oligomers, recruit specific signaling adaptors to their cytoplasmic Toll-interleukin 1 (IL-1) receptor domains1. These adaptors initiate a chain of phosphorylation and ubiquitination reactions that eventually lead to activation of the transcription factor NF-kB, mitogen-acti-vated protein kinases (MAPKs) and inter-feron-response factors (IRFs). Unique among the large family of TLRs, TLR4 engages two distinct adaptor proteins: MyD88, which is recruited by TIRAP (also called Mal) and elicits the production of proinflammatory cytokines; and TRIF, which is recruited by the adaptor TRAM and activates the production of type I interferons as well as proinflammatory cytokines. As TIRAP and TRAM are thought to bind to a common motif on TLR4 in dimers, precisely how TLR4 coordinates recruitment and signaling through two potentially competing adaptor systems remains unclear