The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling

In this Review, Luke O'Neill and Andrew Bowie discuss the role of the five adaptor proteins that are involved in Toll-like receptor (TLR) signalling, and provide a detailed molecular description of the earliest phase of TLR signal transduction. Signalling by Toll-like receptors (TLRs) involves five adaptor proteins known as MyD88, MAL, TRIF, TRAM and SARM. Recent insights have revealed additional functions for MyD88 apart from NF-κB activation, including activation of the transcription factors IRF1, IRF5 and IRF7, and also a role outside the TLRs in interferon-γ signalling. Biochemical information on MAL and TRAM has shown that both act as bridging adaptors, with MAL recruiting MyD88 to TLR2 and TLR4, and TRAM recruiting TRIF to TLR4 to allow for IRF3 activation. Finally, the function of the fifth adaptor, SARM, has been revealed, which negatively regulates TRIF. These new insights allow for a detailed description of the function of the five TIR-domain-containing adaptors in the initiation of TLR signalling.