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

• Published in: Nature Reviews: Immunology Vol. 7; no. 5; pp. 353 - 364
• Main Authors: O'Neill, Luke A. J., Bowie, Andrew G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2007; Nature Publishing Group
• Subjects: Adaptor proteins; Adaptor Proteins, Signal Transducing - physiology; Adaptor Proteins, Vesicular Transport - metabolism; Adaptor Proteins, Vesicular Transport - physiology; Amino acids; Animals; Apoptosis; Armadillo Domain Proteins - metabolism; Biomedical and Life Sciences; Biomedicine; Bruton's tyrosine kinase; Cytokines; Cytoskeletal Proteins - metabolism; DNA binding proteins; Humans; Immunology; Interferon; Interferon regulatory factor 1; Interferon regulatory factor 3; Interferon regulatory factor 7; Interleukin 1; Interleukin 18; Kinases; Ligands; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; NF-κB protein; Phosphatidylinositol 4,5-diphosphate; Physiological aspects; Protein kinase C; Protein-tyrosine kinase; Proteins; review-article; Signal transduction; Signal Transduction - physiology; SOCS-1 protein; TLR2 protein; TLR3 protein; TLR4 protein; Toll-like receptors; Toll-Like Receptors - physiology; Transcription activation; Transcription factors; β-Interferon; γ-Interferon; Ireland
• DOI: 10.1038/nri2079
• ISSN: 1474-1733

Key Points TLR (Toll-like receptor) signal transduction involves five adaptor proteins. MyD88 (myeloid differentiation primary-response gene 88), MAL (MyD88-adaptor-like protein), TRIF (TIR-domain-containing adaptor protein inducing interferon-β (IFNβ)) and TRAM (TRIF-related adaptor molecule) are recruited to TIR (Toll/interleukin-1 (IL-1) receptor) domains to initiate signalling, whereas SARM (sterile α- and armadillo-motif-containing protein) inhibits TRIF-dependent signalling. MyD88 is the universal adaptor used by all TLRs with the exception of TLR3. MyD88 couples to pathways that lead to the activation of transcription factors such as NF-κB (nuclear factor-κB), IRF1 (IFN-regulatory factor 1), IRF5 and IRF7. It is also involved in TLR-independent signals activated by IL-1, IL-18 and IFNγ. MAL is required to recruit MyD88 to TLR2 and TLR4. It is membrane associated through a phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 )-binding domain and is subject to regulation by Bruton's tyrosine kinase and SOCS1 (suppressor of cytokine signalling 1), which interacts with MAL causing it to be degraded. TRIF is used by TLR3, and leads to the activation of IRF3 through TBK1 (TRAF-family-member-associated NF-κB activator-binding kinase 1). It is also involved in the NF-κB activation pathway, which it achieves through recruitment of RIP1 (receptor-interacting protein 1). TRIF has also be shown to mediate apoptosis through RIP1. TRAM is used only by TLR4, and its main function is recruitment of TRIF. TRAM is membrane localized through a myristic-acid group, which is attached to its amino terminus. It is subject to regulation by protein kinase Cε. SARM is a negative regulator of TRIF, and therefore serves to regulate TLR3 and TLR4 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.