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

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)P2)-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.

Abstract

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.

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Figure 1: Schematic representation of protein domains and motifs found in the human TIR-domain-containing adaptor family.
Figure 2: Overview of transcription-factor activation through TIR-domain-containing adaptors for the TLR/IL-1R superfamily.
Figure 3: The world of MyD88.
Figure 4: Signalling pathways mediated by TRIF and their regulation by SARM.
Figure 5: TIR-domain-containing adaptor usage by TLR4.

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Acknowledgements

We thank Science Foundation Ireland, the Irish Research Council of Science, Engineering and Technology, and the Health Research Board of Ireland for providing financial support for the research programmes in our laboratories.

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Glossary

Imiquimod

An imidazoquinolene-based compound that is sensed by TLR7 and is currently used for the treatment of genital warts and basal-cell carcinoma.

Smooth and rough LPS

Smooth LPS contains the O-antigen, which comprises a long-chain polysaccharide, an oligosaccharide core and lipid A. Rough LPS is identical with the notable difference that it lacks the O-antigen.

Electrostatic complementarity

A situation in which the electrical charge of atoms in two molecules are opposite, such that an interaction between the molecules is favoured.

C3H/HeJ mice

A strain of mice hyporesponsive to LPS in which there is a missense mutation in the gene encoding TLR4, which changes a proline to a histidine in the TIR domain, rendering TLR4 unable to signal.

Random germline mutagenesis

A technique whereby mutagenesis with a chemical, such as the ethylating chemical N-ethyl-N-nitrosurea (ENU), produces a high rate of genome-wide point mutations at random in the mouse germline. Mutagenized mice can then be tested for functional defects, and the mutant gene that is responsible identified.

Phenovariant

A variant in which the phenotype is different, which can then be linked back to the genotype and thereby lead to the identification of the protein responsible for the phenotype.

Yeast two-hybrid screen

A system used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

Polyinosinic–polycytidylic acid

(PolyI:C). A substance that is used as a mimic of viral double-stranded RNA.

IFN-sensitive response elements

(ISREs). DNA motifs found in the promoters of interferon (IFN)-sensitive genes that binds the transcription factor IRF3.

RIG-I pathway

A signalling pathway activated by the receptor retinoic acid-inducible gene I (RIG-I) by viral RNA, which through the adaptor protein IPS1 (also known as VISA, MAVS or CARDIF) activates the transcription factors IRF3 and IRF7, leading to the production of type I interferons.

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O'Neill, L., Bowie, A. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7, 353–364 (2007). https://doi.org/10.1038/nri2079

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