TIRAP, TRAM, and Toll-Like Receptors: The Untold Story

Abstract

Toll-like receptors (TLRs) are the most studied receptors among the pattern recognition receptors (PRRs). They act as microbial sensors, playing major roles in the regulation of the innate immune system. TLRs mediate their cellular functions through the activation of MyD88-dependent or MyD88-independent signaling pathways. Myd88, or myeloid differentiation primary response 88, is a cytosolic adaptor protein essential for the induction of proinflammatory cytokines by all TLRs except TLR3. While the crucial role of Myd88 is well described, the contribution of other adaptors in mediating TLR signaling and function has been underestimated. In this review, we highlight important results demonstrating that TIRAP and TRAM adaptors are also required for full signaling activity and responses induced by most TLRs.

Figure 1

TLR4 and MyD88 hegemony in TLR research. The number of publications regarding each TLR and TLR-related adaptor referenced in PubMed® was calculated on 27^th October 2022. 28,034 publications regarding TLR4 were found; 13,431 on TLR2; 6,237 on TLR9; 5,516 on TLR3; 4,426 on TLR7; 2,011 on TLR5; 1,435 on TLR8; 10,148 on MyD88; 2,037 on TRIF; 601 on TIRAP; and 118 on TRAM.

Figure 2

Structural view of human TIRAP and TRAM adaptor proteins. TIRAP contains a N-terminal PIP₂-binding motif and a PEST domain, allowing polyubiquitination for rapid proteasomal degradation through suppressor of cytokine signaling 1 (SOCS1) binding [20]. TIRAP contains a C-terminal TIR domain. Its TRAF-6 binding motif permits direct association with TRAF6 for activation [21]. TRAM contains a N-terminal bipartite sorting signal that comprises its myristylation glycine site and controls its trafficking between the plasma membrane and the endosomes [22]. Similar to TIRAP, TRAM contains a C-terminal TIR domain.

Figure 3

Schematic representation of the adaptors that bind the TIR domain of TLRs. TIRAP is preferentially localized at the cytoplasmic membrane through a PIP₂-binding domain and recruits MyD88. Myristoylated TRAM localizes at the endosomes and triggers IFN I production via TRIF. Abbreviations: MAPKs: mitogen-activated protein kinases; MyD88: myeloid differentiation primary response 88; NF-κB: nuclear factor-κB; PIP₂: phosphatidylinositol bisphosphate; TIRAP: Toll/interleukin-1 receptor domain-containing adaptor protein; TLR: Toll-like receptor; TRAM: TRIF-related adaptor molecule; TRIF: TIR domain-containing adaptor-inducing interferon-β.

Figure 4

The history of Toll-like receptors and their signaling: summarized timeline of discoveries. Abbreviations: CpG-DNA: cytosine-phosphate-guanine-deoxyribo-nucleic acid; LPS: lipopolysaccharide; MyD88: myeloid differentiation primary response 88; PRRs: pattern recognition receptors; ssRNA: single-stranded ribonucleic acid; TIRAP: Toll/interleukin-1 receptor domain-containing adaptor protein; TLR4/5/7/8/9: Toll-like receptor 4/5/7/8/9; TRAM: TRIF-related adaptor molecule.

Figure 5

Emerging model for TLR signaling. Recent data suggest a new model according to which all TLRs, but TLR3, are TIRAP-dependent for MyD88-mediated pathways and TRAM-dependent for the TRIF cascade. TLR3 directly recruits the TRIF adaptor to the endosomal compartment. TRAF3: TNF receptor-associated factor 3.