Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family

Abstract

The Toll/interleukin-1 (IL-1) receptor (TIR) family comprises two groups of transmembrane proteins, which share functional and structural properties. The members of the IL-1 receptor (IL-1R) subfamily are characterized by three extracellular immunoglobulin (Ig)-like domains. They form heterodimeric signaling receptor complexes consisting of receptor and accessory proteins. The members of the Toll-like receptor (TLR) subfamily recognize alarm signals that can be derived either from pathogens or the host itself. TLRs possess leucine-rich repeats in their extracellular part. TLRs can form dimeric receptor complexes consisting of two different TLRs or homodimers in the case of TLR4. The TLR4 receptor complex requires supportive molecules for optimal response to its ligand lipopolysaccharide (LPS). A hallmark of the TIR family is the cytoplasmic TIR domain that is indispensable for signal transduction. The TIR domain serves as a scaffold for a series of protein-protein interactions which result in the activation of a unique signaling module consisting of MyD88, interleukin-1 receptor associated kinase (IRAK) family members and Tollip, which is used exclusively by TIR family members. Subsequently, several central signaling pathways are activated in parallel, the activation of NFkappaB being the most prominent event of the inflammatory response. Recent developments indicate that in addition to the common signaling module MyD88/IRAK/Tollip, other molecules can modulate signaling by TLRs, especially of TLR4, resulting in differential biological answers to distinct pathogenic structures. Subtle differences in TLR signaling pathways are now becoming apparent, which reveal how the innate immune system decides at a very early stage the direction in which the adaptive immune response will develop. The creation of pathogen-specific mediator environments by dendritic cells defines whether a cellular or humoral response will be activated in response to the pathogen.

Identification of novel susceptibility genes in childhood‐onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform

“…IRAK-1 is a serine/threonine protein kinase involved in the signaling cascade of the Toll/interleukin-1 receptor (TIR) family (37). The TIR family comprises the interleukin-1 (IL-1) receptor subfamily, recognizing the endogenous proinflammatory cytokines IL-1 and IL-18, and the members of the Toll-like receptor subfamily, recognizing pathogen-associated molecular patterns.…”

The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling

“…This domain is also found in the IL-1 receptor (IL-1R) [2]. The engagement of the ectodomains of TLRs and IL-1R by their cognate ligands leads to recruitment of soluble TIR-domain-containing adaptor proteins to their cytoplasmic domains.…”

“…MyD88 also contains a death domain that facilitates the subsequent recruitment of death-domain-containing IRAK1 and IRAK4 to the receptor complex [2] where IRAK1 is phosphorylated and activated by IRAK4 [5][6][7]. This is followed by intensive autophosphorylation of IRAK1 [5,6], its interaction with TRAF6 and subsequent dissociation of IRAK1 and TRAF6 as binding partners from the receptor complex [8][9][10].…”

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

“…TLRs use many of the same signalling components as the IL-1 receptor (IL-1R) as a result of their intracellular regions sharing a conserved Toll-IL-1R (TIR) domain [1]. The proximal signalling events subsequent to TLR engagement by an appropriate ligand have been well characterised ( Figure 1).…”

“…With the exception of TLR3, all TLRs recruit the TIR domain-containing adaptor molecule myeloid differentiation factor 88 (Myd88) [2]. Myd88 then associates with members of the IL-1R-associated kinase (IRAK) family (IRAK-1-4) [1]. IRAK-1 is recruited to Myd88 within a complex with another protein termed Tollinteracting protein (Tollip) [3].…”