Abstract
MyD88, a Toll/interleukin-1 receptor homology (TIR) domain-containing adaptor protein, mediates signals from the Toll-like receptors (TLR) or IL-1/IL-18 receptors to downstream kinases. In MyD88-dependent TLR4 signaling, the function of MyD88 is enhanced by another TIR domain-containing adaptor, Mal/TIRAP, which brings MyD88 to the plasma membrane and promotes its interaction with the cytosolic region of TLR4. Hence, Mal is recognized as the “sorting adaptor” for MyD88. In this study, a direct interaction between MyD88-TIR and another membrane-sorting adaptor, TRAM/TICAM-2, was demonstrated in vitro. Cell-based assays including RNA interference experiments and TRAM deficient mice revealed that the interplay between MyD88 and TRAM in cells is important in mediating IL-18 signal transduction. Live cell imaging further demonstrated the co-localized accumulation of MyD88 and TRAM in the membrane regions in HEK293 cells. These findings suggest that TRAM serves as the sorting adaptor for MyD88 in IL-18 signaling, which then facilitates the signal transduction. The binding sites for TRAM are located in the TIR domain of MyD88 and actually overlap with the binding sites for Mal. MyD88, the multifunctional signaling adaptor that works together with most of the TLR members and with the IL-1/IL-18 receptors, can interact with two distinct sorting adaptors, TRAM and Mal, in a conserved manner in a distinct context.
Highlights
Toll-like receptors (TLRs) are representative innate immune receptors that recognize pathogen-associated molecular patterns (PAMPs)
PAMPs first bind to the extracellular domain of the TLRs, and the cytosolic region of TLRs interact with MyD88, which allows the signal to be transmitted to the downstream kinase Interleukin (IL) -1 receptor associated kinase 4 (IRAK4)
Homotypic interactions of these protein interaction modules play a pivotal role in transmitting the signals downstream from the TLR; the Toll/Interleukin-1 receptor homology (TIR) of MyD88 interacts with the TIR of the TLRs, and the death domain (DD) of MyD88 interacts with the DD of IRAK4, which forms a large protein complex called the Myddosome [4]
Summary
Toll-like receptors (TLRs) are representative innate immune receptors that recognize pathogen-associated molecular patterns (PAMPs). PAMPs first bind to the extracellular domain of the TLRs, and the cytosolic region of TLRs interact with MyD88, which allows the signal to be transmitted to the downstream kinase Interleukin (IL) -1 receptor associated kinase 4 (IRAK4). In contrast to the DD, the TIR domain is almost exclusively found in the TLR related cytosolic adaptors or in the cytosolic regions of the TLRs, IL-1 and IL-18 receptors Homotypic interactions of these protein interaction modules play a pivotal role in transmitting the signals downstream from the TLR; the TIR of MyD88 interacts with the TIR of the TLRs, and the DD of MyD88 interacts with the DD of IRAK4, which forms a large protein complex called the Myddosome [4]
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