Members of the Toll-like receptor (TLR) family, named for the closely related Toll receptor in Drosophila, play a pivotal role in innate immune responses. TLRs recognize conserved motifs found in various pathogens and mediate defense responses. Triggering of the TLR pathway leads to the activation of NF-κB and subsequent regulation of immune and inflammatory genes. The TLRs and members of the IL-1 receptor family share a conserved stretch of approximately 200 amino acids known as the TIR domain. Upon activation, TLRs associate with a number of cytoplasmic adaptor proteins containing TIR domains including MyD88 (myeloid differentiation factor), MAL/TIRAP (MyD88-adaptor-like/TIR-associated protein), TRIF (Toll-receptor-associated activator of interferon), and TRAM (Toll-receptor-associated molecule). This association leads to the recruitment and activation of IRAK1 and IRAK4, which form a complex with TRAF6 to activate TAK1 and IKK. Activation of IKK leads to the degradation of IκB that normally maintains NF-κB inactivity by sequestering it in the cytoplasm.MyD88 was originally isolated as a myeloid differentiation primary response gene that is rapidly induced upon IL-6 stimulated differentiation of M1 myeloleukemic cells into macrophages. It contains an amino-terminal death domain separated from a carboxyl-terminal TIR domain and functions as an adaptor in TLR/IL-1 receptor signaling. The death domain of MyD88 mediates interactions with the IRAK complex triggering a signaling cascade that includes the activation of NF-κB.
Members of the Toll-like receptor (TLR) family, named for the closely related Toll receptor in Drosophila, play a pivotal role in innate immune responses. TLRs recognize conserved motifs found in various pathogens and mediate defense responses. Triggering of the TLR pathway leads to the activation of NF-κB and subsequent regulation of immune and inflammatory genes. The TLRs and members of the IL-1 receptor family share a conserved stretch of approximately 200 amino acids known as the TIR domain. Upon activation, TLRs associate with a number of cytoplasmic adaptor proteins containing TIR domains including MyD88 (myeloid differentiation factor), MAL/TIRAP (MyD88-adaptor-like/TIR-associated protein), TRIF (Toll-receptor-associated activator of interferon), and TRAM (Toll-receptor-associated molecule). This association leads to the recruitment and activation of IRAK1 and IRAK4, which form a complex with TRAF6 to activate TAK1 and IKK. Activation of IKK leads to the degradation of IκB that normally maintains NF-κB inactivity by sequestering it in the cytoplasm.MyD88 was originally isolated as a myeloid differentiation primary response gene that is rapidly induced upon IL-6 stimulated differentiation of M1 myeloleukemic cells into macrophages. It contains an amino-terminal death domain separated from a carboxyl-terminal TIR domain and functions as an adaptor in TLR/IL-1 receptor signaling. The death domain of MyD88 mediates interactions with the IRAK complex triggering a signaling cascade that includes the activation of NF-κB.
Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response. Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Increases IL-8 transcription. Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine.