The article by Shizuo Akira reviews the signaling pathways of Toll-like receptors (TLRs), which play a crucial role in the innate immune response to microbial infections. TLRs are a family of receptors that recognize conserved motifs in microorganisms, triggering immediate defensive responses such as the production of antimicrobial peptides and cytokines. The TLR family shares significant homology with the interleukin-1 receptors (IL-1Rs) and is characterized by the Toll/IL-1R (TIR) domain in their cytoplasmic regions. The extracellular regions of TLRs contain leucine-rich repeats (LRRs) that help in pathogen recognition. The signaling pathways of TLRs involve several downstream molecules, including MyD88, IL-1R-associated kinases (IRAKs), TAK1, TAB1, and TRAF6. MyD88 acts as an adaptor protein, recruiting IRAKs to the receptor complex. IRAKs are activated upon receptor stimulation, leading to the activation of TRAF6 and subsequent phosphorylation of TAB1 and TAB2. This interaction with TAK1 and TAB proteins activates the NF-κB and MAP kinase pathways, resulting in the production of inflammatory cytokines and other cellular responses. The article also discusses the role of specific adaptors in different TLR signaling pathways. For example, TRIF is essential for TLR3 and TLR4 signaling, while MyD88 is crucial for TLR2 and TLR4 signaling. The MyD88-independent pathway, involving TRIF, is important for the production of type I interferons. Additionally, other adaptors like TIRAP and Pellino have been identified and play roles in specific TLR signaling pathways. Overall, the diversity in TLR signaling pathways is likely due to the combinatorial action of different adaptors, and a deeper understanding of these pathways could lead to the development of effective therapies for various diseases.The article by Shizuo Akira reviews the signaling pathways of Toll-like receptors (TLRs), which play a crucial role in the innate immune response to microbial infections. TLRs are a family of receptors that recognize conserved motifs in microorganisms, triggering immediate defensive responses such as the production of antimicrobial peptides and cytokines. The TLR family shares significant homology with the interleukin-1 receptors (IL-1Rs) and is characterized by the Toll/IL-1R (TIR) domain in their cytoplasmic regions. The extracellular regions of TLRs contain leucine-rich repeats (LRRs) that help in pathogen recognition. The signaling pathways of TLRs involve several downstream molecules, including MyD88, IL-1R-associated kinases (IRAKs), TAK1, TAB1, and TRAF6. MyD88 acts as an adaptor protein, recruiting IRAKs to the receptor complex. IRAKs are activated upon receptor stimulation, leading to the activation of TRAF6 and subsequent phosphorylation of TAB1 and TAB2. This interaction with TAK1 and TAB proteins activates the NF-κB and MAP kinase pathways, resulting in the production of inflammatory cytokines and other cellular responses. The article also discusses the role of specific adaptors in different TLR signaling pathways. For example, TRIF is essential for TLR3 and TLR4 signaling, while MyD88 is crucial for TLR2 and TLR4 signaling. The MyD88-independent pathway, involving TRIF, is important for the production of type I interferons. Additionally, other adaptors like TIRAP and Pellino have been identified and play roles in specific TLR signaling pathways. Overall, the diversity in TLR signaling pathways is likely due to the combinatorial action of different adaptors, and a deeper understanding of these pathways could lead to the development of effective therapies for various diseases.