Understanding early TLR signaling through the Myddosome

TLRs are expressed on the plasma and endosomal membranes of innate immune cells acting as sensors of foreign and inherent danger signals that threaten the host. Upon activation, TLRs facilitate the assembly of large intracellular oligomeric signaling complexes, termed Myddosomes, which initiate key signal transduction pathways to elicit critical inflammatory immune responses. The formation of the Myddosome is integral for TLR signaling; however, the molecular mechanisms controlling its formation, disassembly, and the subsequent proximal signaling events remain to be clearly defined. In this review, we present a brief overview of TLR signal transduction pathways, summarize the current understanding of the Myddosome and the proteins that comprise its structure, including MyD88 and members of the IL-1 receptor-associated kinase (IRAK) family. Finally, we will discuss recent advances and open questions regarding early TLR signaling in the context of the Myddosome complex.