MyD88: a central player in innate immune signaling

Abstract

MyD88 is the canonical adaptor for inflammatory signaling pathways downstream of members of the Toll-like receptor (TLR) and interleukin-1 (IL-1) receptor families. MyD88 links IL-1 receptor (IL-1R) or TLR family members to IL-1R-associated kinase (IRAK) family kinases via homotypic protein-protein interaction. Activation of IRAK family kinases leads to a variety of functional outputs, including the activation of nuclear factor-kappa B (NFκB), mitogen-activated protein kinases, and activator protein 1, making MyD88 a central node of inflammatory pathways. As more details of MyD88-dependent signaling have been elucidated, it has become clear that the functions of this critical signaling component can be influenced by multiple interaction partners in distinct subcellular compartments. In this review, we will focus on recent developments in the understanding of the assembly of MyD88 signaling complexes and the mechanisms leading to the diversification of MyD88-based signaling.

Figure 1.. Organization of MyD88 domains

MyD88 is composed of three main domains: a death domain (DD) (54 to 109), intermediate domain (INT) (110 to 155), and Toll-interleukin-1 receptor domain (TIR) (159 to 296). Although the DD is annotated as 54 to 109, proper folding of the DD seems to require amino acids 110 to 117. Point mutations inducing a loss (blue) or gain (red) of function are indicated by amino acid number. The site implicated in interferon regulatory factor 7 (IRF-7) binding (1 to 59) and the domain lost in the splice variant MyD88s (110 to 155) are indicated in black.