The myddosome is a multi-protein assembly that acts as a central switchboard for the body’s innate immune system. This structure recognizes signs of danger, such as invading pathogens, and translates that recognition into a robust inflammatory response. The complex is built around the scaffold protein Myeloid differentiation primary response 88 (MyD88). MyD88 is an adaptor protein required by nearly all Toll-like receptors (TLRs) and the Interleukin-1 receptor (IL-1R) superfamily to initiate signaling. Without the proper function of the myddosome, the immune system would be significantly impaired in its ability to detect and respond to microbial threats.
The Architecture of the Myddosome
The physical construction of the myddosome is designed for signal amplification. The structure is built upon the MyD88 protein, which contains a Toll/Interleukin-1 Receptor (TIR) domain and a Death Domain (DD). The TIR domain of MyD88 interacts with the corresponding TIR domain on an activated cell surface receptor. The DD is the structural unit that facilitates the assembly of the complex.
The Death Domains of multiple MyD88 molecules spontaneously associate to form a large, helical filament structure. This MyD88 scaffold serves as a platform to sequentially recruit other components, primarily the Interleukin-1 Receptor Associated Kinase (IRAK) proteins. IRAK4 is recruited first, followed by IRAK1 or IRAK2, which join the complex through interactions between their Death Domains and those of the MyD88 scaffold.
The final myddosome assembly is a large, supramolecular organizing center, often described as a single-stranded, left-handed helix or a tower-shaped structure. Structural studies suggest a composition frequently involving six MyD88 molecules, four IRAK4 molecules, and four IRAK2 or IRAK1 molecules. This filamentous arrangement is designed to bring the IRAK kinases into close proximity. This enables them to activate each other through mutual phosphorylation, converting a single receptor binding event into a powerful, localized signaling cascade.
Translating Danger: The Myddosome Signaling Cascade
The myddosome’s formation is triggered by the cell’s detection of a threat, typically sensed by cell surface or endosomal receptors, such as Toll-like receptors (TLRs). When a TLR binds to a foreign molecule, the receptor’s cytoplasmic domain changes shape and recruits MyD88. This initial interaction acts as a nucleation point, causing multiple MyD88 proteins to polymerize rapidly into the myddosome’s filament structure.
Once assembled, the IRAK kinases within the myddosome initiate signal amplification. The IRAK4 molecules undergo self-association and autophosphorylation, activating their kinase function. Activated IRAK4 then phosphorylates the IRAK1 and IRAK2 components, turning them into active signaling molecules. This phosphorylation cascade is the core mechanism translating the initial danger signal into a biochemical command.
The newly activated IRAK proteins, particularly IRAK1 and IRAK2, then dissociate from the myddosome complex and interact with the E3 ubiquitin ligase, TNF Receptor-Associated Factor 6 (TRAF6). This interaction leads to the ubiquitination and subsequent activation of the TAK1 kinase, which is a central hub for downstream signaling. Activated TAK1 then activates the IκB kinase (IKK) complex. The IKK complex phosphorylates the inhibitor of NF-κB, causing it to release the transcription factor NF-κB. NF-κB then translocates into the cell nucleus, where it binds to specific gene promoters to initiate the transcription of genes responsible for generating inflammatory mediators, such as cytokines and chemokines.
Implications in Health and Chronic Inflammation
The myddosome’s role as a central signaling hub means its dysregulation can have widespread consequences for health, particularly in conditions involving excessive or sustained inflammation. When the myddosome pathway becomes overactive, it leads to the continuous production of inflammatory molecules, establishing chronic inflammation. This chronic state contributes to the progression of various diseases, including autoimmune disorders and inflammatory conditions.
The importance of this pathway is demonstrated in cancer research, where uncontrolled MyD88 signaling is a factor in some malignancies. Specific gain-of-function mutations in MyD88, such as the L265P variant, cause the myddosome to assemble and signal constantly, even without an external trigger. This constitutive activation of the NF-κB pathway promotes cell survival and proliferation, creating a microenvironment conducive to tumor growth.
Given its central position in the inflammatory response, the myddosome complex is a promising target for new therapeutic strategies. Researchers are exploring ways to block the aberrant signaling that drives chronic inflammatory diseases and cancer by interfering with the assembly or activation of the myddosome. Targeting the specific protein-protein interactions within the complex could offer a selective method to dampen unwanted inflammation while preserving other necessary immune functions.