The myddosome is a protein complex that serves as a fundamental component of the body’s innate immune system. It functions as an early detector of potential threats, such as those posed by invading microbes or tissue damage. This assembly of proteins is responsible for initiating robust defense responses, coordinating the body’s rapid, non-specific reactions to perceived dangers.
Building Blocks of the Myddosome
The myddosome is an oligomeric complex primarily formed by the adapter proteins Myeloid Differentiation Primary Response 88 (MyD88) and TIR domain-containing adaptor protein (TIRAP), also known as MAL. These proteins come together when certain receptors, particularly Toll-like Receptors (TLRs) and Interleukin-1 Receptors (IL-1Rs), are activated by recognizing specific molecular patterns associated with pathogens or cellular damage. MyD88 contains a Toll-interleukin 1 receptor (TIR) domain and a death domain (DD), crucial for its interactions and assembly. The TIR domain of MyD88 interacts with the TIR domains of activated TLRs or IL-1Rs, while its death domain facilitates self-assembly into helical oligomers.
TIRAP acts as a bridging adapter, particularly for TLR4 signaling, helping to recruit MyD88 to the activated receptor complex. The myddosome assembles rapidly, often within minutes of TLR stimulation. This dynamic assembly provides a platform for recruiting other proteins, which then propagate the immune signal further into the cell.
How the Myddosome Triggers Immune Responses
Once formed, the myddosome acts as a central signaling hub that initiates innate immune responses. Its assembly facilitates the recruitment of Interleukin-1 Receptor-Associated Kinases (IRAKs), specifically IRAK4, IRAK1, and sometimes IRAK2, to the complex. IRAK4 plays a significant role in this process, with its scaffold function being particularly important for myddosome formation, even though its kinase activity is not always required for initial assembly. The recruitment of IRAK4 leads to its autophosphorylation and the subsequent phosphorylation of IRAK1.
This phosphorylation cascade enables the recruitment and activation of TNF Receptor-Associated Factor 6 (TRAF6), an E3 ubiquitin ligase. TRAF6, once activated, can detach from the myddosome and move into the cytosol, where it catalyzes the addition of ubiquitin chains to various target proteins, including the IκB kinase (IKK) complex. This chain of events ultimately leads to the activation and nuclear translocation of transcription factors such as Nuclear Factor-kappa B (NF-κB), Activator Protein 1 (AP-1), and Interferon Regulatory Factor 5 (IRF5). The activation of these transcription factors drives the expression of genes responsible for producing inflammatory molecules, including pro-inflammatory cytokines and chemokines, which are necessary for combating infections.
Myddosome’s Impact on Health and Illness
The myddosome orchestrates immune responses against various pathogens like bacteria, viruses, and fungi. By activating appropriate immune pathways, it ensures the body can effectively clear infections. For instance, it contributes to macrophage activation and the release of pro-inflammatory cytokines, which are necessary for a robust defense.
Conversely, dysregulation of the myddosome pathway can lead to adverse health outcomes. An overactive myddosome pathway can contribute to chronic inflammation and autoimmune conditions, where the immune system mistakenly attacks the body’s own tissues. For example, specific mutations in MyD88, such as the L265P variant found in certain B-cell lymphomas, can lead to the myddosome assembling constitutively without receptor activation, causing uncontrolled cell growth and survival by persistently activating NF-κB signaling.
Conversely, an underactive myddosome pathway can result in increased susceptibility to infections. Patients with specific mutations in IRAK4, a myddosome component, exhibit an immunologic syndrome characterized by defective immunity to certain bacterial and viral infections, as well as impaired responses to IL-1, IL-8, and various TLR ligands. Targeting myddosome components, particularly IRAK4, with inhibitors or degraders (such as PROTACs like KT-474) is being explored as a strategy to modulate immune responses in inflammatory diseases and certain cancers.