Myeloid differentiation primary response 88, or MyD88, is an adapter protein inside our cells involved in immune signaling. It connects the parts of the cell that sense danger with the internal machinery that responds to it. The gene MYD88 holds the instructions for building this protein. First identified in 1990 as a gene that increases in activity during the development of myeloid cells, its full role was understood years later.
Role in the Innate Immune System
The MyD88 protein is a component of the innate immune system, the body’s non-specific first line of defense. This system relies on pattern recognition receptors (PRRs) that are always on alert. Some of the most well-known of these are the Toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs). These receptors act as sensors on immune cells, recognizing molecular patterns from pathogens (PAMPs) or signals from damaged cells (DAMPs).
Once a TLR or IL-1R detects a threat, it needs to relay this information to the cell’s nucleus to initiate a defensive response. MyD88 functions as the adapter that bridges the activated receptor to the response pathways inside the cell. MyD88 is required for the signaling of almost all TLRs, with the notable exception of TLR3, and is also used by the IL-1 family of receptors. Without this connection, the warning signal from the receptor would be lost.
The connection is highly specific and mediated by a physical interaction. The C-terminal Toll/Interleukin-1 receptor (TIR) domain of MyD88 binds directly to the corresponding TIR domain of the activated TLR or IL-1R. This binding event is the first step that brings the signal from the cell’s exterior into the cytoplasm, making MyD88 a hub for initiating inflammatory responses.
The MyD88 Signaling Cascade
Once MyD88 is recruited to an activated receptor, it kicks off a chain reaction inside the cell known as a signaling cascade. This process involves one protein activating the next in a specific sequence, rapidly amplifying the initial signal. The first step in this cascade involves MyD88’s N-terminal death domain, which allows it to recruit and bind to another family of proteins called Interleukin-1 receptor-associated kinases (IRAKs).
The recruitment of IRAKs to MyD88 forms a large protein complex sometimes called the “Myddosome.” The formation of this complex brings multiple IRAK proteins into close proximity, allowing them to activate one another. This activation leads to a series of downstream events, including the engagement of other proteins like TRAF6. This culminates in the activation of a group of proteins called nuclear factor-kappa B (NF-κB).
NF-κB acts as a master switch for gene activity. When activated by the MyD88 pathway, NF-κB travels into the cell’s nucleus and turns on hundreds of genes responsible for inflammation and immune defense. This includes the genes for producing cytokines, which are signaling molecules that act as chemical messengers. These cytokines are released from the cell to rally other immune cells to the site of infection or injury.
Consequences of MyD88 Dysfunction
When the MyD88 protein or its signaling pathway does not function correctly, it can have significant health consequences. These issues can be divided into two categories: loss of function, where the protein is missing or inactive, and gain of function, where the protein is permanently switched on. MyD88 deficiency is a rare, inherited immunodeficiency where the bridge between the TLR/IL-1R sensors and the internal response machinery is broken.
This defect leaves individuals highly susceptible to a specific range of life-threatening infections, particularly from pyogenic bacteria. Infections with pathogens like Streptococcus pneumoniae and Staphylococcus aureus can be severe and recurrent. These individuals are not unusually vulnerable to most viral, fungal, or parasitic infections, highlighting the specific role of this pathway in immunity, as the immune system has other pathways to handle those threats.
Conversely, problems arise when MyD88 is constantly active due to acquired genetic mutations, known as somatic mutations. An overactive MyD88 protein continuously stimulates the NF-κB pathway without any signal from the TLR or IL-1R sensors. This chronic signaling can prevent abnormal cells from self-destructing and promote their survival, contributing to certain types of cancer. A primary example is Waldenström macroglobulinemia, a type of non-Hodgkin lymphoma, where a specific MYD88 gene mutation is found in most cases.
Therapeutic Targeting of MyD88
Because of its role in orchestrating inflammation and immunity, the MyD88 pathway is a focus for therapeutic development. Researchers are exploring two main strategies: inhibiting the pathway to treat diseases driven by its overactivity, and stimulating it to boost immune responses. A major goal is developing small-molecule inhibitors that block MyD88 signaling to treat autoimmune diseases and cancers where the pathway is chronically active.
These inhibitors are being designed to physically block the interaction between MyD88 proteins, preventing the formation of the signaling complex. By disrupting this first step, these drugs could potentially reduce harmful inflammation associated with conditions like rheumatoid arthritis or slow the growth of cancers like Waldenström macroglobulinemia. Studies in animal models have shown that blocking MyD88 can limit the impact of severe inflammation.
Activating the MyD88 pathway holds promise for enhancing the body’s ability to fight infections and improving vaccine effectiveness. For instance, some vaccine adjuvants—substances added to vaccines to provoke a stronger immune response—work by activating TLRs that signal through MyD88. Stimulating this pathway can reprogram immune cells like macrophages to be more effective at killing bacteria. Carefully controlled stimulation of MyD88 could provide a way to bolster innate immunity during times of high infection risk.