MYD88 - Myeloid differentiation primary response 88 | Elisa - Clia - Antibody - Protein

Background

Myeloid differentiation primary response 88 (MYD88) is a key adaptor protein involved in the signaling pathways of the innate immune system. It plays a crucial role in the activation of inflammatory responses by mediating signals from toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). Upon activation by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), MYD88 recruits downstream signaling molecules, leading to the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), which promote the expression of pro-inflammatory cytokines. This process is essential for the host defense against infections and the regulation of immune responses.

Protein Structure

MYD88 is composed of several functional domains:

• Death Domain (DD): Located at the N-terminus, the death domain mediates homotypic protein-protein interactions, particularly with the death domains of IL-1R-associated kinase (IRAK) family members, facilitating signal transduction.
• Intermediate Domain (ID): This region links the death domain to the Toll/IL-1 receptor (TIR) domain, contributing to the structural integrity and function of MYD88.
• TIR Domain: Situated at the C-terminus, the TIR domain is responsible for binding to the TIR domains of TLRs and IL-1Rs, initiating the assembly of the MYD88-dependent signaling complex.

Classification and Subtypes

MYD88 is a unique and essential adaptor protein in the TLR/IL-1R signaling pathways, with no direct subtypes. However, it interacts with various other signaling molecules, such as:

• IRAK Family (IRAK1, IRAK2, IRAK4): Kinases that are recruited to the MYD88 signaling complex and phosphorylated to propagate downstream signaling.
• TRAF6: An E3 ubiquitin ligase that is essential for the activation of NF-κB and MAPKs.
• Other TIR-domain-containing adaptors: Including TIRAP/MAL, which assists MYD88 in signaling from specific TLRs.

Function and Biological Significance

MYD88 is integral to multiple immune functions:

• Innate Immune Response: MYD88 is crucial for the rapid response to pathogens by activating NF-κB and MAPKs, leading to the production of inflammatory cytokines such as IL-6, TNF-α, and IL-1β.
• Adaptive Immune Response: By influencing the production of cytokines and the maturation of antigen-presenting cells, MYD88 indirectly supports the development of adaptive immunity.
• Host Defense: MYD88-dependent signaling is essential for defending against bacterial, viral, and fungal infections.
• Inflammation and Tissue Repair: MYD88-mediated pathways help regulate inflammation and are involved in tissue repair processes following injury.

Clinical Issues

Dysregulation or mutations in MYD88 can lead to various diseases:

• Immunodeficiencies: MYD88 deficiency results in a primary immunodeficiency characterized by increased susceptibility to pyogenic bacterial infections due to impaired TLR/IL-1R signaling.
• Autoimmune Diseases: Aberrant activation of MYD88 signaling can contribute to autoimmune conditions, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, through chronic inflammation.
• Cancer: Somatic mutations in MYD88, particularly the L265P mutation, are frequently found in B-cell lymphomas, such as Waldenström's macroglobulinemia and diffuse large B-cell lymphoma (DLBCL), driving oncogenic signaling pathways.
• Inflammatory Diseases: Overactive MYD88 signaling is implicated in chronic inflammatory diseases, including inflammatory bowel disease (IBD) and atherosclerosis.

Summary

Myeloid differentiation primary response 88 (MYD88) is a critical adaptor protein in the TLR/IL-1R signaling pathways, essential for innate immune responses and inflammation. Structurally, MYD88 comprises a death domain for protein-protein interactions, an intermediate domain, and a TIR domain for receptor binding. MYD88 mediates the activation of NF-κB and MAPKs, leading to the production of pro-inflammatory cytokines. Dysregulation of MYD88 is associated with immunodeficiencies, autoimmune diseases, cancer, and chronic inflammatory conditions. Understanding the role and mechanisms of MYD88 in immune signaling is vital for developing therapeutic interventions for these diseases.