MYD88

Function

The MYD88 gene provides instructions for making a protein involved in signaling within immune cells. The MyD88 protein acts as an adapter, connecting proteins that receive signals from outside the cell to the proteins that relay signals inside the cell.

In innate immunity, the MyD88 plays a pivotal role in immune cell activation through Toll-like receptors (TLRs), which belong to large group of pattern recognition receptors (PRR). In general, these receptors sense common patterns which are shared by various pathogens – Pathogen-associated molecular pattern (PAMPs), or which are produced/released during cellular damage – damage-associated molecular patterns (DAMPs).

TLRs are homologous to Toll receptors, which were first described in the ontogenesis of fruit flies Drosophila, being responsible for dorso-ventral development. Hence, TLRs have been proved in all animals from insects to mammals. TLRs are located either on the cellular surface (TLR1, TLR2, TLR4, TLR5, TLR6) or within endosomes (TLR3, TLR7, TLR8, TLR9) sensing extracellular or phagocytosed pathogens, respectively. TLRs are integral membrane glycoproteins with typical semicircular-shaped extracellular parts containing leucine-rich repeats responsible for ligand binding, and Intracellular parts containing Toll-Interleukin receptor (TIR) domain.

After ligand binding, all TLRs, apart from TLR3, interact with adaptor protein MyD88. Another adaptor protein, which is activated by TLR3 and TLR4, is called TIR domain-containing adapter-inducing IFN-β (TRIF). Subsequently, these proteins activate two important transcription factors:

• NF-κB is a dimeric protein responsible for expression of various inflammatory cytokines, chemokines and adhesion and costimulatory molecules, which in turn triggers acute inflammation and stimulation of adaptive immunity
• IRFs is a group of proteins responsible for expression of type I interferons setting the so-called antiviral state of a cell.

TLR7 and TLR9 activate both NF-κB and IRF3 through MyD88-dependent and TRIF-independent pathway, respectively.

The human ortholog MYD88 seems to function similarly to mice, since the immunological phenotype of human cells deficient in MYD88 is similar to cells from MyD88 deficient mice. However, available evidence suggests that MYD88 is dispensable for human resistance to common viral infections and to all but a few pyogenic bacterial infections, demonstrating a major difference between mouse and human immune responses. Mutation in MYD88 at position 265 leading to a change from leucine to proline have been identified in many human lymphomas including ABC subtype of diffuse large B-cell lymphoma and Waldenström's macroglobulinemia.

Interactions

Myd88 has been shown to interact with:

• IRAK1
• IRAK2
• Interleukin 1 receptor, type I
• RAC1
• TLR 4

Gene polymorphisms

Various single nucleotide polymorphisms (SNPs) of the MyD88 have been identified. For some SNPs an association with susceptibility to various infectious diseases and to some autoimmune diseases like ulcerative colitis was found. SNPs that impair MyD88 protein activity cause MyD88 deficiency, an innate immune system disorder characterised by increased susceptibility to certain bacterial infections.

References

References

1. "Entrez Gene: MYD88 Myeloid differentiation primary response gene (88)".
2. (January 1997). "The cloning and characterization of human MyD88: a member of an IL-1 receptor related family". FEBS Letters.
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6. (February 2011). "Oncogenically active MYD88 mutations in human lymphoma". Nature.
7. (August 2012). "MYD88 L265P somatic mutation in Waldenström's macroglobulinemia". The New England Journal of Medicine.
8. (July 2002). "Inhibition of interleukin-1beta -induced NF-kappa B activation by calcium/calmodulin-dependent protein kinase kinase occurs through Akt activation associated with interleukin-1 receptor-associated kinase phosphorylation and uncoupling of MyD88". The Journal of Biological Chemistry.
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11. (November 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science.
12. (July 2001). "Transactivation by the p65 subunit of NF-kappaB in response to interleukin-1 (IL-1) involves MyD88, IL-1 receptor-associated kinase 1, TRAF-6, and Rac1". Molecular and Cellular Biology.
13. (May 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nature Immunology.
14. (April 2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". Journal of Immunology.
15. (November 2000). "Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase". The Journal of Biological Chemistry.
16. (September 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature.
17. (May 2012). "Genetic variation in Toll-like receptors and disease susceptibility". Nature Immunology.
18. (January 2014). "The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis". Molecular Medicine Reports.
19. Picard, Capucine. (2010). "Clinical Features and Outcome of Patients With IRAK-4 and MyD88 Deficiency". Medicine.