Biology:MYD88

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.[1][2]

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).[3]

TLRs are homologous to Toll receptors, which were first described in the onthogenesis 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.[4]

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.[4]

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.[5] 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[6] and Waldenström's macroglobulinemia.[7]

Interactions

Myd88 has been shown to interact with:


Gene polymorphisms

Various single nucleotide polymorphisms (SNPs) of the MyD88 have been identified. and for some of them an association with susceptibility to various infectious diseases[18] and to some autoimmune diseases like ulcerative colitis was found.[19]

References

  1. ↑ "Entrez Gene: MYD88 Myeloid differentiation primary response gene (88)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4615. 
  2. ↑ "The cloning and characterization of human MyD88: a member of an IL-1 receptor related family". FEBS Letters 402 (1): 81–4. January 1997. doi:10.1016/S0014-5793(96)01506-2. PMID 9013863. 
  3. ↑ "MyD88: a central player in innate immune signaling". F1000Prime Reports 6: 97. 2014-11-04. doi:10.12703/P6-97. PMID 25580251. 
  4. ↑ 4.0 4.1 Cellular and molecular immunology (Ninth ed.). Philadelphia, PA. 10 March 2017. ISBN 978-0-323-52323-3. OCLC 973917896. https://www.worldcat.org/oclc/973917896. 
  5. ↑ "Pyogenic bacterial infections in humans with MyD88 deficiency". Science 321 (5889): 691–6. August 2008. doi:10.1126/science.1158298. PMID 18669862. Bibcode: 2008Sci...321..691V. 
  6. ↑ "Oncogenically active MYD88 mutations in human lymphoma". Nature 470 (7332): 115–9. February 2011. doi:10.1038/nature09671. PMID 21179087. Bibcode: 2011Natur.470..115N. 
  7. ↑ "MYD88 L265P somatic mutation in Waldenström's macroglobulinemia". The New England Journal of Medicine 367 (9): 826–33. August 2012. doi:10.1056/NEJMoa1200710. PMID 22931316. 
  8. ↑ 8.0 8.1 8.2 "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature 413 (6851): 78–83. September 2001. doi:10.1038/35092578. PMID 11544529. Bibcode: 2001Natur.413...78F. 
  9. ↑ 9.0 9.1 "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". The Journal of Biological Chemistry 274 (27): 19403–10. July 1999. doi:10.1074/jbc.274.27.19403. PMID 10383454. 
  10. ↑ "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 277 (27): 24169–79. July 2002. doi:10.1074/jbc.M106014200. PMID 11976320. 
  11. ↑ "IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase". Proceedings of the National Academy of Sciences of the United States of America 99 (8): 5567–72. April 2002. doi:10.1073/pnas.082100399. PMID 11960013. Bibcode: 2002PNAS...99.5567L. 
  12. ↑ 12.0 12.1 "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science 278 (5343): 1612–5. November 1997. doi:10.1126/science.278.5343.1612. PMID 9374458. Bibcode: 1997Sci...278.1612M. 
  13. ↑ "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". Nature Cell Biology 2 (6): 346–51. June 2000. doi:10.1038/35014038. PMID 10854325. 
  14. ↑ "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 21 (14): 4544–52. July 2001. doi:10.1128/MCB.21.14.4544-4552.2001. PMID 11416133. 
  15. ↑ "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nature Immunology 5 (5): 495–502. May 2004. doi:10.1038/ni1066. PMID 15107846. 
  16. ↑ "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". Journal of Immunology 170 (7): 3565–71. April 2003. doi:10.4049/jimmunol.170.7.3565. PMID 12646618. 
  17. ↑ "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 275 (44): 34035–40. November 2000. doi:10.1074/jbc.M007386200. PMID 10952994. 
  18. ↑ "Genetic variation in Toll-like receptors and disease susceptibility". Nature Immunology 13 (6): 535–42. May 2012. doi:10.1038/ni.2284. PMID 22610250. 
  19. ↑ "The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis". Molecular Medicine Reports 9 (1): 28–32. January 2014. doi:10.3892/mmr.2013.1769. PMID 24189845. http://www.spandidos-publications.com/mmr/9/1/28. 

Further reading

External links



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