MYD88 explained

Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.^{[1] [2]} originally discovered in the laboratory of Dan A. Liebermann (Lord et al. Oncogene 1990) as a Myeloid differentiation primary response gene.

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.

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:

• IRAK1^{[8] [9]}
• IRAK2^[10]
• Interleukin 1 receptor, type I^{[11] [12]}
• RAC1^[13]
• TLR 4^{[14] [15] [16] [17]}

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]

Further reading

• Hardiman G, Rock FL, Balasubramanian S, Kastelein RA, Bazan JF . Molecular characterization and modular analysis of human MyD88 . Oncogene . 13 . 11 . 2467–75 . December 1996 . 8957090 .
• Bonnert TP, Garka KE, Parnet P, Sonoda G, Testa JR, Sims JE . The cloning and characterization of human MyD88: a member of an IL-1 receptor related family . FEBS Letters . 402 . 1 . 81–4 . January 1997 . 9013863 . 10.1016/S0014-5793(96)01506-2 . 44843127 .
• Hardiman G, Jenkins NA, Copeland NG, Gilbert DJ, Garcia DK, Naylor SL, Kastelein RA, Bazan JF . Genetic structure and chromosomal mapping of MyD88 . Genomics . 45 . 2 . 332–9 . October 1997 . 9344657 . 10.1006/geno.1997.4940 .
• Muzio M, Ni J, Feng P, Dixit VM . IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling . Science . 278 . 5343 . 1612–5 . November 1997 . 9374458 . 10.1126/science.278.5343.1612 . 1997Sci...278.1612M .
• Jaunin F, Burns K, Tschopp J, Martin TE, Fakan S . Ultrastructural distribution of the death-domain-containing MyD88 protein in HeLa cells . Experimental Cell Research . 243 . 1 . 67–75 . August 1998 . 9716450 . 10.1006/excr.1998.4131 .
• Lan X, Han X, Li Q, Li Q, Gao Y, Cheng T, Wan J, Zhu W, Wang J . Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia . Brain, Behavior, and Immunity . 61 . 326–339 . March 2017 . 28007523 . 5453178 . 10.1016/j.bbi.2016.12.012 .
• Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z . 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 . 10383454 . 10.1074/jbc.274.27.19403 . free .
• Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F . 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 . 10854325 . 10.1038/35014038 . 32036101 .
• Aliprantis AO, Yang RB, Weiss DS, Godowski P, Zychlinsky A . The apoptotic signaling pathway activated by Toll-like receptor-2 . The EMBO Journal . 19 . 13 . 3325–36 . July 2000 . 10880445 . 313930 . 10.1093/emboj/19.13.3325 .
• Rhee SH, Hwang D . 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 . 10952994 . 10.1074/jbc.M007386200 . free .
• Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA . Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction . Nature . 413 . 6851 . 78–83 . September 2001 . 11544529 . 10.1038/35092578 . 4333764 . 2001Natur.413...78F .
• Tauszig-Delamasure S, Bilak H, Capovilla M, Hoffmann JA, Imler JL . Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections . Nature Immunology . 3 . 1 . 91–7 . January 2002 . 11743586 . 10.1038/ni747 . 30884230 .
• Bannerman DD, Tupper JC, Kelly JD, Winn RK, Harlan JM . The Fas-associated death domain protein suppresses activation of NF-kappa B by LPS and IL-1 beta . The Journal of Clinical Investigation . 109 . 3 . 419–25 . February 2002 . 11828002 . 150862 . 10.1172/JCI14774 .
• Tamai R, Sakuta T, Matsushita K, Torii M, Takeuchi O, Akira S, Akashi S, Espevik T, Sugawara S, Takada H . Human gingival CD14(+) fibroblasts primed with gamma interferon increase production of interleukin-8 in response to lipopolysaccharide through up-regulation of membrane CD14 and MyD88 mRNA expression . Infection and Immunity . 70 . 3 . 1272–8 . March 2002 . 11854210 . 127773 . 10.1128/IAI.70.3.1272-1278.2002 .
• Radons J, Gabler S, Wesche H, Korherr C, Hofmeister R, Falk W . Identification of essential regions in the cytoplasmic tail of interleukin-1 receptor accessory protein critical for interleukin-1 signaling . The Journal of Biological Chemistry . 277 . 19 . 16456–63 . May 2002 . 11880380 . 10.1074/jbc.M201000200 . free .
• Janssens S, Burns K, Tschopp J, Beyaert R . Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88 . Current Biology . 12 . 6 . 467–71 . March 2002 . 11909531 . 10.1016/S0960-9822(02)00712-1 . free . 2002CBio...12..467J .
• Li S, Strelow A, Fontana EJ, Wesche H . 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 . 11960013 . 122810 . 10.1073/pnas.082100399 . 2002PNAS...99.5567L . free .
• Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN . Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells . Journal of Immunology . 169 . 9 . 5209–16 . November 2002 . 12391239 . 10.4049/jimmunol.169.9.5209 . free .
• Raschi E, Testoni C, Bosisio D, Borghi MO, Koike T, Mantovani A, Meroni PL . Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies . Blood . 101 . 9 . 3495–500 . May 2003 . 12531807 . 10.1182/blood-2002-08-2349 . free .
• Doyle SE, O'Connell R, Vaidya SA, Chow EK, Yee K, Cheng G . Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4 . Journal of Immunology . 170 . 7 . 3565–71 . April 2003 . 12646618 . 10.4049/jimmunol.170.7.3565 . free .

Notes and References

1. Web site: Entrez Gene: MYD88 Myeloid differentiation primary response gene (88).
2. Bonnert TP, Garka KE, Parnet P, Sonoda G, Testa JR, Sims JE . The cloning and characterization of human MyD88: a member of an IL-1 receptor related family . FEBS Letters . 402 . 1 . 81–4 . January 1997 . 9013863 . 10.1016/S0014-5793(96)01506-2 . 44843127 .
3. Deguine J, Barton GM . MyD88: a central player in innate immune signaling . F1000Prime Reports . 6 . 97 . 2014-11-04 . 25580251 . 4229726 . 10.12703/P6-97 . free .
4. Book: Abbas A, Lichtman AH, Pillai S . Cellular and molecular immunology. 10 March 2017. 978-0-323-52323-3. Ninth. Philadelphia, PA. 973917896.
5. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y, Vasconcelos J, Sirvent N, Guedes M, Vitor AB, Herrero-Mata MJ, Aróstegui JI, Rodrigo C, Alsina L, Ruiz-Ortiz E, Juan M, Fortuny C, Yagüe J, Antón J, Pascal M, Chang HH, Janniere L, Rose Y, Garty BZ, Chapel H, Issekutz A, Maródi L, Rodriguez-Gallego C, Banchereau J, Abel L, Li X, Chaussabel D, Puel A, Casanova JL . Pyogenic bacterial infections in humans with MyD88 deficiency . Science . 321 . 5889 . 691–6 . August 2008 . 18669862 . 2688396 . 10.1126/science.1158298 . Jacques Banchereau . 2008Sci...321..691V .
6. Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM . Oncogenically active MYD88 mutations in human lymphoma . Nature . 470 . 7332 . 115–9 . February 2011 . 21179087 . 5024568 . 10.1038/nature09671 . 2011Natur.470..115N .
7. Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR . MYD88 L265P somatic mutation in Waldenström's macroglobulinemia . The New England Journal of Medicine . 367 . 9 . 826–33 . August 2012 . 22931316 . 10.1056/NEJMoa1200710 . free .
8. Chen BC, Wu WT, Ho FM, Lin WW . 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 . 11976320 . 10.1074/jbc.M106014200 . free .
9. Li S, Strelow A, Fontana EJ, Wesche H . 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 . 11960013 . 122810 . 10.1073/pnas.082100399 . 2002PNAS...99.5567L . free .
10. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z . 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 . 10383454 . 10.1074/jbc.274.27.19403 . free .
11. Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F . 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 . 10854325 . 10.1038/35014038 . 32036101 .
12. Muzio M, Ni J, Feng P, Dixit VM . IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling . Science . 278 . 5343 . 1612–5 . November 1997 . 9374458 . 10.1126/science.278.5343.1612 . 1997Sci...278.1612M .
13. Jefferies C, Bowie A, Brady G, Cooke EL, Li X, O'Neill LA . 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 . 11416133 . 87113 . 10.1128/MCB.21.14.4544-4552.2001 .
14. Chuang TH, Ulevitch RJ . Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors . Nature Immunology . 5 . 5 . 495–502 . May 2004 . 15107846 . 10.1038/ni1066 . 39773935 .
15. Doyle SE, O'Connell R, Vaidya SA, Chow EK, Yee K, Cheng G . Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4 . Journal of Immunology . 170 . 7 . 3565–71 . April 2003 . 12646618 . 10.4049/jimmunol.170.7.3565 . free .
16. Rhee SH, Hwang D . 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 . 10952994 . 10.1074/jbc.M007386200 . free .
17. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA . Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction . Nature . 413 . 6851 . 78–83 . September 2001 . 11544529 . 10.1038/35092578 . 4333764 . 2001Natur.413...78F .
18. Netea MG, Wijmenga C, O'Neill LA . Genetic variation in Toll-like receptors and disease susceptibility . Nature Immunology . 13 . 6 . 535–42 . May 2012 . 22610250 . 10.1038/ni.2284 . 24438756 .
19. Matsunaga K, Tahara T, Shiroeda H, Otsuka T, Nakamura M, Shimasaki T, Toshikuni N, Kawada N, Shibata T, Arisawa T . 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 . 24189845 . 10.3892/mmr.2013.1769 . free .