Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MyD88 (Myeloid Differentiation Primary Response Gene 88)

  • Shaherin Basith
  • Balachandran Manavalan
  • Sangdun Choi
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_588

Synonyms

Historical Background

Myeloid differentiation primary response gene 88 (MyD88) was originally discovered and cloned by Liebermann and Hoffman in 1990 as one of the 12 different mRNA transcripts that were induced in M1 myeloblastic leukemia cells upon activation with lung-conditioned medium or recombinant interleukin (IL)-6 (Lord et al. 1990). The “MyD” portion of the name stands for myeloid differentiation, while “88” refers to the gene number in the list of induced genes (Lord et al. 1990). At the time of its discovery, the MyD88 sequence showed no homology with other sequences available in the databases and contained no recognizable protein motifs. In 1994, the C-terminal portion of MyD88 was found to be similar to a conserved stretch of approximately 200 amino acids in the intracellular regions of the Drosophila Toll receptor and the mammalian interleukin-1 receptor (IL-1R) (Hultmark 1994), and was thus...

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Notes

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF-2015R1A2A2A09001059).

References

  1. Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 1998;9(1):143–50.CrossRefPubMedGoogle Scholar
  2. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.CrossRefGoogle Scholar
  3. Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R, et al. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. J Gastroenterol. 2005;40(1):16–23.CrossRefPubMedGoogle Scholar
  4. Avbelj M, Horvat S, Jerala R. The role of intermediary domain of MyD88 in cell activation and therapeutic inhibition of TLRs. J Immunol. 2011;187(5):2394–404.CrossRefPubMedGoogle Scholar
  5. Bhoj VG, Sun Q, Bhoj EJ, Somers C, Chen X, Torres JP, et al. MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus. Proc Natl Acad Sci USA. 2008;105(37):14046–51.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Brint EK, Xu D, Liu H, Dunne A, McKenzie AN, O'Neill LA, et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol. 2004;5(4):373–9.CrossRefPubMedGoogle Scholar
  7. Buchholz BM, Billiar TR, Bauer AJ. Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus. Am J Physiol Gastrointest Liver Physiol. 2010;299(2):G531–8.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer JL, et al. MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem. 1998;273(20):12203–9.CrossRefPubMedGoogle Scholar
  9. Campos MA, Closel M, Valente EP, Cardoso JE, Akira S, Alvarez-Leite JI, et al. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J Immunol. 2004;172(3):1711–8.CrossRefPubMedGoogle Scholar
  10. Cates EA, Connor EE, Mosser DM, Bannerman DD. Functional characterization of bovine TIRAP and MyD88 in mediating bacterial lipopolysaccharide-induced endothelial NF-kappaB activation and apoptosis. Comp Immunol Microbiol Infect Dis. 2009;32(6):477–90.CrossRefPubMedGoogle Scholar
  11. Coste I, Le Corf K, Kfoury A, Hmitou I, Druillennec S, Hainaut P, et al. Dual function of MyD88 in RAS signaling and inflammation, leading to mouse and human cell transformation. J Clin Invest. 2010;120(10):3663–7.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Esen N, Kielian T. Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns. J Immunol. 2006;176(11):6802–11.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Feinstein E, Kimchi A, Wallach D, Boldin M, Varfolomeev E. The death domain: a module shared by proteins with diverse cellular functions. Trends Biochem Sci. 1995;20(9):342–4.CrossRefPubMedGoogle Scholar
  14. Gelman AE, LaRosa DF, Zhang J, Walsh PT, Choi Y, Sunyer JO, et al. The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation. Immunity. 2006;25(5):783–93.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Hardiman G, Jenkins NA, Copeland NG, Gilbert DJ, Garcia DK, Naylor SL, et al. Genetic structure and chromosomal mapping of MyD88. Genomics. 1997;45(2):332–9.CrossRefPubMedGoogle Scholar
  16. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature. 2005;434(7036):1035–40.CrossRefPubMedGoogle Scholar
  17. Hultmark D. Macrophage differentiation marker MyD88 is a member of the Toll/IL-1 receptor family. Biochem Biophys Res Commun. 1994;199(1):144–6.CrossRefPubMedGoogle Scholar
  18. Janssens S, Beyaert R. A universal role for MyD88 in TLR/IL-1R-mediated signaling. Trends Biochem Sci. 2002;27(9):474–82.CrossRefPubMedGoogle Scholar
  19. Janssens S, Burns K, Vercammen E, Tschopp J, Beyaert R. MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression. FEBS Lett. 2003;548(1–3):103–7.CrossRefPubMedGoogle Scholar
  20. Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci USA. 2006;103(29):10961–6.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7(10):827–40.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Koh YS, Koo JE, Biswas A, Kobayashi KS. MyD88-dependent signaling contributes to host defense against ehrlichial infection. PLoS One. 2010;5(7):e11758.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Li C, Zienkiewicz J, Hawiger J. Interactive sites in the MyD88 Toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1beta signaling pathway. J Biol Chem. 2005;280(28):26152–9.CrossRefPubMedGoogle Scholar
  24. Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature. 2010;465(7300):885–90.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Loiarro M, Gallo G, Fanto N, De Santis R, Carminati P, Ruggiero V, et al. Identification of critical residues of the MyD88 death domain involved in the recruitment of downstream kinases. J Biol Chem. 2009;284(41):28093–103.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Lord KA, Hoffman-Liebermann B, Liebermann DA. Complexity of the immediate early response of myeloid cells to terminal differentiation and growth arrest includes ICAM-1, Jun-B and histone variants. Oncogene. 1990;5(3):387–96.PubMedGoogle Scholar
  27. Ma Y, Liu H, Tu-Rapp H, Thiesen HJ, Ibrahim SM, Cole SM, et al. Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation. Nat Immunol. 2004;5(4):380–7.CrossRefPubMedGoogle Scholar
  28. Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell. 1998;2(2):253–8.CrossRefPubMedGoogle Scholar
  29. Muraille E, De Trez C, Brait M, De Baetselier P, Leo O, Carlier Y. Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response. J Immunol. 2003;170(8):4237–41.CrossRefPubMedGoogle Scholar
  30. Muzio M, Ni J, Feng P, Dixit VM. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science. 1997;278(5343):1612–5.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Naiki Y, Michelsen KS, Zhang W, Chen S, Doherty TM, Arditi M. Transforming growth factor-beta differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling. J Biol Chem. 2005;280(7):5491–5.CrossRefPubMedGoogle Scholar
  32. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–4.PubMedCrossRefGoogle Scholar
  33. Nishiya T, Kajita E, Horinouchi T, Nishimoto A, Miwa S. Distinct roles of TIR and non-TIR regions in the subcellular localization and signaling properties of MyD88. FEBS Lett. 2007;581(17):3223–9.CrossRefPubMedGoogle Scholar
  34. Ochi A, Nguyen AH, Bedrosian AS, Mushlin HM, Zarbakhsh S, Barilla R, et al. MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med. 2012;209(9):1671–87.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Ohnishi H, Tochio H, Kato Z, Orii KE, Li A, Kimura T, et al. Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling. Proc Natl Acad Sci U S A. 2009;106(25):10260–5.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Piggott DA, Eisenbarth SC, Xu L, Constant SL, Huleatt JW, Herrick CA, et al. MyD88-dependent induction of allergic Th2 responses to intranasal antigen. J Clin Invest. 2005;115(2):459–67.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Rahman AH, Cui W, Larosa DF, Taylor DK, Zhang J, Goldstein DR, et al. MyD88 plays a critical T cell-intrinsic role in supporting CD8 T cell expansion during acute lymphocytic choriomeningitis virus infection. J Immunol. 2008;181(6):3804–10.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Rakoff-Nahoum S, Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science. 2007;317(5834):124–7.CrossRefPubMedGoogle Scholar
  39. Scanga CA, Aliberti J, Jankovic D, Tilloy F, Bennouna S, Denkers EY, et al. Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J Immunol. 2002;168(12):5997–6001.CrossRefPubMedGoogle Scholar
  40. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R. Toll-like receptors control activation of adaptive immune responses. Nat Immunol. 2001;2(10):947–50.CrossRefPubMedGoogle Scholar
  41. Seki E, Tsutsui H, Tsuji NM, Hayashi N, Adachi K, Nakano H, et al. Critical roles of myeloid differentiation factor 88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes in mice. J Immunol. 2002;169(7):3863–8.CrossRefPubMedGoogle Scholar
  42. Shi S, Nathan C, Schnappinger D, Drenkow J, Fuortes M, Block E, et al. MyD88 primes macrophages for full-scale activation by interferon-gamma yet mediates few responses to Mycobacterium tuberculosis. J Exp Med. 2003;198(7):987–97.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Sun D, Ding A. MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nat Immunol. 2006;7(4):375–81.CrossRefPubMedGoogle Scholar
  44. Swann JB, Vesely MD, Silva A, Sharkey J, Akira S, Schreiber RD, et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci U S A. 2008;105(2):652–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005;434(7030):243–9.CrossRefPubMedGoogle Scholar
  46. Takeuchi O, Hoshino K, Akira S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol. 2000a;165(10):5392–6.CrossRefPubMedGoogle Scholar
  47. Takeuchi O, Takeda K, Hoshino K, Adachi O, Ogawa T, Akira S. Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol. 2000b;12(1):113–7.CrossRefPubMedGoogle Scholar
  48. Tartaglia LA, Ayres TM, Wong GH, Goeddel DV. A novel domain within the 55 kd TNF receptor signals cell death. Cell. 1993;74(5):845–53.CrossRefPubMedGoogle Scholar
  49. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med. 2005;201(6):915–23.PubMedPubMedCentralCrossRefGoogle Scholar
  50. van der Sar AM, Stockhammer OW, van der Laan C, Spaink HP, Bitter W, Meijer AH. MyD88 innate immune function in a zebrafish embryo infection model. Infect Immun. 2006;74(4):2436–41.PubMedPubMedCentralCrossRefGoogle Scholar
  51. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321(5889):691–6.CrossRefGoogle Scholar
  52. Vyncke L, Bovijn C, Pauwels E, Van Acker T, Ruyssinck E, Burg E, et al. Reconstructing the TIR Side of the Myddosome: a Paradigm for TIR-TIR Interactions. Structure. 2016;24(3):437–47.CrossRefPubMedGoogle Scholar
  53. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2003;4(9):920–7.CrossRefPubMedGoogle Scholar
  54. 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. J Biol Chem. 1999;274(27):19403–10.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity. 1997;7(6):837–47.CrossRefPubMedGoogle Scholar
  56. Yu S, Cho HH, Joo HJ, Bae YC, Jung JS. Role of MyD88 in TLR agonist-induced functional alterations of human adipose tissue-derived mesenchymal stem cells. Mol Cell Biochem. 2008;317(1–2):143–50.CrossRefPubMedGoogle Scholar
  57. Zhu J, Huang X, Yang Y. The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J Clin Invest. 2009;119(8):2388–98.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Shaherin Basith
    • 1
    • 2
  • Balachandran Manavalan
    • 1
    • 3
  • Sangdun Choi
    • 1
  1. 1.Department of Molecular Science and TechnologyAjou UniversitySuwonKorea
  2. 2.National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy and Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoulKorea
  3. 3.Center for In Silico Protein Science, School of Computational SciencesKorea Institute for Advanced StudySeoulKorea