MYD88

Not to be confused with MyoD.

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

MYD88
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2JS7, 2Z5V, 3MOP, 4DOM, 4EO7
Identifiers
Aliases	MYD88, MYD88D, myeloid differentiation primary response 88, innate immune signal transduction adaptor, MYD88 innate immune signal transduction adaptor, IMD68
External IDs	OMIM: 602170; MGI: 108005; HomoloGene: 1849; GeneCards: MYD88; OMA:MYD88 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3p22.2 Start 38,138,478 bp End 38,143,022 bp
Gene location (Mouse) Chr. Chromosome 9 (mouse) Band 9 F3|9 71.33 cM Start 119,165,000 bp End 119,170,477 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in white blood cell mononuclear cell monocyte granulocyte blood gingival epithelium mucosa of ileum periodontal fiber nasal epithelium palpebral conjunctiva Top expressed in granulocyte stroma of bone marrow right lung lobe lip ankle joint uterus esophagus tibiofemoral joint blood duodenum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function death receptor binding protein binding TIR domain binding identical protein binding protein self-association Toll-like receptor binding Cellular component cytosol plasma membrane endosome membrane cytoplasm nucleus Biological process response to interleukin-1 immune system process negative regulation of apoptotic process MyD88-dependent toll-like receptor signaling pathway toll-like receptor signaling pathway cell surface receptor signaling pathway cellular response to mechanical stimulus regulation of inflammatory response positive regulation of interleukin-6 production positive regulation of I-kappaB kinase/NF-kappaB signaling toll-like receptor 9 signaling pathway positive regulation of interleukin-17 production inflammatory response 3'-UTR-mediated mRNA stabilization positive regulation of type I interferon production positive regulation of interleukin-23 production signal transduction defense response to Gram-positive bacterium positive regulation of NF-kappaB transcription factor activity apoptotic process innate immune response type I interferon signaling pathway positive regulation of gene expression positive regulation of interleukin-8 production defense response to bacterium interleukin-1-mediated signaling pathway cellular response to oxidised low-density lipoprotein particle stimulus positive regulation of cytokine production involved in inflammatory response phagocytosis Toll signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4615 17874 Ensembl ENSG00000172936 ENSMUSG00000032508 UniProt Q99836 P22366 RefSeq (mRNA) NM_001172566 NM_001172567 NM_001172568 NM_001172569 NM_002468 NM_001365876 NM_001365877 NM_001374787 NM_001374788 NM_010851 RefSeq (protein) NP_001166037 NP_001166038 NP_001166039 NP_001166040 NP_002459 NP_001352805 NP_001352806 NP_001361716 NP_001361717 NP_034981 Location (UCSC) Chr 3: 38.14 – 38.14 Mb Chr 9: 119.17 – 119.17 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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 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.

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. and for some of them an association with susceptibility to various infectious diseases and to some autoimmune diseases like ulcerative colitis was found.

Further reading

• Hardiman G, Rock FL, Balasubramanian S, Kastelein RA, Bazan JF (December 1996). "Molecular characterization and modular analysis of human MyD88". Oncogene. 13 (11): 2467–75. PMID 8957090.
• Bonnert TP, Garka KE, Parnet P, Sonoda G, Testa JR, Sims JE (January 1997). "The cloning and characterization of human MyD88: a member of an IL-1 receptor related family". FEBS Letters. 402 (1): 81–4. doi:10.1016/S0014-5793(96)01506-2. PMID 9013863. S2CID 44843127.
• Hardiman G, Jenkins NA, Copeland NG, Gilbert DJ, Garcia DK, Naylor SL, et al. (October 1997). "Genetic structure and chromosomal mapping of MyD88". Genomics. 45 (2): 332–9. doi:10.1006/geno.1997.4940. PMID 9344657.
• Muzio M, Ni J, Feng P, Dixit VM (November 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science. 278 (5343): 1612–5. Bibcode:1997Sci...278.1612M. doi:10.1126/science.278.5343.1612. PMID 9374458.
• Jaunin F, Burns K, Tschopp J, Martin TE, Fakan S (August 1998). "Ultrastructural distribution of the death-domain-containing MyD88 protein in HeLa cells". Experimental Cell Research. 243 (1): 67–75. doi:10.1006/excr.1998.4131. PMID 9716450.
• Lan X, Han X, Li Q, Li Q, Gao Y, Cheng T, et al. (March 2017). "Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia". Brain, Behavior, and Immunity. 61: 326–339. doi:10.1016/j.bbi.2016.12.012. PMC 5453178. PMID 28007523.
• Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (July 1999). "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. doi:10.1074/jbc.274.27.19403. PMID 10383454.
• Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, et al. (June 2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". Nature Cell Biology. 2 (6): 346–51. doi:10.1038/35014038. PMID 10854325. S2CID 32036101.
• Aliprantis AO, Yang RB, Weiss DS, Godowski P, Zychlinsky A (July 2000). "The apoptotic signaling pathway activated by Toll-like receptor-2". The EMBO Journal. 19 (13): 3325–36. doi:10.1093/emboj/19.13.3325. PMC 313930. PMID 10880445.
• Rhee SH, Hwang D (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. 275 (44): 34035–40. doi:10.1074/jbc.M007386200. PMID 10952994.
• Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, et al. (September 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature. 413 (6851): 78–83. Bibcode:2001Natur.413...78F. doi:10.1038/35092578. PMID 11544529. S2CID 4333764.
• Tauszig-Delamasure S, Bilak H, Capovilla M, Hoffmann JA, Imler JL (January 2002). "Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections". Nature Immunology. 3 (1): 91–7. doi:10.1038/ni747. PMID 11743586. S2CID 30884230.
• Bannerman DD, Tupper JC, Kelly JD, Winn RK, Harlan JM (February 2002). "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. doi:10.1172/JCI14774. PMC 150862. PMID 11828002.
• Tamai R, Sakuta T, Matsushita K, Torii M, Takeuchi O, Akira S, et al. (March 2002). "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. doi:10.1128/IAI.70.3.1272-1278.2002. PMC 127773. PMID 11854210.
• Radons J, Gabler S, Wesche H, Korherr C, Hofmeister R, Falk W (May 2002). "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. doi:10.1074/jbc.M201000200. PMID 11880380.
• Janssens S, Burns K, Tschopp J, Beyaert R (March 2002). "Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88". Current Biology. 12 (6): 467–71. Bibcode:2002CBio...12..467J. doi:10.1016/S0960-9822(02)00712-1. PMID 11909531.
• Li S, Strelow A, Fontana EJ, Wesche H (April 2002). "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. Bibcode:2002PNAS...99.5567L. doi:10.1073/pnas.082100399. PMC 122810. PMID 11960013.
• Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN (November 2002). "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. doi:10.4049/jimmunol.169.9.5209. PMID 12391239.
• Raschi E, Testoni C, Bosisio D, Borghi MO, Koike T, Mantovani A, et al. (May 2003). "Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies". Blood. 101 (9): 3495–500. doi:10.1182/blood-2002-08-2349. PMID 12531807.
• Doyle SE, O'Connell R, Vaidya SA, Chow EK, Yee K, Cheng G (April 2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". Journal of Immunology. 170 (7): 3565–71. doi:10.4049/jimmunol.170.7.3565. PMID 12646618.

External links

• MyD88 Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)