Myeloid differentiation primary response 88 (MYD88) is aprotein that, in humans, is encoded by theMYD88gene.[5][6] originally discovered in the laboratory of Dan A. Liebermann (Lord et al. Oncogene 1990) as a Myeloid differentiation primary response gene.
The MYD88 gene provides instructions for making a protein involved in signaling within immune cells. The MyD88 protein acts as anadapter, connecting proteins that receive signals from outside the cell to the proteins that relay signals inside the cell.
TLRs are homologous to Toll receptors, which were first described in the ontogenesis of fruit fliesDrosophila, 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 withinendosomes (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 containingToll-Interleukin receptor (TIR) domain.[8]
After ligand binding, all TLRs, apart fromTLR3, interact with adaptor protein MyD88. Another adaptor protein, which is activated by TLR3 and TLR4, is calledTIR 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 andTLR9 activate both NF-κB and IRF3 through MyD88-dependent and TRIF-independent pathway, respectively.[8]
The humanortholog 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 fewpyogenic bacterial infections, demonstrating a major difference between mouse and human immune responses.[9] Mutation in MYD88 at position 265 leading to a change from leucine to proline have been identified in many human lymphomas including ABC subtype ofdiffuse large B-cell lymphoma[10] andWaldenström's macroglobulinemia.[11]
Various single nucleotide polymorphisms (SNPs) of the MyD88 have been identified. For some SNPs an association with susceptibility to various infectious diseases[22] and to some autoimmune diseases likeulcerative colitis was found.[23] SNPs that impair MyD88 protein activity causeMyD88 deficiency, an innate immune system disorder characterised by increased susceptibility to certain bacterial infections.[24]
^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.PMID9013863.S2CID44843127.
^abcFitzgerald 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.PMID11544529.S2CID4333764.
^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.PMID10854325.S2CID32036101.
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.PMID8957090.
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.PMID9013863.S2CID44843127.
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.PMID9344657.
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.PMID9716450.
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.PMID10854325.S2CID32036101.
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.PMID11544529.S2CID4333764.
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.PMID11743586.S2CID30884230.
