MYD88
Myeloid differentiation primary response gene (88) (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.[1][2]
Model organisms
Model organisms have been used in the study of MYD88 function. The gene was originally discovered and cloned by Dan Liebermann and Barbara Hoffman in mice.[3] In that species it is a universal adapter protein as it is used by all TLRs (except TLR 3) to activate the transcription factor NF-κB. Mal (also known as TIRAP) is necessary to recruit Myd88 to TLR 2 and TLR 4, and MyD88 then signals through IRAK.[4] It also interacts functionally with amyloid formation and behavior in a transgenic mouse model of Alzheimer's disease.[5]
| Characteristic | Phenotype |
|---|---|
| Homozygote viability | Normal |
| Fertility | Normal |
| Body weight | Normal |
| Anxiety | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Hot plate | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Body temperature | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology | Normal |
| Peripheral blood lymphocytes | Normal |
| Micronucleus test | Normal |
| Heart weight | Normal |
| Salmonella infection | Abnormal[6] |
| All tests and analysis from[7][8] |
A conditional knockout mouse line, called Myd88tm1a(EUCOMM)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[11][12][13] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty-one tests were carried out on homozygous mutant animals, revealing one abnormality: male mutants had an increased susceptibility to bacterial infection.
Function
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.[15]
Interactions
Myd88 has been shown to interact with TLR 4,[16][17][18][19]Interleukin 1 receptor, type I,[20][21]RAC1,[22]IRAK2[19][21][23] and IRAK1.[19][23][24][25]
References
- ^ "Entrez Gene: MYD88 Myeloid differentiation primary response gene (88)".
- ^ 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.
- ^ Lord KA, Hoffman-Liebermann B, Liebermann DA (1990). "Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6". Oncogene 5 (7): 1095–7. PMID 2374694.
- ^ Arancibia SA, Beltrán CJ, Aguirre IM, Silva P, Peralta AL, Malinarich F, Hermoso MA. (2007). "Toll-like receptors are key participants in innate immune responses". Biological research 40 (2): 97–112. doi:10.4067/S0716-97602007000200001. PMID 18064347.
- ^ Lim, JE; Kou J, Song M, Pattanayak A, Jin J, Lalonde R, Fukuchi K (September 2011). "MyD88 Deficiency Ameliorates β-Amyloidosis in an Animal Model of Alzheimer's Disease". Am. J. Pathol. (United States) 179 (3): 1095–103. doi:10.1016/j.ajpath.2011.05.045. PMC 3157279. PMID 21763676.
- ^ "Salmonella infection data for Myd88". Wellcome Trust Sanger Institute.
- ^ a b Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
- ^ "International Knockout Mouse Consortium".
- ^ "Mouse Genome Informatics".
- ^ Skarnes Wc, R. B.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M. et al. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMID 21677750.
- ^ Dolgin E (2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ^ Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
- ^ von Bernuth H, Picard C, Jin Z, et al. (August 2008). "Pyogenic Bacterial Infections in Humans with MyD88 Deficiency". Science 321 (5889): 691–6. doi:10.1126/science.1158298. PMC 2688396. PMID 18669862.
- ^ Chuang, Tsung-Hsien; Ulevitch Richard J (May. 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nat. Immunol. (United States) 5 (5): 495–502. doi:10.1038/ni1066. ISSN 1529-2908. PMID 15107846.
- ^ Doyle, Sean E; O'Connell Ryan, Vaidya Sagar A, Chow Edward K, Yee Kathleen, Cheng Genhong (April 2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". J. Immunol. (United States) 170 (7): 3565–71. ISSN 0022-1767. PMID 12646618.
- ^ Rhee, S H; 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". J. Biol. Chem. (UNITED STATES) 275 (44): 34035–40. doi:10.1074/jbc.M007386200. ISSN 0021-9258. PMID 10952994.
- ^ a b c Fitzgerald, K A; Palsson-McDermott E M, Bowie A G, Jefferies C A, Mansell A S, Brady G, Brint E, Dunne A, Gray P, Harte M T, McMurray D, Smith D E, Sims J E, Bird T A, O'Neill L A (September 2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature (England) 413 (6851): 78–83. doi:10.1038/35092578. ISSN 0028-0836. PMID 11544529.
- ^ Burns, K; Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F (June 2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". Nat. Cell Biol. (ENGLAND) 2 (6): 346–51. doi:10.1038/35014038. ISSN 1465-7392. PMID 10854325.
- ^ a b Muzio, M; Ni J, Feng P, Dixit V M (November 1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science (UNITED STATES) 278 (5343): 1612–5. doi:10.1126/science.278.5343.1612. ISSN 0036-8075. PMID 9374458.
- ^ Jefferies, C; Bowie A, Brady G, Cooke E L, Li X, O'Neill L A (July 2001). "Transactivation by the p65 Subunit of NF-κB in Response to Interleukin-1 (IL-1) Involves MyD88, IL-1 Receptor-Associated Kinase 1, TRAF-6, and Rac1". Mol. Cell. Biol. (United States) 21 (14): 4544–52. doi:10.1128/MCB.21.14.4544-4552.2001. ISSN 0270-7306. PMC 87113. PMID 11416133.
- ^ a b Wesche, H; Gao X, Li X, Kirschning C J, Stark G R, Cao Z (July 1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". J. Biol. Chem. (UNITED STATES) 274 (27): 19403–10. doi:10.1074/jbc.274.27.19403. ISSN 0021-9258. PMID 10383454.
- ^ Chen, Bing-Chang; Wu Wen-Tung, Ho Feng-Ming, Lin Wan-Wan (July 2002). "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". J. Biol. Chem. (United States) 277 (27): 24169–79. doi:10.1074/jbc.M106014200. ISSN 0021-9258. PMID 11976320.
- ^ Li, Shyun; Strelow Astrid, Fontana Elizabeth J, Wesche Holger (April 2002). "IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (8): 5567–72. doi:10.1073/pnas.082100399. ISSN 0027-8424. PMC 122810. PMID 11960013.
Further reading
- Hardiman G, Rock FL, Balasubramanian S, et al. (1997). "Molecular characterization and modular analysis of human MyD88". Oncogene 13 (11): 2467–75. PMID 8957090.
- Bonnert TP, Garka KE, Parnet P, et al. (1997). "The cloning and characterization of human MyD88: a member of an IL-1 receptor related family". FEBS Lett. 402 (1): 81–4. doi:10.1016/S0014-5793(96)01506-2. PMID 9013863.
- Hardiman G, Jenkins NA, Copeland NG, et al. (1998). "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 (1997). "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science 278 (5343): 1612–5. doi:10.1126/science.278.5343.1612. PMID 9374458.
- Jaunin F, Burns K, Tschopp J, et al. (1998). "Ultrastructural distribution of the death-domain-containing MyD88 protein in HeLa cells". Exp. Cell Res. 243 (1): 67–75. doi:10.1006/excr.1998.4131. PMID 9716450.
- Wesche H, Gao X, Li X, et al. (1999). "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". J. Biol. Chem. 274 (27): 19403–10. doi:10.1074/jbc.274.27.19403. PMID 10383454.
- Burns K, Clatworthy J, Martin L, et al. (2000). "Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor". Nat. Cell Biol. 2 (6): 346–51. doi:10.1038/35014038. PMID 10854325.
- Aliprantis AO, Yang RB, Weiss DS, et al. (2000). "The apoptotic signaling pathway activated by Toll-like receptor-2". EMBO J. 19 (13): 3325–36. doi:10.1093/emboj/19.13.3325. PMC 313930. PMID 10880445.
- Rhee SH, Hwang D (2000). "Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase". J. Biol. Chem. 275 (44): 34035–40. doi:10.1074/jbc.M007386200. PMID 10952994.
- Fitzgerald KA, Palsson-McDermott EM, Bowie AG, et al. (2001). "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction". Nature 413 (6851): 78–83. doi:10.1038/35092578. PMID 11544529.
- Tauszig-Delamasure S, Bilak H, Capovilla M, et al. (2002). "Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections". Nat. Immunol. 3 (1): 91–7. doi:10.1038/ni747. PMID 11743586.
- Bannerman DD, Tupper JC, Kelly JD, et al. (2002). "The Fas-associated death domain protein suppresses activation of NF-κB by LPS and IL-1β". J. Clin. Invest. 109 (3): 419–25. doi:10.1172/JCI14774. PMC 150862. PMID 11828002.
- Tamai R, Sakuta T, Matsushita K, et al. (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". Infect. Immun. 70 (3): 1272–8. doi:10.1128/IAI.70.3.1272-1278.2002. PMC 127773. PMID 11854210.
- Radons J, Gabler S, Wesche H, et al. (2002). "Identification of essential regions in the cytoplasmic tail of interleukin-1 receptor accessory protein critical for interleukin-1 signaling". J. Biol. Chem. 277 (19): 16456–63. doi:10.1074/jbc.M201000200. PMID 11880380.
- Janssens S, Burns K, Tschopp J, Beyaert R (2002). "Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88". Curr. Biol. 12 (6): 467–71. doi:10.1016/S0960-9822(02)00712-1. PMID 11909531.
- Li S, Strelow A, Fontana EJ, Wesche H (2002). "IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5567–72. doi:10.1073/pnas.082100399. PMC 122810. PMID 11960013.
- Medvedev AE, Lentschat A, Wahl LM, et al. (2002). "Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells". J. Immunol. 169 (9): 5209–16. PMID 12391239.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Raschi E, Testoni C, Bosisio D, et al. (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, et al. (2003). "Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4". J. Immunol. 170 (7): 3565–71. PMID 12646618.
External links
- MyD88 Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
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