MYD88

Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.[5][6]

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
External IDs	OMIM: 602170 MGI: 108005 HomoloGene: 1849 GeneCards: MYD88
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p22.2 Start 38,138,478 bp[1] End 38,143,022 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 F3|9 71.33 cM Start 119,335,934 bp[2] End 119,341,411 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • death receptor binding • GO:0001948 protein binding • TIR domain binding • identical protein binding • protein self-association • Toll-like receptor binding Cellular component • cytosol • cell membrane • endosome membrane • cytoplasm • cell 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 system • 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: 119.34 – 119.34 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[7] In that species it is a universal adapter protein as it is used by almost 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.[8] It also interacts functionally with amyloid formation and behavior in a transgenic mouse model of Alzheimer's disease.[9]

Myd88 knockout mouse phenotype

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[10]
All tests and analysis from[11][12]

A conditional knockout mouse line, called Myd88^{tm1a(EUCOMM)Wtsi}[13][14] 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.[15][16][17] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[11][18] Twenty-one tests were carried out on homozygous mutant animals, revealing one abnormality: male mutants had an increased susceptibility to bacterial infection.

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. 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.[19] 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[20] and Waldenström's macroglobulinemia.[21]

Interactions

Myd88 has been shown to interact with:

• IRAK1[22][23][24][25]
• IRAK2[22][26][23]
• Interleukin 1 receptor, type I[27][26]
• RAC1[28]
• TLR 4[29][30][31][22]

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[32] and to some autoimmune diseases like ulcerative colitis was found.[33]

References

1. GRCh38: Ensembl release 89: ENSG00000172936 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032508 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: MYD88 Myeloid differentiation primary response gene (88)".
6. Bonnert TP, Garka KE, Parnet P, Sonoda G, Testa JR, Sims JE (Jan 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.
7. Lord KA, Hoffman-Liebermann B, Liebermann DA (Jul 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.
8. 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.
9. Lim JE, Kou J, Song M, Pattanayak A, Jin J, Lalonde R, Fukuchi K (Sep 2011). "MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer's disease". The American Journal of Pathology. 179 (3): 1095–103. doi:10.1016/j.ajpath.2011.05.045. PMC 3157279. PMID 21763676.
10. "Salmonella infection data for Myd88". Wellcome Trust Sanger Institute.
11. 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.
12. Mouse Resources Portal, Wellcome Trust Sanger Institute.
13. "International Knockout Mouse Consortium".
14. "Mouse Genome Informatics".
15. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
16. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
17. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
18. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
19. 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 (Aug 2008). "Pyogenic bacterial infections in humans with MyD88 deficiency". Science. 321 (5889): 691–6. Bibcode:2008Sci...321..691V. doi:10.1126/science.1158298. PMC 2688396. PMID 18669862.
20. 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 (2011). "Oncogenically active MYD88 mutations in human lymphoma". Nature. 470 (7332): 115–9. Bibcode:2011Natur.470..115N. doi:10.1038/nature09671. PMC 5024568. PMID 21179087.
21. 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 (2012). "MYD88 L265P somatic mutation in Waldenström's macroglobulinemia". N. Engl. J. Med. 367 (9): 826–33. doi:10.1056/NEJMoa1200710. PMID 22931316.
22. 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 (Sep 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.
23. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (Jul 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.
24. Chen BC, Wu WT, Ho FM, Lin WW (Jul 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". The Journal of Biological Chemistry. 277 (27): 24169–79. doi:10.1074/jbc.M106014200. PMID 11976320.
25. Li S, Strelow A, Fontana EJ, Wesche H (Apr 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.
26. Muzio M, Ni J, Feng P, Dixit VM (Nov 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.
27. Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F (Jun 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.
28. Jefferies C, Bowie A, Brady G, Cooke EL, Li X, O'Neill LA (Jul 2001). "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. doi:10.1128/MCB.21.14.4544-4552.2001. PMC 87113. PMID 11416133.
29. Chuang TH, Ulevitch RJ (May 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nature Immunology. 5 (5): 495–502. doi:10.1038/ni1066. PMID 15107846.
30. Doyle SE, O'Connell R, Vaidya SA, Chow EK, Yee K, Cheng G (Apr 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.
31. Rhee SH, Hwang D (Nov 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.
32. Netea MG, Wijmenga C, O'Neill LA (Jun 2012). "Genetic variation in Toll-like receptors and disease susceptibility". Nature Immunology. 13 (6): 535–42. doi:10.1038/ni.2284. PMID 22610250.
33. Matsunaga K, Tahara T, Shiroeda H, Otsuka T, Nakamura M, Shimasaki T, Toshikuni N, Kawada N, Shibata T, Arisawa T (Jan 2014). "The *1244 A>G polymorphism of MyD88 (rs7744) is closely associated with susceptibility to ulcerative colitis". Molecular Medicine Reports. 9 (1): 28–32. doi:10.3892/mmr.2013.1769. PMID 24189845.

Further reading

• Hardiman G, Rock FL, Balasubramanian S, Kastelein RA, Bazan JF (Dec 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 (Jan 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.
• Hardiman G, Jenkins NA, Copeland NG, Gilbert DJ, Garcia DK, Naylor SL, Kastelein RA, Bazan JF (Oct 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 (Nov 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 (Aug 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, Wan J, Zhu W, Wang J (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 (Jul 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, Lewis A, Ray K, Tschopp J, Volpe F (Jun 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.
• Aliprantis AO, Yang RB, Weiss DS, Godowski P, Zychlinsky A (Jul 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 (Nov 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, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O'Neill LA (Sep 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.
• Tauszig-Delamasure S, Bilak H, Capovilla M, Hoffmann JA, Imler JL (Jan 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.
• Bannerman DD, Tupper JC, Kelly JD, Winn RK, Harlan JM (Feb 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, Akashi S, Espevik T, Sugawara S, Takada H (Mar 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 (Mar 2002). "Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88". Current Biology. 12 (6): 467–71. doi:10.1016/S0960-9822(02)00712-1. PMID 11909531.
• Li S, Strelow A, Fontana EJ, Wesche H (Apr 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 (Nov 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, Meroni PL (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 (Apr 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 US National Library of Medicine Medical Subject Headings (MeSH)