Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly
Open accessAbstract
Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life-threatening infections. Here we analyzed the functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system. Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction. Structural modeling highlights Ser-34 and Arg-98 as residues important for the assembly of the Myddosome, a death domain (DD) post-receptor complex involving the DD of MyD88, IRAK4, and IRAK2 or IRAK1. Using S34Y and R98C as functional probes, our data show that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD88 TIR and IRAK4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure. The differential interference of S34Y and R98C with some (IL-1 receptor, TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways also suggests that receptor specificities exist at the level of the Myddosome. Given their detrimental effect on signaling, it is not surprising that our epidemiological analysis in several case-control studies confirms that S34Y and R98C are rare variants that may drastically contribute to susceptibility to infection in only few individuals.
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There is extensive precedent for rare variants contributing substantially to special cases of complex disease, including infection risk.
“There is thus extensive precedent for rare variants contributing substantially to special cases of complex disease, including risk of infection44.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [44]
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Cites
The International HapMap Project
†The International HapMap Consortium, Genotyping centres: Baylor College of Medicine and ParAllele BioScience, Gibbs, R. A., Belmont, J. W., Hardenbol, P., Willis, T. D., Yu, F., Chinese HapMap Consortium, Yang, H., Ch'ang, L.-Y., et al. (2003) · Nature · doi:10.1038/nature02168 · Cited by 6,057 · see citing works
Self-citationToll-like receptor control of the adaptive immune responses
Iwasaki, A., & Medzhitov, R. M. (2004) · Nature Immunology · doi:10.1038/ni1112 · Cited by 4,166 · see citing works
Unresponsiveness of MyD88-deficient mice to endotoxin.
Kawai, T., Adachi, O., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80086-2 · Cited by 2,367 · see citing works
Human non-synonymous SNPs: server and survey
Ramensky, V. E. (2002) · Nucleic Acids Research · doi:10.1093/nar/gkf493 · Cited by 2,267 · see citing works
A family of human receptors structurally related to Drosophila Toll.
Rock, F., Hardiman, G., Timans, J., Kastelein, R., & Bazan, J. (1998) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.95.2.588 · Cited by 2,009 · see citing works
The c-fos protein interacts with c-JunAP-1 to stimulate transcription of AP-1 responsive genes
Chiu, R., Boyle, W. J., Meek, J., Smeal, T., Hunter, T. R., & Karin, M. (1988) · Cell · doi:10.1016/0092-8674(88)90076-1 · Cited by 1,336 · see citing works
IRAK-M Is a Negative Regulator of Toll-like Receptor Signaling
Kobayashi, K. S., Hernandez, L. D., Galán, J. E., Janeway, C. A., Medzhitov, R. M., & Flavell, R. A. (2002) · Cell · doi:10.1016/s0092-8674(02)00827-9 · Cited by 1,289 · see citing works
Pyogenic Bacterial Infections in Humans with MyD88 Deficiency
von Bernuth, H., Pïcard, C., Jin, Z., Sranujit, R. P., Xiao, H. Q., Ku, C., Chrabieh, M., Ben‐Mustapha, I., Ghandil, P., Çamcıoğlu, Y., et al. (2008) · Science · doi:10.1126/science.1158298 · Cited by 1,287 · see citing works
MyD88: an adapter that recruits IRAK to the IL-1 receptor complex.
Wesche, H., Henzel, W., Shillinglaw, W., Li, S., & Cao, Z.-D. (1997) · Immunity · doi:10.1016/s1074-7613(00)80402-1 · Cited by 1,247 · see citing works
Identification of Lps2 as a key transducer of MyD88-independent TIR signalling
Hoebe, K. H. N., Du, X., Georgel, P., Janssen, E. M., Tabeta, K., Kim, S. O., Goode, J., Lin, P., Mann, N., Mudd, S., et al. (2003) · Nature · doi:10.1038/nature01889 · Cited by 1,232 · see citing works
TLR3 Deficiency in Patients with Herpes Simplex Encephalitis
Zhang, S., Jouanguy, E., Ugolini, S., Smahi, A., Elain, G., Romero, P. J., Segal, D. M., Sancho‐Shimizu, V., Lorenzo, L., Puel, A., et al. (2007) · Science · doi:10.1126/science.1139522 · Cited by 1,165 · see citing works
Helical Assembly in the MyD88-IRAK4-IRAK2 Complex in TLR/IL-1R Signalling
Lin, S.-C., Lo, Y.-C., & Wu, H. (2010) · Nature · doi:10.1038/nature09121 · Cited by 1,111 · see citing works
Toll‐like Receptor and RIG‐1‐like Receptor Signaling
Kawai, T., & Akira, S. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1443.020 · Cited by 985 · see citing works
Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency
Pïcard, C., Puel, A., Bonnet, M., Ku, C., Bustamante, J. C., Yang, K., Soudais, C., Boisson‐Dupuis, S., Feinberg, J. M., Fieschi, C., et al. (2003) · Science · doi:10.1126/science.1081902 · Cited by 828 · see citing works
High-Throughput Mapping of a Dynamic Signaling Network in Mammalian Cells
Barrios‐Rodiles, M., Brown, K. R., Ozdamar, B., Bose, R., Liu, Z., Donovan, R. S., Shinjo, F., Liu, Y., Dembowy, J., Taylor, I. W., et al. (2005) · Science · doi:10.1126/science.1105776 · Cited by 726 · see citing works
IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase
Li, S., Strelow, A., Fontana, E. J., & Wesche, H. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.082100399 · Cited by 714 · see citing works
Common vs. rare allele hypotheses for complex diseases
Schork, N. J., Murray, S. S., Frazer, K. A., & Topol, E. J. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.04.010 · Cited by 649 · see citing works
MyD88, an Adapter Protein Involved in Interleukin-1 Signaling
Burns, K., Martinon, F., Esslinger, C., Pahl, H. L., Schneider, P., Bodmer, J.-L., Marco, F. D., French, L. E., & Tschopp, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.20.12203 · Cited by 631 · see citing works
The interleukin‐1 receptor/Toll‐like receptor superfamily: 10 years of progress
O'Neill, L. A. J. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00701.x · Cited by 612 · see citing works
Burns, K., Janssens, S., Brissoni, B., Olivos, N., Beyaert, R., & Tschopp, J. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021790 · Cited by 512 · see citing works
Sequential control of Toll-like receptor–dependent responses by IRAK1 and IRAK2
Kawagoe, T., Sato, S., Matsushita, K., Kato, H., Matsui, K., Kumagai, Y., Saitoh, T., Kawai, T., Takeuchi, O., & Akira, S. (2008) · Nature Immunology · doi:10.1038/ni.1606 · Cited by 443 · see citing works
Khor, C. C., Chapman, S. J., Vannberg, F. O., Dunne, A., Murphy, C., Ling, E. Y. S., Frodsham, A. J., Walley, A. J., Kyrieleis, O. J. P., Khan, A. R., et al. (2007) · Nature Genetics · doi:10.1038/ng1976 · Cited by 431 · see citing works
Self-citationMotshwene, P. G., Moncrieffe, M. C., Grossmann, J. G., Kao, C. C., Murali, A., Sandercock, A. M., Robinson, C. V., Latz, E., & Gay, N. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.022392 · Cited by 394 · see citing works
Self-citationThe Fas–FADD death domain complex structure unravels signalling by receptor clustering
Scott, F. L., Stec, B., Pop, C., Dobaczewska, M. K., Lee, J. J., Monosov, E., Robinson, H., Salvesen, G. S., Schwarzenbacher, R., & Riedl, S. J. (2009) · Nature · doi:10.1038/nature07606 · Cited by 384 · see citing works
Derivation of rules for comparative protein modeling from a database of protein structure alignments
Šali, A., & Overington, J. P. (1994) · Protein Science · doi:10.1002/pro.5560030923 · Cited by 294 · see citing works
Janssens, S., Burns, K., Tschopp, J., & Beyaert, R. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00712-1 · Cited by 287 · see citing works
The death domain superfamily: a tale of two interfaces?
Weber, C. H., & Vincenz, C. (2001) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(01)01905-3 · Cited by 267 · see citing works
Toll-like receptor polymorphisms and susceptibility to human disease
Misch, E. A., & Hawn, T. R. (2008) · Clinical Science · doi:10.1042/cs20070214 · Cited by 263 · see citing works
Li, X.-X., Commane, M., Burns, C., Vithalani, K. K., Cao, Z.-D., & Stark, G. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.7.4643 · Cited by 253 · see citing works
Structure, function and regulation of the Toll/IL‐1 receptor adaptor proteins
Watters, T. M., Kenny, E. F., & O'Neill, L. A. J. (2007) · Immunology and Cell Biology · doi:10.1038/sj.icb.7100095 · Cited by 217 · see citing works
Toll-Like Receptor 9 Affects Severity of IgA Nephropathy
Suzuki, H., Suzuki, Y., Narita, I., Aizawa, M., Kihara, M., Yamanaka, T., Kanou, T., Tsukaguchi, H., Novák, J., Horikoshi, S., et al. (2008) · Journal of the American Society of Nephrology · doi:10.1681/asn.2007121311 · Cited by 184 · see citing works
Wan, Y., Xiao, H. Q., Affolter, J. T., Kim, T. W., Bulek, K., Chaudhuri, S., Carlson, D., Hamilton, T. A., Mazumder, B., Stark, G. R., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m807822200 · Cited by 89 · see citing works
Loiarro, M., Gallo, G., Fantò, N., Santis, R. D., Carminati, P., Ruggiero, V., & Sette, C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.004465 · Cited by 82 · see citing works
Brikos, C., Wait, R., Begum, S., et al. (2007) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m600455-mcp200 · Cited by 73 · see citing works
Pothlichet, J., Burtey, A., Kubarenko, A. V., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007582 · Cited by 53 · see citing works
Self-citationKubarenko, A. V., Frank, M., & Weber, A. N. R. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351515 · Cited by 42 · see citing works
Self-citationMyD88 Adaptor-Like D96N Is a Naturally Occurring Loss-of-Function Variant of TIRAP
George, J., Kubarenko, A. V., Rautanen, A., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901156 · Cited by 34 · see citing works
Self-citationComprehensive modeling and functional analysis of Toll‐like receptor ligand‐recognition domains
Kubarenko, A. V., Ranjan, S., Colak, E., et al. (2010) · Protein Science · doi:10.1002/pro.333 · Cited by 25 · see citing works
Self-citationConner, J. R., Smirnova, I., & Poltorak, A. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20090490 · Cited by 22 · see citing works
Park, H. H., & Wu, H. (2007) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309107007889 · Cited by 17 · see citing works
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- [22]Barrios-Rodiles M. Brown K. R. Ozdamar B. Bose R. Liu Z. Donovan R. S. Shinjo F. Liu Y. Dembowy J. Taylor I. W. Luga V. Przulj N. Robinson M. Suzuki H. Hayashizaki Y. Jurisica I. Wrana J. L. (2005) Science 307, 1621– 1625 15761153
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Gay, N. J., Symmons, M. F., Gangloff, M., & Bryant, C. E. (2014) · Nature Reviews Immunology · doi:10.1038/nri3713 · Cited by 832 · see citing works
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Deguine, J., & Barton, G. M. (2014) · F1000Prime Reports · doi:10.12703/p6-97 · Cited by 692 · see citing works
- Authors
- George, J., Motshwene, P. G., Wang, H., Kubarenko, A. V., Rautanen, A., Mills, T. C., Hill, A. V. S., Gay, N. J., & Weber, A. N. R.
- Affiliations
- German Cancer Research Center (DE)
- University of Cambridge (GB)
- Centre for Human Genetics (GB)
- Corresponding author
- Weber, Alexander N.R.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 286
- Issue
- 2
- Pages
- 1341-1353
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3020742
- OpenAlex
- W1990975597
- Cited by
- 66
- References
- 40
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 3 · 2014: 7 · 2013: 5 · 2012: 7
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- British Heart Foundation
- Biotechnology and Biological Sciences Research Council (BB/G002797/1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- MyD88, Myddosome, IRAK4, IRAK2, IRAK1, death domain, NF-κB activation, Toll-like receptor signaling, IL-1 signaling, homo-oligomerization, innate immunity, infection susceptibility, single nucleotide polymorphisms, TIR domain, receptor specificity
- MeSH terms
- Crystallography, Genotype, Humans, Infections, Models, Chemical, Phenotype, Structure-Activity Relationship, Genetic Variation, Signal Transduction, Protein Structure, Tertiary, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Interleukin-1 Receptor-Associated Kinases, Myeloid Differentiation Factor 88
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