ArticleThe Journal of biological chemistry2011
Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Application potential of toll-like receptors in cancer immunotherapy: Systematic review.Medicine · 2016Pooled it
- MyD88 self-assembles into supramolecular filaments to amplify NF-κB signaling.Fundamental research · 2026Article
- Polymorphism in the TLR Adaptors of the Toll Signalling Pathway for Use in Livestock Breeding for Health Traits.International journal of molecular sciences · 2026Review
- Case Report: Novel variants in theFrontiers in immunology · 2025Article
- OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.Cell death and differentiation · 2024Article
- Mechanism of MyD88S mediated signal termination.Cell communication and signaling : CCS · 2022Article
- Absence of Non-Canonical, InhibitoryFrontiers in immunology · 2021Article
- RNF152 positively regulates TLR/IL-1R signaling by enhancing MyD88 oligomerization.EMBO reports · 2020Article
- Conformational Changes Induced by S34Y and R98C Variants in the Death Domain of Myd88.Frontiers in molecular biosciences · 2020Article
- Putative link between Polo-like kinases (PLKs) and Toll-like receptor (TLR) signaling in transformed and primary human immune cells.Scientific reports · 2019Article
- Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus.Nature communications · 2019Article
- Innate Immune Signaling Organelles Display Natural and Programmable Signaling Flexibility.Cell · 2019Article
- Immune signalling by supramolecular assemblies.Immunology · 2018Review
- Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities.Cancer immunology, immunotherapy : CII · 2018Review
- Defective MyD88 and IRAK4 but not TLR-2 expression in HIV+ individuals with latent tuberculosis infection.Cytokine · 2018Article
- IRAK2 is associated with susceptibility to rheumatoid arthritis.Clinical rheumatology · 2018Article
- Biochemical Isolation of the Myddosome from Murine Macrophages.Methods in molecular biology (Clifton, N.J.) · 2018Article
- TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology.EMBO reports · 2017Article
- Cell-Based Screen Identifies Human Interferon-Stimulated Regulators of Listeria monocytogenes Infection.PLoS pathogens · 2016Article
- The N-terminal loop of IRAK-4 death domain regulates ordered assembly of the Myddosome signalling scaffold.Scientific reports · 2016Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
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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