Affinage

MYD88

Myeloid differentiation primary response protein MyD88 · UniProt Q99836

Length
296 aa
Mass
33.2 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MYD88 is a cytoplasmic adaptor with an N-terminal death domain (DD) and C-terminal TIR domain that serves as the central signaling scaffold for the IL-1R and Toll-like receptor (TLR) families (PMID:9575168, PMID:9344657). Upon ligand engagement it homodimerizes through DD-DD and TIR-TIR interactions, couples to the receptor, and activates JNK and NF-κB; mutations that block DD dimerization abolish this activity (PMID:9575168). MYD88 nucleates assembly of the 'Myddosome', recruiting IRAK4 and IRAK1/2 via DD interactions that depend on specific residues such as Ser-34 and Arg-98 (PMID:20966070), whereupon IRAK4 kinase activity drives downstream signaling while the IRAK4 scaffold function integrates MYD88- and TRIF-dependent arms of TLR4 (PMID:35977521). Signal propagation requires K63-linked polyubiquitin chains generated redundantly by TRAF6 and Pellino1/2, which ubiquitinate IRAK1, IRAK4 and MYD88 itself to activate TAK1 and downstream MAPK/NF-κB cascades (PMID:28404732), with PKD1 acting downstream of MYD88/IRAK to license TRAF6 ubiquitination (PMID:19414785). Genetic studies established MYD88 as essential for responses to LPS via TLR4, peptidoglycan via TLR2, and CpG DNA via TLR9, while revealing parallel MYD88-independent TLR4 outputs (PMID:10435584, PMID:11313410, PMID:11254583). Beyond canonical NF-κB signaling, MYD88 scaffolds PKCε and PYK2 to TLR4 (PMID:18458086, PMID:19955209), couples IFN-γR1 to p38-dependent post-transcriptional stabilization of TNF and IP-10 mRNAs (PMID:16491077), and drives a non-canonical IL-1β→MYD88→ARNO→ARF6 pathway controlling endothelial barrier function (PMID:23143332). MYD88 abundance is restrained by SPOP/Cullin-3-mediated proteasomal degradation (PMID:32365080). The recurrent TIR-domain L265P mutation is a gain-of-function oncogenic driver in ABC-DLBCL and Waldenström's macroglobulinemia: it spontaneously assembles IRAK1/IRAK4 complexes, producing constitutive IRAK4 kinase activity, NF-κB and JAK/STAT3 signaling, and SYK activation (PMID:21179087, PMID:22931316, PMID:32005797), is selectively K63-polyubiquitinated by RNF138 to amplify signaling (PMID:33025009), and can be transferred between cells via extracellular vesicles to recruit endogenous wild-type MYD88 (PMID:29358175). MYD88 also functions in non-immune contexts including myoblast fusion via non-canonical NF-κB and Wnt signaling (PMID:29158520), RAS-driven keratinocyte transformation (PMID:22908325), osteocyte-driven osteolysis through RANKL (PMID:36333322), and tauopathy-associated inflammasome activation (PMID:34551296).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 Medium

    Establishing the modular DD-TIR architecture of MYD88 provided the structural framework for understanding how it would later be shown to bridge receptors and downstream kinases.

    Evidence cDNA cloning, gene structure analysis, and chromosomal mapping

    PMID:9344657

    Open questions at the time
    • Did not establish function of either domain
    • No interaction partners identified at this stage
  2. 1998 High

    Demonstrating that MYD88 homodimerizes via its death domain and activates NF-κB/JNK downstream of the IL-1R established it as an adaptor that transmits receptor signals to TRAF6 and IRAK.

    Evidence Co-IP, dominant-negative and point mutants, reporter assays in 293 cells

    PMID:9575168

    Open questions at the time
    • Stoichiometry and ordered assembly of the complex not resolved
    • Did not address TLR signaling
  3. 1999 High

    Genetic knockout showed MYD88 is essential for LPS/TLR4-driven inflammation yet revealed a parallel MYD88-independent pathway, defining the bifurcation of TLR4 signaling.

    Evidence MyD88-knockout mice, LPS challenge, cytokine and NF-κB/MAPK assays

    PMID:10435584

    Open questions at the time
    • Identity of the MYD88-independent adaptor not defined here
    • Did not map which TLRs strictly require MYD88
  4. 2001 High

    Comparative TLR studies positioned MYD88 immediately downstream of TLR2 in a defined NF-κB cascade and showed differential MYD88 requirements across TLR4, TLR9 and distinct DC outputs.

    Evidence Dominant-negative epistasis in HEK293/TLR2 cells and MyD88/TLR4-deficient DCs and macrophages

    PMID:11254583 PMID:11313410 PMID:11500829

    Open questions at the time
    • Mechanism distinguishing MYD88-dependent and -independent DC maturation unresolved
    • Did not address receptor-proximal complex assembly
  5. 2006 High

    Discovery that MYD88 associates with IFN-γR1 and stabilizes cytokine mRNAs via p38 extended its role beyond canonical NF-κB transcription to post-transcriptional control.

    Evidence Reciprocal Co-IP, mRNA half-life assays, MyD88-deficient cells, kinase inhibitors

    PMID:16491077

    Open questions at the time
    • Direct vs indirect IFN-γR1–MYD88 binding not resolved
    • Trans-acting AU-rich element-binding effectors not identified
  6. 2007 High

    Characterization of the neuron-enriched MYD88-5 family member at mitochondria with JNK3 showed MYD88-family proteins can act outside microbial immunity in neuronal death.

    Evidence BAC transgenic and KO mice, Co-IP with JNK3, mitochondrial fractionation, oxygen-glucose deprivation

    PMID:17724133

    Open questions at the time
    • Relationship of MYD88-5 to canonical MYD88 signaling unclear
    • Mechanism of JNK3 mitochondrial recruitment not detailed
  7. 2008 High

    Showing MYD88 scaffolds PKCε phosphorylation and recruitment to TLR4 broadened the adaptor's role to organizing additional kinases required for NF-κB activation.

    Evidence MyD88 KO/KD/OE, PKCε phosphorylation assays, TLR4 Co-IP, reconstitution in PKCε-/- cells

    PMID:18458086

    Open questions at the time
    • Whether PKCε binds MYD88 directly not established
    • Position of PKCε relative to the Myddosome unresolved
  8. 2009 Medium

    Identification of PI3K p85, PKD1 and PYK2 as MYD88-associated regulators refined the proximal signaling network, including a negative-regulatory MYD88/PI3K interaction.

    Evidence Co-IP with domain/motif mutants, RNAi knockdown, KO macrophages, TRAF6 ubiquitination and NF-κB readouts

    PMID:19289601 PMID:19414785 PMID:19955209

    Open questions at the time
    • Indirect support for PI3K negative regulation
    • Direct vs scaffolded interactions not all resolved
  9. 2010 High

    Defining DD residues required for Myddosome assembly and showing that the L265P TIR mutation drives spontaneous IRAK1/4 assembly transformed MYD88 from a normal adaptor into a defined oncogenic driver.

    Evidence Structural modeling, mutagenesis, Co-IP, RNAi/rescue, kinase and NF-κB/STAT3 assays in ABC-DLBCL

    PMID:20400509 PMID:20966070 PMID:21179087

    Open questions at the time
    • High-resolution structure of mutant Myddosome not provided
    • Why L265P specifically destabilizes the autoinhibited state unclear
  10. 2012 High

    Linking MYD88 L265P to Waldenström's macroglobulinemia and uncovering non-canonical (ARNO/ARF6 vascular, RAS-keratinocyte) functions expanded the disease and signaling scope of the adaptor.

    Evidence Whole-genome sequencing of WM, MYD88 inhibition in WM cells; direct ARNO binding assays; MyD88/IL-1R KO RAS keratinocyte grafts

    PMID:22908325 PMID:22931316 PMID:23143332

    Open questions at the time
    • Structural basis of ARNO–MYD88 binding not resolved
    • How L265P selects NF-κB vs alternative outputs unclear
  11. 2017 High

    Triple-knockout and reconstitution work resolved that TRAF6 and Pellino1/2 redundantly build the K63-ubiquitin chains that ubiquitinate IRAK1/4 and MYD88 to activate TAK1.

    Evidence TRAF6/Pellino1/2 triple-KO cells, ligase-dead TRAF6 knockin mice, in vitro TAK1 activation

    PMID:28404732

    Open questions at the time
    • Relative physiological contribution of each ligase across cell types unresolved
    • Chain architecture on MYD88 itself not detailed
  12. 2018 High

    Demonstrating cell-autonomous MYD88 control of myoblast fusion via non-canonical NF-κB and Wnt showed a developmental role distinct from immune signaling.

    Evidence Conditional KO and overexpression, in vitro myogenesis, overload hypertrophy models

    PMID:29158520

    Open questions at the time
    • Upstream receptor driving myogenic MYD88 unknown
    • Direct effectors linking MYD88 to Wnt unidentified
  13. 2019 High

    Showing that L265P MYD88 packaged in extracellular vesicles can transfer between cells and recruit endogenous wild-type MYD88 revealed a receptor-independent, intercellular mode of oncogenic signaling.

    Evidence EV isolation, confocal uptake, Co-IP, in vivo injection, patient bone marrow analysis

    PMID:29358175

    Open questions at the time
    • Efficiency and physiological extent of transfer unclear
    • Whether recipient signaling sustains transformation not shown
  14. 2020 Medium

    Identifying SPOP-mediated degradation, BANK1 binding, and L265P-driven SYK activation defined both turnover control of MYD88 and additional partners shaping pathway output.

    Evidence Co-IP with domain mapping, SPOP KO/proteasome inhibition with Salmonella model; BANK1 Co-IP/co-localization; p-SYK Co-IP and perturbation in mutant lymphoma

    PMID:31243359 PMID:32005797 PMID:32365080

    Open questions at the time
    • Direct vs indirect MYD88–SYK association unresolved
    • Functional consequence of BANK1–MYD88 binding limited
  15. 2021 High

    Discovery of RNF138-catalyzed mutation-specific K63-ubiquitination, with A20 counter-regulation, and a MYD88/NLRP3 axis in tauopathy refined mechanisms amplifying or extending MYD88 signaling.

    Evidence Linkage-specific ubiquitination assays, RNF138 knockdown and site mutagenesis, NF-κB readouts; MyD88 deletion in hTau mice

    PMID:33025009 PMID:34551296

    Open questions at the time
    • Why RNF138 selects mutant over wild-type MYD88 not fully explained
    • Whether MYD88 acts upstream of inflammasome assembly directly unclear
  16. 2022 High

    Dissecting IRAK4 scaffold vs kinase roles, osteocyte MYD88-driven RANKL/osteolysis, and a MYD88→STING1→ACOD1 itaconate axis revealed how MYD88 integrates distinct downstream programs in different cell types.

    Evidence IRAK4 scaffold/kinase-dead reconstitution; osteocyte-specific KO/restoration with ChIP and ubiquitination assays; STING1/MYD88 deletion and itaconate measurement

    PMID:35769880 PMID:35977521 PMID:36333322

    Open questions at the time
    • Direct MYD88–STING1 interaction not biochemically confirmed
    • How MYD88 selects transcriptional vs metabolic outputs unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the wild-type vs L265P Myddosome achieves distinct conformational states and selects among the diverse downstream programs (NF-κB, STAT3, Wnt, ARF6, mRNA stabilization, itaconate) in a cell-type-specific manner remains unresolved.
  • No high-resolution structure of the mutant Myddosome
  • Rules governing output selection across cell types undefined
  • Quantitative contribution of vesicular MYD88 transfer in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
IFNGR1IRAK1IRAK4PRKCEPTK2BRNF138SPOPTRAF6
Complex memberships
Myddosome

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 MyD88 functions as an adaptor protein in IL-1 signaling: it forms homodimers via DD-DD and Toll-Toll interactions, co-immunoprecipitates with the IL-1R signaling complex in an IL-1-dependent manner, and overexpression activates JNK and NF-κB through its death domain. A point mutation (F56N/MyD88-lpr) that prevents DD dimerization blocks these activities. Dominant negative versions of TRAF6 and IRAK inhibit MyD88-induced NF-κB activation. Co-immunoprecipitation, overexpression/dominant-negative constructs, point mutagenesis, reporter assays in 293 cells The Journal of biological chemistry High 9575168
1999 MyD88 is essential for LPS (endotoxin) responses downstream of TLR4: MyD88 knockout mice lack LPS-induced shock, B-cell proliferation, and cytokine secretion by macrophages and fibroblasts. However, NF-κB and MAP kinase activation are not abolished in MyD88-KO cells, demonstrating a MyD88-independent pathway also emanates from TLR4. MyD88 knockout mouse model; LPS challenge; cytokine measurement; NF-κB/MAPK assays Immunity High 10435584
2001 MyD88 is required for LPS-induced cytokine production from dendritic cells but not for LPS-induced functional DC maturation (upregulation of costimulatory molecules). Both pathways originate from the TLR4 intracytoplasmic region, as both were abolished in C3H/HeJ (TLR4 mutant) DCs. MyD88 is absolutely required for TLR9 (bacterial DNA)-induced DC maturation, demonstrating differential pathway requirements across TLRs. MyD88-deficient and TLR4-mutant mouse DCs; LPS and CpG stimulation; costimulatory molecule upregulation; APC activity assays; cytokine measurement Journal of immunology High 11313410
2001 Taxol (paclitaxel) LPS-mimetic activity requires both TLR4 and MyD88 for TNF and NO production and NF-κB-driven gene expression. Macrophages from TLR4-null or MyD88-KO mice produced minimal TNF/NO upon Taxol. However, Taxol-induced MAPK activation and NF-κB nuclear translocation were preserved in MyD88-KO macrophages (with slight kinetic delay), indicating a TLR4-dependent/MyD88-independent pathway also exists for these signals. TLR4-deficient and MyD88-KO primary macrophages; dominant-negative MyD88 transfection; TNF/NO measurement; NF-κB reporter/luciferase assay; MAPK activation assay European journal of immunology High 11500829
2001 Peptidoglycan (PGN) and micrococci signal through TLR2 to induce IL-8 via a sequential pathway TLR2→MyD88→IRAK→TRAF6→NIK→IKK→NF-κB. Dominant-negative MyD88 completely blocked PGN/micrococcus-induced NF-κB activation and IL-8 gene expression, positioning MyD88 immediately downstream of TLR2. Dominant-negative expression constructs (MyD88, IRAK, NIK, IKK, TRAF6) in HEK293 cells expressing TLR2/CD14; NF-κB reporter assay; IL-8 gene expression Infection and immunity High 11254583
2006 MyD88 mediates a post-transcriptional mechanism downstream of IFN-γ receptor signaling: IFN-γ stimulation induces physical association between IFN-γR1 and MyD88. MyD88 increases the mRNA half-life (not synthesis) of IFN-γ-induced TNF and IP-10 transcripts via activation of mixed-lineage kinase 3 and p38 MAPK, requiring an AU-rich element in the 3′ UTR. Co-immunoprecipitation of IFN-γR1 with MyD88; mRNA stability assay; MyD88-deficient cells; kinase inhibitors; RNA half-life measurement Nature immunology High 16491077
2007 MyD88-5 (a vertebrate MyD88 family member) is preferentially expressed in neurons, co-localizes with mitochondria and JNK3, and recruits JNK3 from cytosol to mitochondria. Co-immunoprecipitation confirmed MyD88-5 interacts with JNK3. Hippocampal neurons from MyD88-5-deficient mice are protected from oxygen-glucose deprivation-induced death, whereas MyD88-5-null macrophages respond normally to microbial products. MyD88-5/GFP BAC transgenic mice; co-immunoprecipitation of MyD88-5 with JNK3; mitochondrial co-fractionation; MyD88-5-KO neurons; oxygen-glucose deprivation assay The Journal of experimental medicine High 17724133
2008 MyD88 acts as a scaffold to couple PKCε to TLRs: LPS-induced PKCε phosphorylation at Ser-346 and Ser-368, 14-3-3β binding, and recruitment to TLR4 are all MyD88-dependent. MyD88 overexpression causes constitutive PKCε phosphorylation; acute MyD88 knockdown abolishes Ser-346 phosphorylation. PKCε phosphorylation at these sites is required for TLR4- and TLR2-induced NF-κB activation and IκB degradation. MyD88-KO mouse embryo fibroblasts and macrophages; MyD88 knockdown in 293 cells; MyD88 overexpression; PKCε phosphorylation assays; TLR4 co-immunoprecipitation; NF-κB reporter assay in PKCε-/- reconstituted cells The Journal of biological chemistry High 18458086
2009 MyD88 interacts with PI3K p85 subunit via a YXXM motif in its TIR domain, and this interaction negatively regulates TLR4 signaling. A YXXM→YXXA mutant MyD88 bound more strongly to p85, TLR4, and wild-type MyD88, yet was less active than wild-type, suggesting sustained MyD88/PI3K interaction at the TLR4 signaling platform limits downstream output. LPS-induced Akt phosphorylation was blunted in MyD88−/− macrophages. Co-immunoprecipitation of MyD88 variants with PI3K p85, TLR4, and wild-type MyD88; MyD88 TIR/DD domain deletion and YXXM point mutants; Akt phosphorylation in MyD88-KO macrophages Journal of leukocyte biology Medium 19289601
2009 Protein kinase D1 (PKD1) is activated downstream of MyD88 and IRAK4/1 (but not TRAF6) in TLR signaling. PKD1 is required for MyD88-dependent TRAF6 ubiquitination, TAK1 activation, MAPK and transcription factor activation, and proinflammatory gene expression. PKD1 does not contribute to TRIF-dependent type I IFN responses. PKD1 knockdown in macrophages and DCs; TLR ligand stimulation; TRAF6 ubiquitination assay; TAK1, MAPK and NF-κB activation assays; cytokine/IFN measurement Journal of immunology Medium 19414785
2009 PYK2 interacts with MyD88 (requiring MyD88's death domain) in vitro and in macrophages; this interaction is increased upon LPS stimulation. PYK2-deficient macrophages show reduced IκB phosphorylation/degradation, decreased NF-κB activation, and reduced IL-1β expression in response to LPS, placing PYK2 as a co-regulator upstream of NF-κB via interaction with MyD88. Co-immunoprecipitation of PYK2 with MyD88 in vitro and in macrophages; PYK2-KO macrophages; LPS stimulation; IκB phosphorylation/degradation; NF-κB activation assay Journal of leukocyte biology Medium 19955209
2010 The L265P mutation in the MYD88 TIR domain is a gain-of-function oncogenic driver in ABC DLBCL. The MYD88 L265P mutant spontaneously assembles a protein complex containing IRAK1 and IRAK4, leading to constitutive IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB activation, JAK kinase activation of STAT3, and secretion of IL-6, IL-10, and IFN-β. Wild-type MYD88 did not substitute for L265P in sustaining ABC DLBCL cell survival. RNA interference screening; RNA resequencing; co-immunoprecipitation of MYD88 L265P with IRAK1/4; kinase activity assays; IRAK1 phosphorylation; NF-κB/STAT3 signaling assays; cytokine secretion measurement; rescue experiments with WT vs. L265P MYD88 Nature High 21179087
2010 Two naturally occurring human MYD88 death-domain variants, S34Y and R98C, show severely reduced NF-κB activation due to impaired MyD88 homo-oligomerization and reduced IRAK4 interaction. Structural modeling identifies Ser-34 and Arg-98 as key residues for Myddosome assembly (the DD complex of MyD88, IRAK4, and IRAK2/1). MyD88 TIR domain and IRAK4 kinase domain modulate DD homo-oligomerization. S34Y and R98C differentially impair signaling through IL-1R, TLR2, TLR4, TLR5, and TLR7, but not TLR9. In vitro cellular NF-κB activation assay; co-immunoprecipitation for homo-oligomerization and IRAK4 binding; structural modeling; receptor-specific signaling assays with TLR2/4/5/7/9 and IL-1R The Journal of biological chemistry High 20966070
2010 IRAK1 and IRAK4 directly phosphorylate Mal (MyD88 adaptor-like/TIRAP), promoting its ubiquitination and proteasomal degradation. MyD88 itself is not a substrate for either IRAK and does not undergo degradation. This process negatively regulates TLR2 and TLR4 signaling. In vitro kinase assay with IRAK1/4; co-expression and immunoprecipitation; kinase-inactive IRAK mutants; LPS-induced ubiquitination assay; IRAK1/4 inhibitor; IRAK1/4 knockdown The Journal of biological chemistry High 20400509
2012 MYD88 L265P triggers IRAK-mediated NF-κB signaling and is a somatic gain-of-function mutation found in ~91% of Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma patients. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation and NF-κB nuclear translocation in WM cells expressing MYD88 L265P. Whole-genome sequencing; Sanger sequencing validation; MYD88 signaling inhibition assay; IκBα/NF-κB phosphorylation and nuclear staining in WM cells The New England journal of medicine High 22931316
2012 MYD88 mediates an NF-κB-independent pathway downstream of IL-1β in endothelial cells: ARNO directly binds MYD88, and IL-1β signals through MYD88→ARNO→ARF6 to disrupt endothelial barrier function and vascular stability. This pathway is distinct from the canonical NF-κB transcriptional pathway. Direct binding assay (ARNO–MYD88 interaction); human endothelial cell model; NF-κB-independent assay; ARF6/ARNO functional experiments; animal models of inflammatory arthritis Nature High 23143332
2012 In keratinocytes, oncogenic RAS establishes an autocrine signaling loop through IL-1α→IL-1R→MyD88 that leads to IκBα phosphorylation and NF-κB activation, driving proinflammatory gene expression and impairing differentiation. MyD88 exerts a cell-intrinsic function in RAS-mediated transformation; MyD88-/- RAS-expressing keratinocytes form only a few small tumors in orthotopic grafts. MyD88-/- and IL-1R-/- mice; oncogenic RAS expression in keratinocytes; orthotopic graft model; pharmacological and genetic IL-1α/NF-κB blockade; proinflammatory gene expression analysis The Journal of experimental medicine High 22908325
2017 TRAF6 and Pellino1/2 E3 ligases redundantly generate K63-linked ubiquitin chains for MyD88-dependent IL-1 signaling. In TRAF6/Pellino1/Pellino2 triple-KO cells, IL-1-induced K63-Ub chains, ubiquitylation of IRAK1, IRAK4, and MyD88, and TAK1 activation are abolished. Pellino1-generated K63-Ub chains activate TAK1 complex with similar efficiency to TRAF6-generated chains in vitro. TRAF6/Pellino1/Pellino2 triple-KO cells; E3 ligase-inactive TRAF6 knockin mice; ubiquitination assays; TAK1 activation assay in vitro; cytokine measurement; osteoclast differentiation assay Proceedings of the National Academy of Sciences of the United States of America High 28404732
2017 MyD88 promotes myoblast fusion in a cell-autonomous manner. MyD88 protein levels increase during in vitro myogenesis and in conditions of skeletal muscle growth. Deletion of MyD88 impairs fusion without affecting myoblast survival, proliferation, or differentiation. MyD88 regulates non-canonical NF-κB and canonical Wnt signaling during myogenesis and promotes overload-induced myofiber hypertrophy. MyD88 conditional deletion in myoblasts; in vitro myogenesis assay; overexpression of MyD88 in exogenous myoblasts; muscle regeneration and overload hypertrophy in vivo mouse models; NF-κB and Wnt signaling assays Nature communications High 29158520
2018 MyD88 L265P protein is present in extracellular vesicles (EVs) shed from WM cells and can be transferred into recipient mast cells and macrophages. Transferred MyD88 L265P recruits endogenous wild-type MyD88, triggering proinflammatory signaling in the absence of receptor activation. This transfer was also observed in vivo in mice and MyD88-loaded EVs were detected in bone marrow aspirates of WM patients. EV isolation and characterization; confocal microscopy of EV uptake; co-immunoprecipitation of MyD88 L265P with endogenous MyD88; signaling assays in recipient cells; in vivo mouse EV injection; patient bone marrow aspirate analysis Blood High 29358175
2019 BANK1 directly binds MyD88 (and TRAF6) via its TIR domain, as demonstrated by co-immunoprecipitation. The natural BANK1-40C variant shows increased binding to MyD88. BANK1 co-localizes with TLR7/9, TRAF6, and MyD88 in mouse splenic B cells and co-localization increases after TLR7/9 agonist stimulation. Co-immunoprecipitation of BANK1 with MyD88 and TRAF6; domain deletion and point mutation experiments; confocal co-localization in mouse splenic B cells; TLR7/9 agonist stimulation Cellular & molecular immunology Medium 31243359
2020 SPOP (a Cullin 3-based ubiquitin ligase adaptor) recognizes the intermediate domain of MyD88 and promotes its proteasomal degradation, negatively regulating NF-κB pathway activity. Knockdown or genetic ablation of SPOP leads to elevated MyD88 protein and increased IL-1β production upon LPS challenge in macrophages. Spop-deficient mice are more susceptible to Salmonella infection. Co-immunoprecipitation of SPOP with MyD88; domain mapping of MyD88 interaction; SPOP knockdown and KO; proteasome inhibitor experiments; NF-κB/IL-1β functional assays; Salmonella infection model PLoS pathogens High 32365080
2020 Mutated MYD88 L265P activates SYK (a BCR signaling component): p-SYK co-immunoprecipitates with MYD88 in MYD88-mutated lymphoma cells, and confocal microscopy confirms co-localization. MYD88 knockdown or signaling inhibition abrogates SYK activation, while expression of mutated (but not wild-type) MYD88 amplifies p-SYK. SYK supports p-STAT3 and p-AKT signaling in MYD88-mutated cells. Co-immunoprecipitation of p-SYK with MYD88; confocal co-localization; MYD88 knockdown; MYD88 signaling inhibitor; expression of mutant vs WT MYD88; SYK inhibitor/knockdown; cell viability assays Blood cancer journal Medium 32005797
2021 E3 ligase RNF138 catalyzes K63-linked non-proteolytic polyubiquitination of MYD88 L265P (but not wild-type MYD88), which enhances IRAK recruitment and NF-κB activation. A20 mediates K48-linked ubiquitination of RNF138 for proteasomal degradation, acting as a counter-regulatory mechanism. Mutation of MYD88 L265P ubiquitination sites or RNF138 knockdown abolishes constitutive NF-κB activation. Ubiquitination assay distinguishing K63 vs K48 linkage; RNF138 knockdown; MYD88 L265P ubiquitination site mutagenesis; co-immunoprecipitation; NF-κB activity assays; lymphoma growth experiments Blood High 33025009
2021 Pathological tau (pTau) activates IL-1β via a MyD88- and NLRP3-ASC-dependent pathway in myeloid cells/microglia. Deletion of MyD88 prevents both IL-1β expression and activation in the hTau mouse model of tauopathy. MyD88 deletion in hTau mice; NLRP3/ASC/caspase-1 inhibition; inflammasome activation assays; IL-1β measurement; mouse behavioral/cognitive assessment Cell reports Medium 34551296
2022 The IRAK4 scaffold (independent of its kinase activity) is required for TRAF6 activation by both MYD88 and TRIF downstream of TLR4, integrating the two TLR4 signaling pathways. IRAK4 kinase activity is essential for MYD88-dependent signaling specifically. IRAK4 knockout and kinase-inactive/scaffold mutant reconstitution in TLR4-stimulated cells; TRAF6 activation assays; MYD88 and TRIF signaling readouts Cell reports High 35977521
2022 MYD88 in osteocytes directly drives bacterially-induced osteolysis via RANKL upregulation. Osteocyte-specific MYD88 deletion protects against PAMP-induced calvarial osteolysis and P. gingivalis-driven alveolar bone resorption. Mechanistically, osteocyte MYD88 activation increases CREB and STAT3 binding to RANKL enhancers and suppresses K48-ubiquitination of CREB/CBP and STAT3. Osteocyte-specific MYD88 KO and restoration mice; calvarial PAMP injection model; oral P. gingivalis infection model; RANKL expression assay; ChIP for CREB/STAT3 at Rankl enhancers; ubiquitination assay; systemic MYD88 inhibitor treatment Nature communications High 36333322
2022 MYD88 directly blocks autophagic degradation of STING1, causing subsequent IRF3/JUN-mediated ACOD1 (IRG1) gene transcription and itaconate production in myeloid cells following TLR4 signaling. CGAS (the DNA sensor) does not contribute to this STING1-dependent ACOD1 expression; MYD88 is the key adaptor. STING1 deletion in myeloid cells abolishes ACOD1/itaconate production. STING1 and MYD88 deletion/interaction studies; cyclic dinucleotide stimulation; autophagic degradation assay; ACOD1 expression and itaconate measurement; myeloid-specific STING1 KO mice; endotoxemia and sepsis models iScience Medium 35769880
1997 MyD88 has a modular gene structure with an N-terminal death domain (encoded by exon 1) and C-terminal TIR (Toll/IL-1 receptor) domain. It is an evolutionarily conserved, widely expressed gene mapped to mouse chromosome 9 distal region and human chromosome 3p22-p21.3. cDNA cloning; gene structure analysis (5 exons); interspecific backcross mapping; somatic cell hybrid mapping; Northern blot; RT-PCR Genomics Medium 9344657
2016 In adenovirus keratitis, MyD88 co-immunoprecipitates with Src kinase in infected mouse corneas and human corneal fibroblasts, and MyD88 inhibitory peptide reduces Src phosphorylation. TLR2 and TLR9 act synergistically; MyD88-/- mice show markedly reduced keratitis and inflammatory cytokine expression. Co-immunoprecipitation of MyD88 with Src kinase; MyD88 inhibitory peptide; MyD88-/-, TLR2-/-, TLR9-/-, and TLR2/9 double-KO mouse infection model; Src phosphorylation assay; cytokine expression Immunology and cell biology Medium 27528076

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1574 10435584
2010 Oncogenically active MYD88 mutations in human lymphoma. Nature 1221 21179087
2012 MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. The New England journal of medicine 978 22931316
2014 MyD88: a central player in innate immune signaling. F1000prime reports 560 25580251
1998 MyD88, an adapter protein involved in interleukin-1 signaling. The Journal of biological chemistry 500 9575168
2001 Endotoxin-induced maturation of MyD88-deficient dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 371 11313410
2002 A universal role for MyD88 in TLR/IL-1R-mediated signaling. Trends in biochemical sciences 335 12217523
2010 Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 319 21057262
2009 TLR4/MyD88/PI3K interactions regulate TLR4 signaling. Journal of leukocyte biology 277 19289601
2007 MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. Journal of immunology (Baltimore, Md. : 1950) 266 17202381
2001 The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. European journal of immunology 224 11500829
2007 MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. The Journal of experimental medicine 191 17724133
2013 MYD88 L265P mutation in Waldenstrom macroglobulinemia. Blood 188 23532735
2006 MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nature immunology 180 16491077
2014 Toll-Like Receptors and Cancer: MYD88 Mutation and Inflammation. Frontiers in immunology 144 25132836
2012 Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability. Nature 140 23143332
2001 Micrococci and peptidoglycan activate TLR2-->MyD88-->IRAK-->TRAF-->NIK-->IKK-->NF-kappaB signal transduction pathway that induces transcription of interleukin-8. Infection and immunity 140 11254583
2012 Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. European journal of immunology 139 23255009
2016 Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. The Journal of clinical investigation 123 27869651
2020 Myeloid Differentiation Primary Response Protein 88 (MyD88): The Central Hub of TLR/IL-1R Signaling. Journal of medicinal chemistry 110 32931267
2014 A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nature cell biology 103 25362351
2010 SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. European journal of immunology 103 20306472
2005 MyD88 and TLR2, but not TLR4, are required for host defense against Cryptococcus neoformans. European journal of immunology 102 15714580
2021 MyD88 and beyond: a perspective on MyD88-targeted therapeutic approach for modulation of host immunity. Immunologic research 99 33834387
2018 MYD88 L265P Mutation in Lymphoid Malignancies. Cancer research 99 29703722
2017 Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling. Proceedings of the National Academy of Sciences of the United States of America 96 28404732
2009 Identification and characterization of TLR8 and MyD88 homologs in Atlantic salmon (Salmo salar). Developmental and comparative immunology 95 19422846
2008 T cell expression of MyD88 is required for resistance to Toxoplasma gondii. Proceedings of the National Academy of Sciences of the United States of America 93 18308927
2012 IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. The Journal of experimental medicine 92 22908325
2008 Uropathogenic Escherichia coli block MyD88-dependent and activate MyD88-independent signaling pathways in rat testicular cells. Journal of immunology (Baltimore, Md. : 1950) 90 18390738
2022 The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways. Cell reports 85 35977521
2021 Proteopathic tau primes and activates interleukin-1β via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway. Cell reports 76 34551296
2021 MyD88: At the heart of inflammatory signaling and cardiovascular disease. Journal of molecular and cellular cardiology 74 34371036
2013 MyD88 and its divergent toll in carcinogenesis. Trends in immunology 73 23660392
2022 Schisandrin B Attenuates Diabetic Cardiomyopathy by Targeting MyD88 and Inhibiting MyD88-Dependent Inflammation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 68 36180407
2014 MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome. British journal of haematology 64 25160558
2003 Mycobacterial infection in MyD88-deficient mice. Microbiology and immunology 63 14638995
2013 MYD88 expression and L265P mutation in diffuse large B-cell lymphoma. Human pathology 60 23380077
2003 Mal and MyD88: adapter proteins involved in signal transduction by Toll-like receptors. Journal of endotoxin research 60 12691620
2018 MyD88 as a therapeutic target for inflammatory lung diseases. Expert opinion on therapeutic targets 59 29658361
2005 Cross talk between MyD88 and focal adhesion kinase pathways. Journal of immunology (Baltimore, Md. : 1950) 56 15905587
2022 Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection. Nature communications 55 36333322
2010 Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly. The Journal of biological chemistry 55 20966070
2017 MyD88 promotes myoblast fusion in a cell-autonomous manner. Nature communications 54 29158520
2010 IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal). The Journal of biological chemistry 52 20400509
2009 Protein kinase D1 is essential for MyD88-dependent TLR signaling pathway. Journal of immunology (Baltimore, Md. : 1950) 51 19414785
2008 Differential induction of MyD88- and TRIF-dependent pathways in equine monocytes by Toll-like receptor agonists. Veterinary immunology and immunopathology 51 19019456
2018 Dual functional roles of the MyD88 signaling in colorectal cancer development. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 50 30086464
2013 Penta-O-galloyl-β-D-glucose ameliorates inflammation by inhibiting MyD88/NF-κB and MyD88/MAPK signalling pathways. British journal of pharmacology 50 23941302
2013 Mal, more than a bridge to MyD88. IUBMB life 50 23983209
2019 BANK1 interacts with TRAF6 and MyD88 in innate immune signaling in B cells. Cellular & molecular immunology 49 31243359
2014 MYD88 L265P mutation analysis helps define nodal lymphoplasmacytic lymphoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 48 25216226
2021 Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas. Blood 47 33232972
2015 TLR4-HMGB1-, MyD88- and TRIF-dependent signaling in mouse intestinal ischemia/reperfusion injury. World journal of gastroenterology 47 26217083
2013 CD79B and MYD88 mutations in diffuse large B-cell lymphoma. Human pathology 47 24444466
2008 The scaffold MyD88 acts to couple protein kinase Cepsilon to Toll-like receptors. The Journal of biological chemistry 47 18458086
2022 The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity. iScience 45 35769880
2015 Significance of TLR4/MyD88 expression in breast cancer. International journal of clinical and experimental pathology 44 26261595
2014 Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses. Journal of immunology (Baltimore, Md. : 1950) 43 25355920
2007 MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses. Journal of immunology (Baltimore, Md. : 1950) 43 17339472
2019 Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis. Cell reports 42 30650348
2016 TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology. EMBO reports 41 27979975
2013 Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. Oncogene 40 23728346
2020 SYK is activated by mutated MYD88 and drives pro-survival signaling in MYD88 driven B-cell lymphomas. Blood cancer journal 39 32005797
2008 MyD88 intrinsically regulates CD4 T-cell responses. Journal of virology 38 19052080
2018 Extracellular vesicle-mediated transfer of constitutively active MyD88L265P engages MyD88wt and activates signaling. Blood 37 29358175
2017 Synergistic cooperation and crosstalk between MYD88 and mutations that dysregulate CD79B and surface IgM. The Journal of experimental medicine 37 28701369
2020 SPOP promotes ubiquitination and degradation of MyD88 to suppress the innate immune response. PLoS pathogens 35 32365080
2018 MyD88 Deficiency Protects Against Dry Eye-Induced Damage. Investigative ophthalmology & visual science 34 30025110
2024 Gut microbiota regulates host melatonin production through epithelial cell MyD88. Gut microbes 33 38353638
2021 MYD88 L265P elicits mutation-specific ubiquitination to drive NF-κB activation and lymphomagenesis. Blood 33 33025009
2009 PYK2 interacts with MyD88 and regulates MyD88-mediated NF-kappaB activation in macrophages. Journal of leukocyte biology 33 19955209
1997 Genetic structure and chromosomal mapping of MyD88. Genomics 33 9344657
2022 Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma. Science advances 32 35044826
2018 Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma. Blood cancer journal 32 30301877
2015 High prevalence of the MYD88 mutation in testicular lymphoma: Immunohistochemical and genetic analyses. Pathology international 32 26388135
2018 Oncogenic MYD88 mutations in lymphoma: novel insights and therapeutic possibilities. Cancer immunology, immunotherapy : CII 31 30203262
2017 MyD88 in Mycobacterium tuberculosis infection. Medical microbiology and immunology 31 28220253
2014 Role of MYD88 in lymphoplasmacytic lymphoma diagnosis and pathogenesis. Hematology. American Society of Hematology. Education Program 31 25696843
2022 MYD88 Mutations: Transforming the Landscape of IgM Monoclonal Gammopathies. International journal of molecular sciences 30 35628381
2014 Dendritic cell specific targeting of MyD88 signalling pathways in vivo. European journal of immunology 30 25403892
2021 Role of Adaptor Protein Myeloid Differentiation 88 (MyD88) in Post-Subarachnoid Hemorrhage Inflammation: A Systematic Review. International journal of molecular sciences 27 33919485
2018 MyD88 and TLR4 Expression in Epithelial Ovarian Cancer. Mayo Clinic proceedings 27 29502561
2016 Myeloid-Specific Gene Deletion of Protein Phosphatase 2A Magnifies MyD88- and TRIF-Dependent Inflammation following Endotoxin Challenge. Journal of immunology (Baltimore, Md. : 1950) 27 27872207
2013 MyD88 in DNA repair and cancer cell resistance to genotoxic drugs. Journal of the National Cancer Institute 26 23766530
2018 Sepsis Upregulates CD14 Expression in a MyD88-Dependent and Trif-Independent Pathway. Shock (Augusta, Ga.) 25 28562479
2017 MYD88 Inhibitor ST2825 Suppresses the Growth of Lymphoma and Leukaemia Cells. Anticancer research 24 29061802
2021 Evolution of Toll, Spatzle and MyD88 in insects: the problem of the Diptera bias. BMC genomics 23 34289811
2014 Dual function of MyD88 in inflammation and oncogenesis: implications for therapeutic intervention. Current opinion in oncology 23 24285099
2020 Expression of the prosurvival kinase HCK requires PAX5 and mutated MYD88 signaling in MYD88-driven B-cell lymphomas. Blood advances 21 31935288
2017 MyD88 contribution to ocular surface homeostasis. PloS one 21 28796783
2017 MyD88-dependent dendritic and epithelial cell crosstalk orchestrates immune responses to allergens. Mucosal immunology 21 29067999
2016 HMGB1 facilitates hypoxia-induced vWF upregulation through TLR2-MYD88-SP1 pathway. European journal of immunology 20 27480067
2020 Abnormal brain structure and behavior in MyD88-deficient mice. Brain, behavior, and immunity 19 33002631
2015 MyD88 Polymorphisms and Association with Susceptibility to Salmonella Pullorum. BioMed research international 19 26881204
2012 Mutational and expressional analyses of MYD88 gene in common solid cancers. Tumori 19 23235763
2024 MyD88 and Its Inhibitors in Cancer: Prospects and Challenges. Biomolecules 18 38785969
2019 Hepatic MyD88 regulates liver inflammation by altering synthesis of oxysterols. American journal of physiology. Endocrinology and metabolism 18 31039009
2016 Role of MyD88 in adenovirus keratitis. Immunology and cell biology 18 27528076
2015 Polysaccharopeptide exerts immunoregulatory effects via MyD88-dependent signaling pathway. International journal of biological macromolecules 18 26546866

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