Affinage

MYD88

Myeloid differentiation primary response protein MyD88 · UniProt Q99836

Round 2 corrected
Length
296 aa
Mass
33.2 kDa
Annotated
2026-04-29
130 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MYD88 is a central adaptor protein in innate immune signaling that couples Toll-like receptors (TLRs) and IL-1 receptor family members to downstream activation of NF-κB, MAPKs, and interferon regulatory factors, thereby orchestrating inflammatory cytokine production, type I interferon induction, and cell fate decisions. Its bipartite architecture—an N-terminal death domain (DD) and a C-terminal TIR domain—enables hierarchical assembly of the Myddosome, a left-handed helical oligomer of 6 MyD88, 4 IRAK4, and 4 IRAK2/IRAK1 death domains that activates IRAK4 kinase activity, IRAK1 phosphorylation, and TRAF6/Pellino-mediated K63-linked ubiquitination to engage NF-κB and IRF5/IRF7 transcription factors (PMID:20485341, PMID:28404732, PMID:15361868, PMID:15665823). Beyond canonical TLR/IL-1R signaling, MYD88 scaffolds PKCε to TLRs, associates with IFN-γR1 to stabilize cytokine-induced mRNAs, binds ARNO/ARF6 to disrupt vascular integrity independently of NF-κB, blocks autophagic degradation of STING1 to promote ACOD1 expression, and promotes myoblast fusion through non-canonical NF-κB and Wnt signaling (PMID:18458086, PMID:16491077, PMID:23143332, PMID:35769880, PMID:29158520). The somatic gain-of-function L265P mutation constitutively assembles the Myddosome and drives NF-κB/STAT3 signaling in B-cell lymphomas including diffuse large B-cell lymphoma and Waldenström macroglobulinemia, while autosomal recessive MYD88 deficiency in humans causes susceptibility to life-threatening pyogenic bacterial infections (PMID:21179087, PMID:22931316, PMID:18669862).

Mechanistic history

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

    The fundamental question of how IL-1R and Toll receptor signals reach NF-κB was resolved by identifying MYD88 as a bipartite DD–TIR adaptor that is recruited to the receptor complex via its TIR domain and activates IRAK and TRAF6 via its death domain, establishing the core signaling architecture of TLR/IL-1R pathways.

    Evidence Co-immunoprecipitation, dominant-negative overexpression, deletion mutagenesis, reporter assays across multiple labs

    PMID:9374458 PMID:9430229 PMID:9575168 PMID:9734363

    Open questions at the time
    • Stoichiometry and structural basis of the MYD88 signaling complex were unknown
    • Whether MYD88 served all TLRs or only a subset was not established
    • Mechanism of IRAK activation by MYD88 was not resolved
  2. 1999 High

    The in vivo requirement for MYD88 in innate immunity was established by knockout mice that lacked LPS shock, macrophage cytokine responses, and B cell proliferation—but retained delayed NF-κB activation—revealing a bifurcation into MYD88-dependent and MYD88-independent TLR4 pathways.

    Evidence MYD88 knockout mice with cytokine ELISA, NF-κB assays, and proliferation assays

    PMID:10435584

    Open questions at the time
    • Identity of the MYD88-independent adaptor (later TRIF) was unknown
    • Whether MYD88 was required for all TLRs beyond TLR4 had not been tested
  3. 2000 High

    MYD88 was shown to bifurcate signaling not only toward NF-κB but also toward apoptosis through direct binding of FADD and caspase-8 downstream of TLR2, establishing MYD88 as a decision node for cell fate.

    Evidence Co-immunoprecipitation of MyD88–FADD, dominant-negative constructs, caspase activity assays

    PMID:10880445

    Open questions at the time
    • How the choice between apoptotic and NF-κB pathways is regulated at MYD88 was not resolved
    • Whether necroptotic pathways are also governed by MYD88 was unexplored
  4. 2001 High

    The adaptor TIRAP/Mal was identified as a TIR-domain heterodimer partner that bridges TLR4 to MYD88, establishing a two-adaptor recruitment model later shown to involve PIP2-mediated membrane targeting of TIRAP.

    Evidence Co-immunoprecipitation, dominant-negative Mal, reporter assays; followed by live imaging of PIP2-dependent Mal localization (2006)

    PMID:11544529 PMID:16751103

    Open questions at the time
    • Whether TIRAP serves all TLRs or only a subset was debated
    • Structural basis for the TIRAP–MYD88 heterodimer was not resolved
  5. 2003 High

    The alternatively spliced isoform MyD88s was shown to act as a natural dominant-negative inhibitor because it lacks the intermediate domain required to recruit IRAK-4, providing the first evidence of negative regulation at the level of MYD88 itself.

    Evidence Co-immunoprecipitation demonstrating loss of IRAK-4 binding by MyD88s, phosphorylation analysis, NF-κB reporter assays

    PMID:12538665

    Open questions at the time
    • Physiological contexts and regulation of MyD88s splicing were not defined
    • Whether MyD88s affects IRF signaling was untested
  6. 2005 High

    MYD88 was connected to interferon regulatory factor signaling: its death domain directly binds IRF7 to drive IFN-α responses downstream of TLR7/8/9, and IRF5 acts downstream of MYD88-TRAF6 to induce proinflammatory cytokine genes, diversifying MYD88 output beyond NF-κB.

    Evidence Co-immunoprecipitation, IRF5 knockout mice, nuclear translocation, ubiquitination assays, reporter assays

    PMID:15361868 PMID:15665823

    Open questions at the time
    • How pathway choice between NF-κB, IRF5, and IRF7 is determined at the Myddosome was unknown
    • Whether IRF5 and IRF7 are activated through the same or distinct MYD88 complexes was unresolved
  7. 2008 High

    MYD88 was found to scaffold PKCε to TLRs and to associate with IFN-γR1 for post-transcriptional mRNA stabilization, expanding its function beyond TLR/IL-1R to a non-canonical IFN-γ signaling role and to kinase scaffolding.

    Evidence Co-immunoprecipitation in MYD88 KO cells, phosphorylation-site mutagenesis, mRNA half-life assays

    PMID:16491077 PMID:18458086

    Open questions at the time
    • Structural basis for MYD88–IFN-γR1 and MYD88–PKCε interactions was unknown
    • Whether MYD88 scaffolding of PKCε is relevant to all TLRs was not tested comprehensively
  8. 2008 High

    Human autosomal recessive MYD88 deficiency was shown to cause life-threatening pyogenic bacterial infections but surprising resistance to most other pathogens, defining the essential and redundant roles of MYD88-dependent signaling in human immunity.

    Evidence Human genetic study with functional cellular assays confirming loss of MYD88-dependent signaling in patient cells

    PMID:18669862

    Open questions at the time
    • Why only a narrow range of pyogenic bacteria requires MYD88-dependent defense was not mechanistically explained
    • Long-term outcomes and compensatory mechanisms in MYD88-deficient patients were incompletely characterized
  9. 2010 High

    The crystal structure of the Myddosome (6 MyD88 DD : 4 IRAK4 DD : 4 IRAK2 DD) revealed a left-handed helical assembly with hierarchical recruitment and composite binding interfaces, providing the structural basis for signal amplification and explaining why specific DD mutations (S34Y, R98C) impair oligomerization.

    Evidence X-ray crystallography with mutagenesis validation of interface residues; functional assays of human DD variants

    PMID:20485341 PMID:20966070

    Open questions at the time
    • How the TIR domain oligomer connects to the DD oligomer structurally was not resolved
    • Full-length MYD88 structure remained unavailable
    • How Myddosome disassembly is regulated was unknown
  10. 2010 High

    The MYD88 L265P somatic mutation was identified as an oncogenic driver in ABC-DLBCL that constitutively assembles a Myddosome complex activating IRAK4/IRAK1, NF-κB, and JAK-STAT3 signaling—later confirmed in Waldenström macroglobulinemia—establishing MYD88 as a bona fide oncogene in B-cell malignancies.

    Evidence RNAi screening, RNA resequencing, Co-IP of constitutive complex, kinase assays, WGS in WM patients, pharmacological inhibition

    PMID:21179087 PMID:22931316

    Open questions at the time
    • Mechanism of spontaneous Myddosome assembly by L265P was not structurally resolved
    • Whether L265P cooperates with specific secondary mutations was unclear
  11. 2012 High

    MYD88 was shown to signal through a non-canonical NF-κB-independent pathway by directly binding ARNO/CYTH2 to activate ARF6 and disrupt vascular integrity, demonstrating functional outputs beyond transcription factor activation.

    Evidence Co-immunoprecipitation, siRNA knockdown, endothelial cell models, in vivo inflammatory arthritis models

    PMID:23143332

    Open questions at the time
    • Which domain of MYD88 mediates ARNO binding was not mapped
    • Whether the MYD88-ARNO axis operates in cell types beyond endothelium was untested
  12. 2017 High

    K63-linked ubiquitination in the MYD88 pathway was shown to require combined TRAF6 and Pellino E3 ligase activity, as triple-KO cells (but not single KOs) abolished ubiquitination of IRAK1, IRAK4, and MYD88, redefining the ubiquitin-mediated activation step.

    Evidence TRAF6/Pellino1/Pellino2 triple-KO cells, E3 ligase-inactive knockin mice, in vitro ubiquitination assays

    PMID:28404732

    Open questions at the time
    • Relative contributions of each Pellino isoform in different TLR contexts were unclear
    • Specific ubiquitination sites on MYD88 were not mapped in this study
  13. 2017 High

    MYD88 was found to promote myoblast fusion in a cell-autonomous, TLR-independent manner through non-canonical NF-κB and Wnt pathways, expanding its physiological roles beyond immunity to muscle development.

    Evidence Conditional MYD88 knockout, in vitro myoblast differentiation, in vivo muscle overload model, lentiviral overexpression

    PMID:29158520

    Open questions at the time
    • The receptor or upstream signal activating MYD88 during myogenesis was unknown
    • Whether MYD88 Myddosome assembly occurs in myoblasts was not determined
  14. 2020 High

    SPOP was identified as the Cullin3-based E3 ligase adaptor that targets MYD88 for proteasomal degradation via its intermediate domain, providing the first defined ubiquitin-proteasome-dependent negative regulatory mechanism for MYD88 protein levels.

    Evidence Co-immunoprecipitation, ubiquitination assays, SPOP KO cells and mice, in vivo Salmonella infection model

    PMID:32365080

    Open questions at the time
    • Whether SPOP-mediated degradation is regulated by stimulation or post-translational modifications was untested
    • Interplay between SPOP degradation and NEDDylation-mediated negative regulation was uncharacterized
  15. 2021 High

    Constitutive NF-κB activation by MYD88 L265P was shown to depend on mutation-specific K63-linked ubiquitination by RNF138, which does not modify wild-type MYD88; A20 counteracts this by targeting RNF138 for K48-linked ubiquitination and proteasomal degradation, revealing a mutation-specific regulatory circuit in B-cell lymphomas.

    Evidence Co-immunoprecipitation, ubiquitination assays, RNF138 knockdown, ubiquitination-site mutagenesis, lymphoma growth assays

    PMID:33025009

    Open questions at the time
    • Structural basis for RNF138 selectivity toward L265P over wild-type MYD88 was not resolved
    • Whether RNF138 targeting could serve as a therapeutic strategy in vivo was untested
  16. 2022 High

    MYD88 was shown to block autophagic degradation of STING1, promoting STING1-dependent IRF3/JUN-driven ACOD1 expression and itaconate production—a cross-talk mechanism linking TLR and cGAS-STING pathways that protects against endotoxemia and sepsis.

    Evidence Co-immunoprecipitation, MYD88 and STING1 knockout/conditional KO mice, autophagy assays, sepsis model

    PMID:35769880

    Open questions at the time
    • How MYD88 physically blocks STING1 autophagy was mechanistically unresolved
    • Whether this cross-talk operates in non-myeloid cells was unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of MYD88 bridging the TIR and DD oligomers, the structural mechanism by which L265P spontaneously nucleates the Myddosome, the upstream signals engaging MYD88 in non-immune contexts such as myogenesis and neuronal homeostasis, and the integration of competing post-translational modifications (NEDDylation, SPOP-mediated degradation, K63-ubiquitination) in tuning MYD88 activity in vivo.
  • No full-length MYD88 structure exists bridging TIR oligomer to DD oligomer
  • Mechanism of L265P-driven spontaneous Myddosome assembly is structurally unresolved
  • Integration of NEDDylation, SPOP degradation, and ubiquitination as a regulatory network is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0060089 molecular transducer activity 5
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 16 R-HSA-162582 Signal Transduction 9 R-HSA-1643685 Disease 4 R-HSA-5357801 Programmed Cell Death 2
Partners
ARNOFADDIRAK1IRAK4IRF5IRF7TIRAPTRAF6
Complex memberships
Myddosome (MYD88-IRAK4-IRAK2/IRAK1)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MyD88 is recruited to the IL-1 receptor complex following IL-1 stimulation and mediates association of IRAK with the receptor; the death domain-containing N-terminus of MyD88 activates NF-κB, and its C-terminus interacts with the IL-1 receptor to block NF-κB activation induced by IL-1 but not TNF. Co-immunoprecipitation, dominant-negative overexpression, deletion mutagenesis Immunity High 9430229
1997 MyD88 acts as a death domain-containing adaptor downstream of the human Toll receptor and IL-1R, coupling these receptors to IRAK and TRAF6 to activate NF-κB; Toll and IL-1R signaling pathways differ in AP-1 activation. Overexpression, dominant-negative constructs, reporter assays in cell lines Molecular cell High 9734363
1997 MyD88 is identified as a proximal mediator of IL-1R-induced NF-κB activation alongside IRAK-2; dominant-negative forms of MyD88 attenuate IL-1R-mediated NF-κB activation, and both MyD88 and IRAK-2 associate with the IL-1R signaling complex. Dominant-negative overexpression, co-immunoprecipitation, NF-κB reporter assays Science High 9374458
1997 MyD88 has a modular architecture with an N-terminal death domain and C-terminal TIR domain; it forms homodimers via DD-DD and TIR-TIR interactions; overexpression activates NF-κB and JNK through its DD; a point mutation (F56N, MyD88-lpr) preventing DD dimerization blocks NF-κB and JNK activation; MyD88-induced NF-κB activation requires TRAF6 and IRAK. In vivo dimerization assays, co-immunoprecipitation, mutagenesis, reporter assays The Journal of biological chemistry High 9575168
1997 MyD88 gene structure spans five exons with the first exon encoding the complete death domain; the gene is evolutionarily conserved and maps to mouse chromosome 9 distal region and human chromosome 3p22-p21.3; MyD88 is broadly expressed in many adult tissues, not restricted to myeloid cells. Interspecific backcross mapping, Northern blot, RT-PCR, zooblot analysis Genomics Medium 9344657
1999 MyD88 knockout mice completely lack LPS shock response, B cell proliferative response, and cytokine secretion by macrophages in response to LPS; however, NF-κB and MAP kinase activation are not abolished, revealing a MyD88-dependent and a MyD88-independent pathway downstream of LPS/TLR4. MyD88 knockout mice, cytokine ELISA, NF-κB activation assays, proliferation assays Immunity High 10435584
2000 MyD88 mediates both apoptosis and NF-κB activation downstream of TLR2 stimulated by bacterial lipoproteins; the two pathways bifurcate at MyD88; MyD88 signals apoptosis via FADD and caspase-8; MyD88 directly binds FADD. Co-immunoprecipitation, dominant-negative constructs, apoptosis assays, caspase activity assays The EMBO journal High 10880445
2000 Tollip is present in a pre-formed complex with IRAK before IL-1β stimulation; upon IL-1β treatment, Tollip-IRAK complexes are recruited to the receptor complex through Tollip binding to IL-1RAcP; co-recruited MyD88 triggers IRAK autophosphorylation; IRAK then dissociates from Tollip. Co-immunoprecipitation, overexpression, NF-κB reporter assays Nature cell biology High 10854325
2001 MyD88-deficient dendritic cells can undergo functional maturation (upregulation of costimulatory molecules, enhanced APC activity) in response to LPS despite lacking cytokine production, demonstrating a MyD88-independent pathway downstream of TLR4; TLR9 signaling for DC maturation requires MyD88. MyD88 knockout mice, flow cytometry for costimulatory molecules, in vivo analysis, mixed leukocyte reaction Journal of immunology High 11313410
2001 Micrococci and peptidoglycan activate a TLR2→MyD88→IRAK→TRAF6→NIK→IKK→NF-κB pathway leading to IL-8 transcription; dominant-negative MyD88 completely inhibits this pathway. Dominant-negative constructs, NF-κB reporter assays, HEK293 overexpression system Infection and immunity Medium 11254583
2001 Mal (TIRAP) is an additional TIR-domain adaptor required for TLR4 signaling that forms heterodimers with MyD88; Mal activates NF-κB via IRAK-2 (not IRAK-1, which MyD88 requires); Mal associates directly with TLR4 and a dominant-negative Mal blocks TLR4/LPS-induced NF-κB but not IL-1RI or IL-18R signaling. Co-immunoprecipitation, dominant-negative constructs, reporter assays Nature High 11544529
2002 IRAK-4 directly interacts with IRAK-1 and TRAF6 in an IL-1-dependent manner; IRAK-4 phosphorylates IRAK-1 and acts upstream of IRAK-1 in MyD88-dependent signaling; dominant-negative IRAK-4 blocks IL-1-induced activation and modification of IRAK-1. Co-immunoprecipitation, kinase assays, dominant-negative constructs, NF-κB reporter assays Proceedings of the National Academy of Sciences High 11960013
2003 MyD88s (alternatively spliced short form lacking the intermediate domain) acts as a dominant-negative inhibitor of IL-1/LPS-induced NF-κB activation because it fails to recruit IRAK-4; in the presence of MyD88s, IRAK-1 is not phosphorylated and does not activate NF-κB. Co-immunoprecipitation, overexpression, NF-κB reporter assays, phosphorylation analysis The Journal of experimental medicine High 12538665
2004 MyD88 forms a complex with IRF7 (but not IRF3) through its death domain interacting with an inhibitory domain of IRF7, leading to activation of IFN-α-dependent promoters; TRAF6 also binds and activates IRF7, and TRAF6 ubiquitin ligase activity is required for IRF7 activation downstream of TLR7/8/9-MyD88 signaling. Co-immunoprecipitation, reporter assays, ubiquitination assays, knockout cells Nature immunology High 15361868
2005 IRF-5 acts downstream of the TLR-MyD88 signaling pathway for induction of proinflammatory cytokines (IL-6, IL-12, TNF-α); IRF-5 interacts with and is activated by MyD88 and TRAF6; TLR activation results in nuclear translocation of IRF-5 to activate cytokine gene transcription. Co-immunoprecipitation, IRF-5 knockout mice, subcellular fractionation, reporter assays Nature High 15665823
2006 TIRAP/Mal contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain that mediates its recruitment to the plasma membrane; TIRAP then facilitates delivery of MyD88 to activated TLR4 to initiate signal transduction, establishing a two-step adaptor recruitment mechanism. Subcellular localization by live imaging, PIP2 binding assays, dominant-negative constructs, co-immunoprecipitation Cell High 16751103
2006 MyD88 increases the half-life (but not synthesis) of IFN-γ-induced mRNA transcripts encoding TNF and IP-10; IFN-γ stimulation triggers physical association between IFN-γR1 and MyD88; transcript stabilization requires MLK3 and p38 MAPK activation and AU-rich elements in the 3′UTR. mRNA half-life assays, co-immunoprecipitation of IFN-γR1 and MyD88, kinase inhibitors, mutagenesis Nature immunology High 16491077
2007 The BB-loop of the MyD88 TIR domain is critical for MyD88 homodimerization and for recruitment of IRAK1 and IRAK4; a peptidomimetic (ST2825) modeled on this BB-loop inhibits MyD88 TIR-domain homodimerization specifically (not DD homodimerization), blocks IRAK1/IRAK4 recruitment, and inhibits IL-1β-mediated NF-κB activation. Co-immunoprecipitation, peptidomimetic inhibition, NF-κB reporter assays, in vivo cytokine assays Journal of leukocyte biology High 17548806
2007 MyD88-5 (a MyD88 family member) is preferentially expressed in neurons, colocalizes in part with mitochondria, co-immunoprecipitates with JNK3, and recruits JNK3 from cytosol to mitochondria; hippocampal neurons from MyD88-5-deficient mice are protected from death after oxygen-glucose deprivation. Transgenic GFP mice, subcellular fractionation, co-immunoprecipitation, knockout neurons, live/death assays The Journal of experimental medicine High 17724133
2008 MyD88 acts as a scaffold coupling protein kinase Cε (PKCε) to TLRs; LPS-induced PKCε phosphorylation at Ser-346 and Ser-368 promotes 14-3-3β binding and TLR4 recruitment, all dependent on MyD88 expression; PKCε phosphorylation is required for TLR4- and TLR2-induced NF-κB activation. Co-immunoprecipitation, MyD88 KO mouse cells, MyD88 knockdown, overexpression, phosphorylation-site mutagenesis The Journal of biological chemistry High 18458086
2008 Human individuals with autosomal recessive MyD88 deficiency suffer from recurrent life-threatening pyogenic bacterial infections (especially pneumococcal) but are otherwise healthy, demonstrating that MyD88-dependent TLR/IL-1R signaling is essential for protective immunity to a narrow range of pyogenic bacteria but redundant for defense against most natural infections. Human genetic study, functional cellular assays confirming loss of MyD88-dependent signaling in patient cells Science High 18669862
2010 Crystal structure of the MyD88-IRAK4-IRAK2 death domain complex reveals a left-handed helical oligomer ('Myddosome') consisting of 6 MyD88, 4 IRAK4, and 4 IRAK2 DDs; assembly is hierarchical (MyD88 recruits IRAK4, then MyD88-IRAK4 recruits IRAK2/IRAK1); composite binding sites are required, and specificities are dictated by molecular complementarity and surface electrostatics. X-ray crystallography, mutagenesis, functional validation of interface residues Nature High 20485341
2010 Two human MYD88 variants (S34Y and R98C) in the death domain severely reduce NF-κB activation due to impaired MyD88 homo-oligomerization and reduced IRAK4 interaction; MyD88 homo-oligomerization and IRAK4 interaction are also modulated by the MyD88 TIR domain and IRAK4 kinase domain; differential signaling effects suggest receptor specificities exist at the Myddosome level. Functional NF-κB assays, co-immunoprecipitation, structural modeling, epidemiological case-control analysis The Journal of biological chemistry High 20966070
2010 IRAK1 and IRAK4 directly phosphorylate the adaptor Mal, leading to its ubiquitination and proteasomal degradation upon LPS stimulation; MyD88 is NOT a substrate for either IRAK and does not undergo degradation, distinguishing the turnover mechanisms of these two adaptors. In vitro kinase assays, co-immunoprecipitation, ubiquitination assays, siRNA knockdown, IRAK1/4 inhibitor The Journal of biological chemistry High 20400509
2010 The MYD88 L265P mutation in ABC DLBCL constitutively assembles a signaling complex with IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signaling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and IFN-β; L265P is a gain-of-function driver mutation in the TIR domain at an evolutionarily invariant hydrophobic core residue. RNA interference screening, RNA resequencing, co-immunoprecipitation, kinase activity assays, cytokine measurements, rescue experiments with wild-type vs. mutant MyD88 Nature High 21179087
2012 MYD88 L265P somatic mutation triggers IRAK-mediated NF-κB signaling; inhibition of MYD88 signaling reduces IκBα and NF-κB p65 phosphorylation and NF-κB nuclear staining in Waldenström macroglobulinemia cells expressing MYD88 L265P. Whole-genome sequencing, Sanger sequencing validation, pharmacological inhibition of MyD88 signaling with functional readouts The New England journal of medicine High 22931316
2012 MYD88 directly binds ARNO (CYTH2) and signals through ARF6 to disrupt endothelial vascular stability in response to IL-1β via an NF-κB-independent pathway; ARNO binds directly to MyD88, establishing MYD88-ARNO-ARF6 as a proximal IL-1β signaling pathway distinct from the canonical NF-κB route. Co-immunoprecipitation, siRNA knockdown, in vitro cell model, animal models of inflammatory arthritis and acute inflammation Nature High 23143332
2012 MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes through an autocrine IL-1α→IL-1R→MyD88→NF-κB loop; loss of MyD88 in keratinocytes expressing oncogenic RAS impairs proinflammatory gene upregulation and differentiation block without abolishing their hyperproliferation. Knockout mice, orthotopic grafts, pharmacological NF-κB inhibition, genetic and pharmacological approaches The Journal of experimental medicine High 22908325
2016 MyD88 and downstream IRAK4 intrinsically control pericyte migration and conversion to myofibroblasts; MyD88-specific ablation in pericytes protects against kidney fibrosis; pericytes also activate NLRP3 inflammasome through MyD88, leading to IL-1β and IL-18 secretion, which feeds back through pericyte MyD88. Conditional MyD88 knockout in pericytes, IRAK4 inhibitor in vivo, cell migration assays, fibrosis readouts The Journal of clinical investigation High 27869651
2016 MyD88 NEDDylation antagonizes its ubiquitination; NEDD8 modification negatively regulates MyD88 dimerization and suppresses MyD88-dependent NF-κB signaling; upon IL-1β stimulation, MyD88 NEDDylation decreases while ubiquitination increases; deNEDDylase NEDP1 regulates this balance. Co-immunoprecipitation, ubiquitination/NEDDylation assays, NF-κB reporter assays, NEDP1 overexpression Biochemical and biophysical research communications Medium 27864145
2017 MyD88 promotes myoblast fusion in a cell-autonomous manner; MyD88 protein levels increase during in vitro myogenesis and muscle growth; deletion of MyD88 impairs myoblast fusion without affecting survival, proliferation, or differentiation; MyD88 regulates non-canonical NF-κB and canonical Wnt signaling during myogenesis. MyD88 conditional knockout, in vitro differentiation assays, in vivo muscle overload model, lentiviral overexpression Nature communications High 29158520
2017 TRAF6 E3 ligase activity is not solely responsible for K63-linked ubiquitin chain formation in IL-1 signaling; Pellino1 and Pellino2 generate the K63-Ub chains required when TRAF6 E3 ligase is inactive; IL-1-induced ubiquitylation of IRAK1, IRAK4, and MyD88 requires combined activity of TRAF6 and Pellinos, as it is abolished only in TRAF6/Pellino1/Pellino2 triple-KO cells. Triple-knockout cells, E3 ligase-inactive knockin mice, in vitro ubiquitination assays, TAK1 activation assays Proceedings of the National Academy of Sciences High 28404732
2018 The constitutively active MyD88 L265P mutant is transferred via extracellular vesicles (EVs) into recipient mast cells and macrophages, where it recruits endogenous wild-type MyD88 and triggers proinflammatory signaling in the absence of receptor activation; MyD88-loaded EVs were detected in bone marrow aspirates of Waldenström macroglobulinemia patients. Extracellular vesicle isolation, fluorescent tracking, co-immunoprecipitation, NF-κB activation assays, in vivo mouse experiments, patient samples Blood High 29358175
2020 SPOP (Cullin 3-based ubiquitin ligase adaptor) recognizes the intermediate domain of MyD88 and degrades it through the proteasome; knockdown or knockout of SPOP leads to elevated MyD88 protein; SPOP negatively regulates NF-κB activity and IL-1β production upon LPS challenge; Spop-deficient mice are more susceptible to Salmonella infection. Co-immunoprecipitation, ubiquitination assays, gene knockout (chicken cells and mouse), proteasome inhibition, in vivo infection model PLoS pathogens High 32365080
2021 E3 ligase RNF138 catalyzes K63-linked non-proteolytic polyubiquitination specifically of MYD88 L265P (not wild-type MYD88), enhancing IRAK recruitment and NF-κB activation; A20 mediates K48-linked polyubiquitination of RNF138 for proteasomal degradation, acting as a negative feedback; mutation of MYD88 L265P ubiquitination sites abolishes constitutive NF-κB activation. Co-immunoprecipitation, ubiquitination assays, RNF138 knockdown, mutagenesis of ubiquitination sites, NF-κB reporter assays, lymphoma growth assays Blood High 33025009
2022 IRAK4 scaffold (independent of its kinase activity) is required for activation of TRAF6 by both MYD88 and TRIF downstream of TLR4, integrating the two signaling pathways; IRAK4 kinase activity is essential for MYD88 signaling; IRAK4 thus has dual roles as kinase and scaffold in TLR4 signaling. IRAK4 knockout and kinase-dead knockin cell lines, TRAF6 activation assays, cytokine production assays Cell reports High 35977521
2022 MYD88 directly blocks autophagic degradation of STING1, thereby promoting STING1-dependent ACOD1 (IRG1) expression through IRF3/JUN-mediated transcription; MYD88 (not CGAS) favors this STING1-dependent ACOD1 expression; conditional deletion of STING1 in myeloid cells prevents itaconate production and worsens endotoxemia and sepsis. Co-immunoprecipitation, STING1 and MYD88 knockout/conditional knockout mice, autophagy assays, reporter assays, sepsis model iScience High 35769880
2022 Osteocyte MYD88 activation by bacterial PAMPs upregulates RANKL by increasing binding of transcription factors CREB and STAT3 to Rankl enhancers and by suppressing K48-ubiquitination of CREB/CBP and STAT3; osteocyte-specific MYD88 restoration in KO mice reconstitutes osteolysis with inflammatory cell infiltration. Conditional MYD88 knockout in osteocytes, conditional MYD88 restoration, ChIP assays, ubiquitination assays, in vivo calvarial injection and periodontitis models Nature communications High 36333322
2009 PYK2 interacts with MyD88 via the death domain of MyD88 in vitro and in macrophages; this interaction increases upon LPS stimulation; PYK2-deficient macrophages show reduced IκB phosphorylation/degradation and decreased NF-κB activation and IL-1β expression, placing PYK2 upstream of NF-κB in MyD88-dependent signaling. Co-immunoprecipitation, PYK2 knockout macrophages, NF-κB reporter assays, phosphorylation assays Journal of leukocyte biology Medium 19955209
2019 BANK1 interacts with TRAF6 and MyD88 via its TIR domain as demonstrated by co-immunoprecipitation; the natural BANK1-40C variant shows increased binding to MyD88; BANK1 colocalizes with TLR7 and TLR9 in B cells, and stimulation increases co-localization with MyD88; BANK1 TIR domain is important for K63-linked polyubiquitination. Co-immunoprecipitation, point mutations, decoy peptides, confocal microscopy, IL-8 production assays Cellular & molecular immunology Medium 31243359
2013 MyD88 determines cell fate decision (apoptosis vs. necroptosis) after UV irradiation in macrophages; MyD88-deficient macrophages show decreased apoptosis and increased necroptotic signaling (elevated RIP1, TNF-α release, reduced caspase-3 cleavage); TLR4-deficient macrophages phenocopy MyD88-deficient cells, placing TLR4-MyD88 axis as key regulator of UV-induced cell death pathway choice. MyD88 and TLR4 KO macrophages, caspase assays, DNA laddering, TLR-specific KO comparison Innate immunity Medium 24048771
2016 TLR3 acts through MYD88 to negatively regulate DISC1 expression in neurons, impairing dendritic arborization; impaired dendritic morphology from TLR3 activation is rescued by MYD88 deficiency or DISC1 overexpression; this MYD88-mediated suppression is cytokine-independent. Cultured neurons, in vivo mouse brain, MYD88 knockout, TLR3 agonists, DISC1 overexpression rescue EMBO reports Medium 27979975
2022 MyD88 L265P is found in normal precursor and mature B lymphocytes from patients with lymphoplasmacytic lymphoma, establishing MYD88 L265P as a preneoplastic (pre-malignant) event; a mouse model based on mutated MYD88 in B cell precursors combined with BCL2 overexpression reconstitutes lymphoplasmacytic lymphoma. Multi-stage B lineage sequencing, whole-genome sequencing, transgenic mouse model Science advances Medium 35044826

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 3006 16286016
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
1999 Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1570 10435584
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