Affinage

TIRAP

Toll/interleukin-1 receptor domain-containing adapter protein · UniProt P58753

Length
221 aa
Mass
23.9 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIRAP/MAL is a TIR domain-containing adaptor that provides receptor-proximal specificity to a subset of Toll-like receptor signaling pathways, bridging activated TLR2 and TLR4 to the downstream adaptor MyD88 to drive NF-κB and MAPK activation (PMID:12447441, PMID:12447442). Genetic ablation in mice abolishes LPS- and TLR2-ligand-induced cytokine production and NF-κB/MAPK activation while leaving TLR3, TLR5, TLR7, TLR9, IL-1, and IL-18 responses intact, defining TIRAP as a selective adaptor rather than a universal one (PMID:12447442). TIRAP is targeted to the plasma membrane through a phosphoinositide-binding motif (PBM) that binds PIP2 generated by PIP5Kα, positioning it at the receptor for signal initiation (PMID:23297396, PMID:28225045). From the membrane it directly recruits TRAF6 via a TRAF6-binding motif (E190) to control transcriptional activation through serine phosphorylation of NF-κB p65, and it engages the PKCδ complex to promote p38, IKK, and IκBα phosphorylation (PMID:17161867, PMID:19592497). Structural studies of the MAL TIR domain reveal a distinctive fold with a redox-sensitive cysteine (C91): glutathionylation under oxidizing conditions promotes MyD88 binding and IRAK4 engagement, coupling TIRAP function to cellular redox state (PMID:21873236, PMID:28739909). TIRAP activity is terminated by several converging negative-regulatory mechanisms—Thr28 phosphorylation within the PBM that disrupts membrane binding and triggers ubiquitination/degradation, CLIP170- and CLIP1-mediated ubiquitination and proteasomal degradation, and Src-family-kinase-induced TLR4 tyrosine phosphorylation that dissociates the adaptor from the receptor (PMID:28225045, PMID:29222167, PMID:29175418, PMID:39617791). Beyond canonical TLR signaling TIRAP transduces RAGE signals after PKCζ-mediated Ser391 phosphorylation, forms a complex with c-Jun to amplify AP-1 activity, contributes to TLR8 Myddosome signaling, and drives non-canonical IFNγ–HMGB1-mediated bone marrow suppression (PMID:21829704, PMID:30909134, PMID:35089323, PMID:35884781).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 Medium

    Established TIRAP as a candidate TLR4 adaptor, raising the question of how it relates to MyD88-dependent versus -independent signaling.

    Evidence Cloning with overexpression, reporter, and co-IP assays identifying TIRAP and PKR in TLR4 pathways

    PMID:11526399

    Open questions at the time
    • Overexpression-based; genetic requirement and receptor specificity unresolved
    • Initial assignment to MyD88-independent pathway later refined by knockout studies
  2. 2002 High

    Genetic knockouts settled the question of which TLRs require TIRAP, establishing it as a specificity-conferring adaptor for the MyD88-dependent arm of TLR2 and TLR4 but not TLR3/5/7/9 or IL-1/IL-18.

    Evidence TIRAP-deficient mice with TLR ligand panel, NF-κB/MAPK assays, and cytokine readouts

    PMID:12447441 PMID:12447442

    Open questions at the time
    • Molecular basis of receptor selectivity not defined
    • Cell-type-dependent requirements (e.g., macrophage vs fibroblast) not yet resolved
  3. 2003 Medium

    Showed cell-type-dependent adaptor requirements, indicating TIRAP/MyD88 are essential in some primary human cells but bypassable in macrophages.

    Evidence Dominant-negative MyD88/TIRAP in primary human fibroblasts, endothelial cells, and macrophages with cytokine and reporter readouts

    PMID:14630816

    Open questions at the time
    • Dominant-negative approach without genetic confirmation
    • Mechanism of macrophage-specific bypass unexplained
  4. 2006 Medium

    Identified a direct effector partner, answering how TIRAP couples to MAPK/IKK signaling via PKCδ binding through the TIR domain.

    Evidence GST pulldown, co-IP from macrophage lysates, TIRAP truncation mapping, PKCδ knockdown with signaling readouts

    PMID:17161867

    Open questions at the time
    • Single lab
    • Stoichiometry and ordering relative to MyD88 recruitment unclear
  5. 2009 High

    Defined how TIRAP triggers NF-κB transcriptional output by directly recruiting TRAF6 via a defined binding motif, and mapped the MyD88-interaction interface through a natural hypomorphic variant.

    Evidence Reciprocal co-IP, E190A and D96N mutagenesis, reconstitution of Mal-deficient macrophages, p65 phosphorylation and cytokine assays

    PMID:19509286 PMID:19592497

    Open questions at the time
    • Separation of TRAF6-dependent transcriptional activation from nuclear translocation needs structural detail
    • In vivo consequences of D96N variant not fully defined
  6. 2009 Medium

    Established the membrane-targeting logic of TIRAP through phosphoinositide binding, supported by a bacterial mimic, and defined it as a bridging adaptor bypassable under high-agonist or endosomal conditions.

    Evidence Brucella TcpB phosphoinositide binding and colocalization studies, plus TIRAP-deficient macrophages with phagosome/agonist manipulations

    PMID:19196716 PMID:19889726

    Open questions at the time
    • Direct PIP species and residues mediating TIRAP membrane binding not yet mapped
    • Mechanism of bridging-adaptor bypass at the receptor level unresolved
  7. 2011 High

    Determined the TIRAP TIR domain structure, revealing a unique fold and identifying dimerization and MyD88-interacting surface residues, and showed TIRAP also engages RAGE downstream of PKCζ.

    Evidence X-ray crystallography with mutagenesis/co-IP validation; co-IP and kinase assays linking TIRAP/MyD88 to phospho-Ser391 RAGE

    PMID:21829704 PMID:21873236

    Open questions at the time
    • Structure of full TIRAP signalosome with MyD88/TLR not resolved
    • RAGE-TIRAP coupling shown by DN inhibition only
  8. 2013 High

    Connected membrane recruitment to enzymatic PIP2 production via PIP5Kα and provided crystallographic evidence of a disulfide-bonded TIR fold, while genetic studies revealed Mal-independent MyD88 functions in some tumor contexts.

    Evidence PIP5Kα knockdown/co-IP/imaging with PIP2 measurement; TIRAP crystal structure with HDX-MS; Mal-/- gp130F/F gastric tumor model

    PMID:23297396 PMID:23728346 PMID:24275656

    Open questions at the time
    • Functional relevance of crystallographic disulfide vs solution state not yet reconciled
    • Contextual divergence of Mal vs MyD88 requirement mechanistically unexplained
  9. 2015 High

    Demonstrated that TIRAP is a tractable therapeutic node, as a TIR-derived peptide targeting TIRAP suppresses multiple TLR pathways and confers survival benefit in vivo.

    Evidence 2R9 peptide with co-IP, imaging, in vitro binding, and murine influenza model

    PMID:26095366

    Open questions at the time
    • Peptide selectivity across TIR-domain proteins not exhaustively defined
    • Mechanism of broad TLR (including TLR7/9) coverage incompletely explained
  10. 2017 High

    Resolved how redox state and phosphorylation regulate TIRAP: solution structure plus mass spectrometry showed C91 glutathionylation drives MyD88 binding, while Thr28 phosphorylation in the PBM disrupts membrane targeting and triggers degradation.

    Evidence Reduced-state NMR structure, mass spectrometry of LPS-activated macrophages, C91A/H92P and Thr28 mutagenesis, phosphoinositide binding and ubiquitination assays; CLIP170 co-IP/ubiquitination and SFK-Lyn studies

    PMID:28225045 PMID:28739909 PMID:29175418 PMID:29222167

    Open questions at the time
    • The E3 ligase machinery for Thr28-triggered degradation not fully defined
    • Integration of redox, phospho, and ubiquitin signals in vivo not established
  11. 2018 Low

    Tested the ordering of complex assembly, with BRET supporting TIRAP-dependent recruitment of MyD88 to TLR2 but co-IP failing to confirm constitutive interactions.

    Evidence BRET, co-IP, and confocal microscopy

    PMID:30138457

    Open questions at the time
    • BRET signals partly attributable to overexpression artefacts
    • Constitutive versus stimulus-induced complex composition unresolved
  12. 2022 High

    Expanded TIRAP's roles beyond canonical TLR2/4, showing it amplifies AP-1 via c-Jun, contributes to TLR8 Myddosome signaling and IRF5 activation, and drives non-canonical IFNγ–HMGB1 myelosuppression and TPL2-mediated cancer signaling.

    Evidence Co-IP/AP-1 reporter with sepsis model; TIRAP siRNA in human macrophages with TLR8/Akt/IRF5 readouts; TIRAP overexpression with IFNγ genetic deletion and bone marrow niche analysis; co-IP/KD with TPL2 and bladder cancer phenotypes

    PMID:30909134 PMID:35089323 PMID:35884781 PMID:36240653

    Open questions at the time
    • Whether c-Jun, TLR8, and myelosuppression functions share the canonical membrane-recruitment mechanism is untested
    • IFNγ-HMGB1 axis shown via TIRAP overexpression rather than endogenous regulation
  13. 2023 High

    Revealed pathogen- and disease-context functions, with TIRAP enabling Mtb intracellular survival via blocking phagosomal acidification through Cish, and m6A-regulated TIRAP mRNA stability driving radiation-induced liver fibrosis.

    Evidence TIRAP KO/heterozygous Mtb infection models with phagosomal acidification and CFU assays; ALKBH5/MeRIP-seq with NF-κB/JNK/Smad2 readouts in hepatic stellate cells

    PMID:36792369 PMID:36888688

    Open questions at the time
    • Molecular link between TIRAP and phagosomal acidification machinery incomplete
    • Upstream control of TIRAP m6A status not fully defined
  14. 2024 Medium

    Advanced chemical and regulatory mechanisms, identifying CLIP1 as a TIRAP ubiquitin ligase antagonized by TFPI2, and characterizing covalent small-molecule modification of the MAL TIR domain.

    Evidence Co-IP/ubiquitination with CLIP1/TFPI2 in liver IRI model; NMR-confirmed o-vanillin covalent bond at Lys210 with assembly and cell signaling assays

    PMID:38416868 PMID:39617791

    Open questions at the time
    • Relationship between CLIP1 and earlier CLIP170-mediated degradation not reconciled
    • o-vanillin inhibits TLR2 independently of MAL, so on-target relevance is limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct regulatory layers (PIP2 recruitment, redox glutathionylation, phosphorylation, and multiple ubiquitin ligases) are integrated to time TIRAP activity within an intact signalosome, and whether the non-canonical (RAGE, c-Jun, IFNγ-HMGB1, Mtb) functions use the same molecular interfaces, remains unresolved.
  • No integrated structural model of the assembled TLR–TIRAP–MyD88 signalosome
  • Endogenous-context validation of overexpression-driven non-canonical roles lacking
  • In vivo hierarchy among competing degradation pathways unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 4
Partners
CLIP1JUNMYD88PIP5K1APKCDRAGETLR4TRAF6
Complex memberships
MyD88 MyddosomeTLR4 signaling complexTLR8 Myddosome

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TIRAP (TIR domain-containing adapter protein) was identified as an adaptor protein that controls activation of MyD88-independent signaling pathways downstream of TLR4, and PKR was identified as a component of both TIRAP- and MyD88-dependent signaling pathways. Cloning, overexpression, reporter assays, co-immunoprecipitation Nature immunology Medium 11526399
2002 TIRAP is essential for the MyD88-dependent signaling pathway shared by TLR2 and TLR4 (not TLR3, TLR7, or TLR9); TIRAP-deficient mice show abolished LPS-induced splenocyte proliferation, cytokine production, and delayed NF-κB/MAPK activation, but intact MyD88-independent responses (IFN-inducible genes, DC maturation). TIRAP knockout mouse generation, LPS/TLR ligand stimulation, NF-κB/MAPK assays, cytokine measurement Nature High 12447441 12447442
2002 TIRAP-deficient mice respond normally to TLR5, TLR7, and TLR9 ligands and to IL-1 and IL-18, but have defects in cytokine production and NF-κB/MAPK activation in response to TLR4 ligand LPS and TLR2, TLR1, and TLR6 ligands, demonstrating TIRAP provides signaling specificity for a subset of TLRs. Tirap gene knockout mice, cytokine ELISA, NF-κB/MAPK activation assays, TLR ligand stimulation panel Nature High 12447442
2002 TIRAP is required for LPS-induced NF-κB activation and apoptosis in human endothelial cells, as demonstrated using a TIRAP dominant-negative construct, identifying a role for TIRAP in endothelial cell signaling. Dominant-negative TIRAP construct overexpression, NF-κB reporter assay, apoptosis assay in human endothelial cells Biochemical and biophysical research communications Medium 12083783
2002 TIRAP/MAL is required for LPS-induced IRF-3 activation (but not dsRNA-induced IRF-3 activation), placing TIRAP in the pathway leading to IFN gene induction by TLR4 but not by TLR3. TIRAP overexpression, dominant-negative constructs, IRF-3 reporter assays in cell lines FEBS letters Medium 12062447
2003 In primary human fibroblasts and endothelial cells, both MyD88 and TIRAP are essential for LPS-induced IκBα phosphorylation, NF-κB activation, and IL-6/IL-8 production via IKK2; however, in macrophages, neither MyD88 nor TIRAP nor IKK2 are required for NF-κB activation or TNFα/IL-6/IL-8 production, though TIRAP is involved in IFNβ production. Dominant-negative overexpression of MyD88/TIRAP in primary human cells (fibroblasts, endothelial cells, macrophages), NF-κB reporter, cytokine ELISA, TLR4 neutralization Blood Medium 14630816
2006 PKCδ binds directly to TIRAP/Mal through the TIR domain of TIRAP; PKCδ binding promotes TLR2- and TLR4-mediated phosphorylation of p38 MAPK, IKK, and IκBα in macrophages. GST pulldown, co-immunoprecipitation from macrophage lysates, TIRAP truncation mutants, PKCδ depletion (siRNA/knockdown) with signaling readouts Molecular immunology Medium 17161867
2009 TIRAP directly interacts with TRAF6 in response to TLR2 and TLR4 stimulation; this interaction is not membrane-dependent. A TIRAP E190A mutation in the TRAF6-binding motif abolishes TRAF6 interaction, fails to reconstitute proinflammatory responses in Mal-deficient macrophages, and blocks Ser phosphorylation of the NF-κB p65 subunit (controlling transcriptional activation but not nuclear translocation). Co-immunoprecipitation, site-directed mutagenesis (E190A), reconstitution of Mal-deficient macrophages, NF-κB reporter, cytokine assays, p65 phosphorylation assays The Journal of biological chemistry High 19592497
2009 A naturally occurring TIRAP variant D96N (Mal D96N, rs8177400) is inactive in NF-κB reporter assays, fails to interact with MyD88 by co-immunoprecipitation, and acts as a hypomorphic allele with impaired cytokine production upon TLR2/4 stimulation, demonstrating D96 resides in the MyD88-binding interface. Overexpression in reporter cell lines, co-immunoprecipitation, cytokine assays (LPS, PAM2CSK4), computer modeling The Journal of biological chemistry Medium 19509286
2009 Brucella TIR domain-containing protein TcpB mimics TIRAP by interacting with phosphoinositides through its N-terminal domain and colocalizing with the plasma membrane and cytoskeleton, blocking TIRAP-induced NF-κB activation; this supports a model where TIRAP uses phosphoinositide binding for membrane targeting. Sequence analysis, phosphoinositide binding assays, co-localization microscopy, NF-κB reporter assays The Journal of biological chemistry Medium 19196716
2009 TIRAP requirement for TLR2 signaling can be overcome when Francisella tularensis (Ft) is retained within the phagosome or when higher concentrations of TLR2 agonists are used, revealing TIRAP's function as a 'bridging' adaptor that can be bypassed by enhanced or sustained TLR2-agonist contact from endosomal compartments. MyD88 remains absolutely required. TIRAP-deficient macrophages, bacterial infection, BFA-mediated phagosome acidification inhibition, TLR2 agonist dose-response, NF-κB reporter and cytokine assays Journal of leukocyte biology Medium 19889726
2011 Crystal structure of the MAL/TIRAP TIR domain was determined; it reveals a unique fold with a long loop replacing a β-strand found in other TIR domains, placing the 'BB loop' proline motif in a unique surface position. Site-directed mutants confirmed key dimerization and MyD88-interacting interface residues by co-immunoprecipitation. X-ray crystallography, site-directed mutagenesis, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 21873236
2011 TIRAP and MyD88 bind to the cytoplasmic domain of RAGE after PKCζ-mediated phosphorylation at Ser391, transducing intracellular signals from ligand-activated RAGE; blocking TIRAP and MyD88 function largely abrogated RAGE intracellular signaling. Co-immunoprecipitation, kinase assays, dominant-negative inhibition, phospho-specific assays PloS one Medium 21829704
2013 Crystal structures of both the Brucella TcpB TIR domain and the human TIRAP TIR domain were determined. The TIRAP TIR domain crystal structure reveals a unique N-terminal TIR fold containing a disulfide bond (Cys89–Cys134). Substantial conformational differences in the BB loop region exist between TcpB and TIRAP. TcpB–TIRAP interaction was validated by co-immunoprecipitation and NF-κB reporter assays. X-ray crystallography, hydrogen/deuterium exchange mass spectrometry, co-immunoprecipitation, NF-κB reporter assay The Journal of biological chemistry High 24275656
2013 PIP5Kα (phosphatidylinositol 4-phosphate 5-kinase α) colocalized and interacted with TIRAP at the cell surface; kinase-dead PIP5Kα rendered TIRAP soluble and disrupted its membrane targeting. LPS induced bi-directional TIRAP translocation between membrane and cytosol correlating with PIP2 levels. PIP5Kα-generated PIP2 is required for TIRAP plasma membrane recruitment necessary for TLR4 signaling. shRNA/siRNA knockdown, co-localization microscopy, co-immunoprecipitation, kinase-dead mutant complementation, PIP2 measurement, cytokine assays The Journal of biological chemistry Medium 23297396
2013 In a gastric tumourigenesis model, genetic ablation of Mal/TIRAP in gp130F/F mice did not reduce tumour burden (unlike MyD88 deletion), demonstrating that Mal is dispensable for TLR2-promoted gastric tumour growth whereas MyD88 is required, revealing a differential (Mal-independent) requirement for MyD88 downstream of TLR2 in this context. Genetic ablation (Mal-/- crossed into gp130F/F), tumour burden quantification, apoptosis and proliferation assays, gene expression analysis Oncogene Medium 23728346
2015 A TLR2 TIR-derived D-helix peptide (2R9) preferentially targets TIRAP as demonstrated by cell imaging, co-immunoprecipitation, and in vitro binding studies; 2R9 inhibits TIRAP recruitment to TLRs and suppresses TLR2-, TLR4-, TLR7-, and TLR9- (but not TLR3-) mediated cytokine production in vitro and in vivo, and significantly improved survival in influenza-infected mice. Cell-permeable peptide library screening, co-immunoprecipitation, cell imaging, in vitro binding, in vivo murine influenza model Cell reports High 26095366
2017 The solution NMR structure of reduced MAL/TIRAP TIR domain reveals a structural rearrangement compared to the crystal (disulfide-bonded) structure, including relocation of a β-strand and repositioning of the BB loop to a more typical TIR domain position. Under oxidizing conditions, C91 undergoes glutathionylation (detected by mass spectrometry in LPS-activated macrophages). The C91A mutation limits glutathionylation, acts as a dominant negative blocking MAL–MyD88 interaction, and diminishes TIRAP degradation and IRAK4 interaction; H92P mimics C91A effects. NMR structure determination, mass spectrometry, site-directed mutagenesis (C91A, H92P), co-immunoprecipitation, redox NMR, dominant-negative functional assays in macrophages Proceedings of the National Academy of Sciences of the United States of America High 28739909
2017 TIRAP PBM (phosphoinositide-binding motif) transitions from disordered to helical conformation upon binding phosphoinositides via basic and nonpolar residues. Phosphorylation at Thr28 within the PBM distorts its helical structure, reducing PI interactions and cell membrane targeting, and leads to TIRAP ubiquitination and degradation, serving as a negative regulatory mechanism to terminate innate immune responses. NMR spectroscopy, phosphoinositide binding assays, mutagenesis, cell membrane targeting assays, ubiquitination assays Scientific reports High 28225045
2017 CLIP170 (cytoplasmic linker protein 170) interacts with TIRAP and induces ubiquitination and subsequent proteasomal degradation of TIRAP to negatively regulate TLR4-mediated proinflammatory responses; CLIP170 overexpression suppresses LPS-induced IL-6/TNFα, and CLIP170 silencing potentiates them in vitro and in vivo. Co-immunoprecipitation, ubiquitination assays, CLIP170 overexpression/siRNA knockdown, in vivo siRNA silencing in C57BL/6 mice, cytokine assays Journal of immunology Medium 29222167
2017 Src family kinase (SFK) activation induces tyrosine phosphorylation of TLR4 and dissociates MyD88 and Mal/TIRAP from TLR4, inhibiting LPS-induced NF-κB and JNK1/2 activation. Kinase-active SFK-Lyn strongly binds TLR4 and promotes its phosphorylation, whereas kinase-dead SFK-Lyn has reduced binding and does not phosphorylate TLR4, suggesting a negative feedback loop. Chemical rescue approach for SFK activation, co-immunoprecipitation of TLR4 with MyD88/TIRAP, kinase-dead and constitutively active Lyn mutants, NF-κB/JNK assays, cytokine measurements Biochemical pharmacology Medium 29175418
2018 BRET studies confirmed that TIRAP is necessary for MyD88 interaction with TLR2; TLR2–TIRAP interaction was detected by BRET, and TLR2–MyD88 interaction only occurred in the presence of TIRAP. However, co-immunoprecipitation studies did not demonstrate constitutive interaction between these proteins, suggesting some BRET signals were artefacts of protein overexpression. BRET (bioluminescence resonance energy transfer), co-immunoprecipitation, confocal microscopy PloS one Low 30138457
2019 TIRAP forms a signaling complex with c-Jun protein in macrophages in response to LPS stimulation, increasing AP-1 transcriptional activity and amplifying expression of inflammatory mediators; gefitinib was identified as an inhibitor of this TIRAP–c-Jun interaction, disrupting it in vitro and in a mouse sepsis model. Co-immunoprecipitation, AP-1 reporter assay, molecular docking, in vitro inhibitor assay, murine LPS sepsis model International immunopharmacology Medium 30909134
2020 TIRAP expression is induced in T cells by TCR stimulation and sustained by IL-2 signals via mTORC1 activation. TIRAP is required for TLR2-mediated NF-κB and ERK activation and IFN-γ production in effector T cells. Additionally, TLR2 stimulation induces mTORC1 activation through TIRAP, creating a positive feedback loop. T cell differentiation assays, mTORC1 inhibition (rapamycin), TIRAP overexpression/knockdown, NF-κB/ERK reporter assays, cytokine ELISA, IL-2 dose-response Cell reports Medium 32698010
2022 TIRAP drives myelosuppression through an IFNγ-HMGB1 axis: TIRAP overexpression upregulates IFNγ, which via IFNγR-mediated HMGB1 release disrupts the bone marrow endothelial niche and suppresses all three major hematopoietic lineages. IFNγ deletion blocks HMGB1 release, reverses the endothelial defect, and restores myelopoiesis. This function is independent of T cells or pyroptosis. TIRAP overexpression in mouse model, IFNγ genetic deletion, HMGB1 measurement, bone marrow endothelial niche analysis, hematopoietic lineage profiling The Journal of experimental medicine High 35089323
2022 TIRAP is positively required for TLR8-mediated signaling in human macrophages: TIRAP is recruited to the TLR8 Myddosome signaling complex and contributes to Akt kinase activation and nuclear translocation of IRF5, promoting IFNβ, IL-12p70, and TNF expression following TLR8 stimulation. TIRAP gene silencing (siRNA) in primary human monocyte-derived macrophages, cytokine qPCR/Bioplex, immunofluorescence, cell fractionation/immunoblotting, immunoprecipitation, Akt inhibitors Biomedicines Medium 35884781
2022 TIRAP facilitates the direct recruitment of TRAF6 to the plasma membrane for NF-κB transactivation and controls TLR4 downstream signaling through TPL2; upon S100A8/A9 binding to TLR4, TIRAP enhances TPL2 activation leading to MAPK cascade activation promoting bladder cancer cell growth, migration, and invasion. Co-immunoprecipitation, siRNA knockdown, MAPK signaling assays, in vivo TLR4 inhibition, cancer cell phenotypic assays Biochemical and biophysical research communications Medium 36240653
2023 TIRAP expression is induced by Mycobacterium tuberculosis (Mtb) infection in macrophages, where it prevents phagosomal acidification and rupture, enabling intracellular bacterial replication. TIRAP-deficient macrophages restrict Mtb replication, and TIRAP heterozygous mice are more resistant to Mtb. This anti-phagosomal acidification effect occurs through a Cish-dependent signaling pathway. TIRAP KO and heterozygous mouse infection models, ex vivo macrophage infection, phagosomal acidification assays, bacterial CFU counting, Cish-dependent pathway analysis PLoS pathogens High 36888688
2023 ALKBH5-mediated m6A demethylation of TIRAP mRNA stabilizes TIRAP mRNA in hepatic stellate cells upon irradiation, activating NF-κB and JNK/Smad2 pathways downstream of TIRAP to promote hepatic stellate cell activation and radiation-induced liver fibrosis. MeRIP-seq, RNA-seq, ALKBH5 knockdown/overexpression in HSC, NF-κB/JNK/Smad2 pathway assays, m6A immunoprecipitation Clinical and translational medicine Medium 36792369
2024 The small molecule o-vanillin forms a covalent bond with Lys210 of MAL/TIRAP TIR domain (confirmed by NMR) and inhibits MAL higher-order assembly in vitro; however, o-vanillin inhibits TLR2 but not TLR4 signaling in mouse and human cells independently of MAL, suggesting it covalently modifies TLR2 signaling complexes directly. NMR spectroscopy (covalent bond identification), in vitro higher-order assembly assay, cell-based TLR2/TLR4 signaling assays in mouse and human cells Journal of enzyme inhibition and medicinal chemistry High 38416868
2024 CLIP1 (TIRAP ubiquitin ligase) ubiquitinates TIRAP and promotes its degradation to negatively regulate TLR4/NF-κB signaling; TFPI2 inhibits CLIP1 activity (via R24 of TFPI2 KD1 domain interaction with CLIP1) to prevent TIRAP degradation and amplify inflammatory responses. HOPE (hypothermic oxygenated perfusion) reduces TFPI2 expression, thereby permitting CLIP1-mediated TIRAP ubiquitination and dampening liver ischemia-reperfusion injury. Co-immunoprecipitation, ubiquitination assays, CLIP1/TFPI2 overexpression/knockdown, rat fatty liver IRI model, NF-κB signaling assays Experimental & molecular medicine Medium 39617791

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 738 12447441
2001 TIRAP: an adapter molecule in the Toll signaling pathway. Nature immunology 729 11526399
2002 The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 633 12447442
2011 TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PloS one 193 21829704
2009 MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses. The Journal of biological chemistry 173 19592497
2003 Distinct pathways of LPS-induced NF-kappa B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP. Blood 169 14630816
2007 The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. The American journal of pathology 158 17255320
2009 Brucella TIR Domain-containing Protein Mimics Properties of the Toll-like Receptor Adaptor Protein TIRAP. The Journal of biological chemistry 136 19196716
2011 Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection. Proceedings of the National Academy of Sciences of the United States of America 119 21873236
2006 Toll/IL-1R domain-containing adaptor protein (TIRAP) is a critical mediator of antibacterial defense in the lung against Klebsiella pneumoniae but not Pseudomonas aeruginosa. Journal of immunology (Baltimore, Md. : 1950) 80 16785551
2008 TIRAP (MAL) S180L polymorphism is a common protective factor against developing tuberculosis and systemic lupus erythematosus. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 78 18417424
2009 Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock. Proceedings of the National Academy of Sciences of the United States of America 75 19509334
2010 Toll-like receptor and TIRAP gene polymorphisms in pulmonary tuberculosis patients of South India. Tuberculosis (Edinburgh, Scotland) 73 20797905
2012 IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients. Blood 72 23002119
2002 Toll-like receptor 4 and Toll-IL-1 receptor domain-containing adapter protein (TIRAP)/myeloid differentiation protein 88 adapter-like (Mal) contribute to maximal IL-6 expression in macrophages. Journal of immunology (Baltimore, Md. : 1950) 70 12421970
2013 Crystal structures of the Toll/Interleukin-1 receptor (TIR) domains from the Brucella protein TcpB and host adaptor TIRAP reveal mechanisms of molecular mimicry. The Journal of biological chemistry 67 24275656
2009 A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. The Journal of biological chemistry 65 19509286
2012 Targeting Toll-like receptor (TLR) signaling by Toll/interleukin-1 receptor (TIR) domain-containing adapter protein/MyD88 adapter-like (TIRAP/Mal)-derived decoy peptides. The Journal of biological chemistry 64 22648407
2010 Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts. Critical care (London, England) 62 20525286
2015 Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. Immunologic research 61 25784622
2011 Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. PloS one 61 22073274
2009 Heterozygosity for the S180L variant of MAL/TIRAP, a gene expressing an adaptor protein in the Toll-like receptor pathway, is associated with lower risk of developing chronic Chagas cardiomyopathy. The Journal of infectious diseases 59 19456234
2012 Molecular mechanism of capillarisin-mediated inhibition of MyD88/TIRAP inflammatory signaling in in vitro and in vivo experimental models. Journal of ethnopharmacology 57 23237934
2021 TIRAP in the Mechanism of Inflammation. Frontiers in immunology 55 34305934
2015 A Decoy Peptide that Disrupts TIRAP Recruitment to TLRs Is Protective in a Murine Model of Influenza. Cell reports 53 26095366
2013 Spinal toll-like receptor signaling and nociceptive processing: regulatory balance between TIRAP and TRIF cascades mediated by TNF and IFNβ. Pain 47 23489833
2023 ALKBH5-mediated m6 A demethylation of TIRAP mRNA promotes radiation-induced liver fibrosis and decreases radiosensitivity of hepatocellular carcinoma. Clinical and translational medicine 46 36792369
2013 Phosphatidylinositol 4-phosphate 5-kinase α facilitates Toll-like receptor 4-mediated microglial inflammation through regulation of the Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) location. The Journal of biological chemistry 44 23297396
2012 Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PloS one 42 22970235
2006 Protein kinase Cdelta binds TIRAP/Mal to participate in TLR signaling. Molecular immunology 42 17161867
2010 Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways. American journal of physiology. Heart and circulatory physiology 41 20061547
2016 Comparative genomic evidence for duplication of TLR1 subfamily and miiuy croaker TLR1 perceives LPS stimulation via MyD88 and TIRAP. Fish & shellfish immunology 40 27431585
2013 Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. Oncogene 40 23728346
2002 Involvement of TIRAP/MAL in signaling for the activation of interferon regulatory factor 3 by lipopolysaccharide. FEBS letters 40 12062447
2019 Common variants of genes encoding TLR4 and TLR4 pathway members TIRAP and IRAK1 are effective on MCP1, IL6, IL1β, and TNFα levels in type 2 diabetes and insulin resistance. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 39 31222667
2012 Role of polymorphisms of toll-like receptor (TLR) 4, TLR9, toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A genes in malaria susceptibility and severity in Burundian children. Malaria journal 39 22691414
2009 Low frequency of the TIRAP S180L polymorphism in Africa, and its potential role in malaria, sepsis, and leprosy. BMC medical genetics 37 19602285
2023 TIRAP, TRAM, and Toll-Like Receptors: The Untold Story. Mediators of inflammation 36 36926280
2018 Biochanin A Reduces Inflammatory Injury and Neuronal Apoptosis following Subarachnoid Hemorrhage via Suppression of the TLRs/TIRAP/MyD88/NF-κB Pathway. Behavioural neurology 36 29971136
2017 Src family kinase tyrosine phosphorylates Toll-like receptor 4 to dissociate MyD88 and Mal/Tirap, suppressing LPS-induced inflammatory responses. Biochemical pharmacology 35 29175418
2009 Phagosomal retention of Francisella tularensis results in TIRAP/Mal-independent TLR2 signaling. Journal of leukocyte biology 35 19889726
2008 The Mal/TIRAP S180L and TLR4 G299D polymorphisms are not associated with susceptibility to, or severity of, rheumatoid arthritis. Annals of the rheumatic diseases 35 18180278
2011 Genetic variation of TLR-4, TLR-9 and TIRAP genes in Iranian malaria patients. Malaria journal 34 21457584
2014 Association of TLR4 (D299G, T399I), TLR9 -1486T>C, TIRAP S180L and TNF-α promoter (-1031, -863, -857) polymorphisms with risk for systemic lupus erythematosus among South Indians. Lupus 33 25182168
2002 TIRAP mediates endotoxin-induced NF-kappaB activation and apoptosis in endothelial cells. Biochemical and biophysical research communications 33 12083783
2009 Polymorphic variation in TIRAP is not associated with susceptibility to childhood TB but may determine susceptibility to TBM in some ethnic groups. PloS one 31 19693265
2017 Solution structure of the TLR adaptor MAL/TIRAP reveals an intact BB loop and supports MAL Cys91 glutathionylation for signaling. Proceedings of the National Academy of Sciences of the United States of America 30 28739909
2011 TIRAP Ser180Leu polymorphism is associated with Behcet's disease. Rheumatology (Oxford, England) 30 21705416
2010 Association between single-nucleotide polymorphisms in Mal/TIRAP and interleukin-10 genes and susceptibility to invasive haemophilus influenzae serotype b infection in immunized children. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 30 20804371
2018 Carp Toll-like receptor 8 (Tlr8): An intracellular Tlr that recruits TIRAP as adaptor and activates AP-1 pathway in immune response. Fish & shellfish immunology 29 30077802
2010 MyD88 adaptor-like D96N is a naturally occurring loss-of-function variant of TIRAP. Journal of immunology (Baltimore, Md. : 1950) 28 20164415
2019 Phycocyanin Exerts Anti-Proliferative Effects through Down-Regulating TIRAP/NF-κB Activity in Human Non-Small Cell Lung Cancer Cells. Cells 26 31207932
2010 Genetic variants in the TIRAP gene are associated with increased risk of sepsis-associated acute lung injury. BMC medical genetics 26 21118491
2013 A study on the immunomodulation of polysaccharopeptide through the TLR4-TIRAP/MAL-MyD88 signaling pathway in PBMCs from breast cancer patients. Immunopharmacology and immunotoxicology 25 23802631
2011 Meta-analysis on the association of TIRAP S180L variant and tuberculosis susceptibility. Tuberculosis (Edinburgh, Scotland) 24 21419702
2017 Cytoplasmic Linker Protein CLIP170 Negatively Regulates TLR4 Signaling by Targeting the TLR Adaptor Protein TIRAP. Journal of immunology (Baltimore, Md. : 1950) 22 29222167
2011 Association of TIRAP (MAL) gene polymorhisms with susceptibility to tuberculosis in a Chinese population. Genetics and molecular research : GMR 22 21218381
2009 Morphological and mitochondrial DNA characters for identification and phylogenetic analysis of the myiasis-causing flesh fly Wohlfahrtia magnifica and its relatives, with a description of Wohlfahrtia monegrosensis sp. n. Wyatt & Hall. Medical and veterinary entomology 22 19335831
2020 A peptide derived from the core β-sheet region of TIRAP decoys TLR4 and reduces inflammatory and autoimmune symptoms in murine models. EBioMedicine 21 32014819
2020 mTORC1 Signaling Controls TLR2-Mediated T-Cell Activation by Inducing TIRAP Expression. Cell reports 21 32698010
2019 Inhibition of the TIRAP-c-Jun interaction as a therapeutic strategy for AP1-mediated inflammatory responses. International immunopharmacology 20 30909134
2018 Investigation of interactions between TLR2, MyD88 and TIRAP by bioluminescence resonance energy transfer is hampered by artefacts of protein overexpression. PloS one 20 30138457
2018 GPR108, an NF-κB activator suppressed by TIRAP, negatively regulates TLR-triggered immune responses. PloS one 20 30332431
2022 TIRAP drives myelosuppression through an Ifnγ-Hmgb1 axis that disrupts the endothelial niche in mice. The Journal of experimental medicine 19 35089323
2022 TIRAP-mediated activation of p38 MAPK in inflammatory signaling. Scientific reports 19 35379857
2012 Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice. Toxicology and applied pharmacology 19 23238562
2011 Poxvirus A46 protein binds to TIR domain-containing Mal/TIRAP via an α-helical sub-domain. Molecular immunology 19 21831443
2020 The αC helix of TIRAP holds therapeutic potential in TLR-mediated autoimmune diseases. Biomaterials 18 32220799
2017 Heterotrimeric complex of p38 MAPK, PKCδ, and TIRAP is required for AP1 mediated inflammatory response. International immunopharmacology 17 28528205
2016 Particle-Induced Osteolysis Is Mediated by TIRAP/Mal in Vitro and in Vivo: Dependence on Adherent Pathogen-Associated Molecular Patterns. The Journal of bone and joint surgery. American volume 17 26888676
2006 Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways. Laboratory investigation; a journal of technical methods and pathology 17 16983331
2020 Paradoxical Roles of the MAL/Tirap Adaptor in Pathologies. Frontiers in immunology 16 33072109
2020 Interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. Scientific reports 15 32985578
2014 TIRAP C539T polymorphism contributes to tuberculosis susceptibility: evidence from a meta-analysis. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 15 25003251
2008 Functional characterization of bovine TIRAP and MyD88 in mediating bacterial lipopolysaccharide-induced endothelial NF-kappaB activation and apoptosis. Comparative immunology, microbiology and infectious diseases 15 18760477
2016 Brucella TIR-like protein TcpB/Btp1 specifically targets the host adaptor protein MAL/TIRAP to promote infection. Biochemical and biophysical research communications 14 27311859
2017 Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif. Scientific reports 13 28225045
2020 Ischemia reperfusion injury provokes adverse left ventricular remodeling in dysferlin-deficient hearts through a pathway that involves TIRAP dependent signaling. Scientific reports 12 32839504
2022 Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation. Biochemical and biophysical research communications 11 36240653
2014 TIRAP rs8177374 gene polymorphism increased the risk of pulmonary tuberculosis in Zahedan, southeast Iran. Asian Pacific journal of tropical medicine 11 25066393
2016 Epistatic interaction between MyD88 and TIRAP against Helicobacter pylori. FEBS letters 10 27296467
2015 TLR4/TIRAP polymorphisms are associated with progression and survival of patients with symptomatic myeloma. British journal of haematology 10 26564000
2007 Expression of Toll/IL-1R domain-containing adaptor protein (TIRAP) is detrimental to primary clearance of Salmonella and is not required for the generation of protective immunity. Immunology letters 10 18096248
2023 Dorzolamide suppresses PKCδ -TIRAP-p38 MAPK signaling axis to dampen the inflammatory response. Future medicinal chemistry 9 37129027
2022 TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells. Biomedicines 9 35884781
2022 Identification of novel inhibitors targeting TIRAP interactions with BTK and PKCδ in inflammation through an in silico approach. SAR and QSAR in environmental research 8 35174746
2013 Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice. PloS one 8 24205107
2021 TLR1 in Nile tilapia: The conserved receptor cannot interact with MyD88 and TIRAP but can activate NF-κB in vitro. Developmental and comparative immunology 7 34673140
2020 Expression, signal transduction, and function analysis of TIRAP and TRIF in Nile tilapia (Oreochromis niloticus). Developmental and comparative immunology 7 33387560
2018 TIRAP p.R81C is a novel lymphoma risk variant which enhances cell proliferation via NF-κB mediated signaling in B-cells. Haematologica 7 30381301
2016 Heterozygous mutants of TIRAP (S180L) polymorphism protect adult patients with Plasmodium falciparum infection against severe disease and mortality. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 7 27166096
2016 MyD88 Adapter-like (Mal)/TIRAP Is Required for Cytokine Production by Splenic Ly6CloTLR2hi but Not by Ly6ChiTLR2hi Monocytes during Trypanosoma cruzi Infection. The Journal of biological chemistry 7 27646001
2013 Aberrant TIRAP and MyD88 expression in B-cell chronic lymphocytic leukemia. Blood cells, molecules & diseases 7 23419703
2012 A TIR domain receptor-associated protein (TIRAP) variant SNP (rs8177374) confers protection against premature birth. Journal of perinatology : official journal of the California Perinatal Association 7 23047423
2024 Hypothermic oxygenated perfusion inhibits CLIP1-mediated TIRAP ubiquitination via TFPI2 to reduce ischemia‒reperfusion injury of the fatty liver. Experimental & molecular medicine 6 39617791
2024 Association Between Single-Nucleotide Polymorphisms in Toll-like Receptor 3 (tlr3), tlr7, tlr8 and tirap Genes with Severe Symptoms in Children Presenting COVID-19. Viruses 6 39861824
2020 Absence of Mal/TIRAP Results in Abrogated Imidazoquinolinones-Dependent Activation of IRF7 and Suppressed IFNβ and IFN-I Activated Gene Production. International journal of molecular sciences 6 33255528
2023 Tirap controls Mycobacterium tuberculosis phagosomal acidification. PLoS pathogens 5 36888688
2012 Association of Mal/TIRAP S180L variant polymorphism with decreased infection risk in patients with advanced HIV-1 infection. Cytokine 5 22683004
2024 o-Vanillin binds covalently to MAL/TIRAP Lys-210 but independently inhibits TLR2. Journal of enzyme inhibition and medicinal chemistry 4 38416868

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