Affinage

TIFA

TRAF-interacting protein with FHA domain-containing protein A · UniProt Q96CG3

Round 2 corrected
Length
184 aa
Mass
21.4 kDa
Annotated
2026-04-28
76 papers in source corpus 34 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIFA is a small adaptor protein that functions as a central signaling hub in innate immunity and NF-κB activation by undergoing phosphorylation-dependent oligomerization and liquid-liquid phase separation to recruit and activate TRAF6 and TRAF2. Phosphorylation of Thr9—by ALPK1 in response to bacterial ADP-heptose/HBP, by Aurora A in leukemia, or by Akt under disturbed flow—enables the FHA domain of one TIFA dimer to engage pThr9 on another, driving higher-order oligomer (TIFAsome) assembly that promotes TRAF6 K63-linked polyubiquitination and downstream TAK1/IKK/NF-κB signaling through both classical and alternative pathways (PMID:26068852, PMID:15492226, PMID:26389808, PMID:34328245, PMID:38357697). Beyond canonical NF-κB activation, TIFA oligomerization facilitates NLRP3 inflammasome priming and assembly, DNA damage-induced NF-κB signaling via TRAF2-dependent NEMO ubiquitination on damaged chromatin, and pro-apoptotic JNK/p38 signaling in hepatocellular carcinoma (PMID:27965388, PMID:29581234, PMID:29263897). TIFAB negatively regulates this pathway by forming a pseudo-TIFA heterodimer that lacks the pThr9 site and TRAF6-binding motif, preventing productive oligomerization (PMID:38442163).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 Medium

    Identification of TIFA (T6BP) as a TRAF6-interacting adaptor established the first molecular link between this protein and IL-1/IRAK-dependent NF-κB signaling, answering how TRAF6 receives upstream signals.

    Evidence Yeast two-hybrid screen and co-immunoprecipitation with domain mapping in IL-1-stimulated cells

    PMID:10920205

    Open questions at the time
    • Single lab; endogenous interaction under physiological conditions not fully characterized
    • Upstream kinase unknown
    • TIFA's binding to other TRAF family members not tested
  2. 2002 Medium

    Discovery that TIFA also binds TRAF2 and activates both NF-κB and AP-1 expanded the adaptor's functional scope beyond the TRAF6 axis.

    Evidence Mammalian two-hybrid screen and NF-κB/AP-1 reporter assays with co-immunoprecipitation

    PMID:11798190

    Open questions at the time
    • TRAF2-binding site on TIFA not mapped
    • Physiological stimulus driving TIFA-TRAF2 interaction unknown
    • Relationship between TRAF2 and TRAF6 binding not tested
  3. 2003 High

    Demonstration that TIFA bridges IRAK-1 and TRAF6, and that both the FHA domain and TRAF6-binding motif are required for NF-κB/JNK activation, defined TIFA as a scaffolding adaptor rather than a passive binder.

    Evidence Reciprocal co-IP with endogenous proteins, IL-1 stimulation, FHA and TRAF6-binding mutants in reporter assays

    PMID:12566447

    Open questions at the time
    • FHA domain ligand (phosphopeptide source) not identified
    • In vivo relevance not tested
    • Stoichiometry of the IRAK-1/TIFA/TRAF6 complex undefined
  4. 2004 High

    In vitro reconstitution proved that only oligomeric TIFA activates TRAF6 K63-linked polyubiquitination and downstream TAK1/IKK, establishing oligomerization as the activating switch and ruling out proteasome dependence.

    Evidence Purified protein reconstitution with TIFA, TRAF6, TAK1 complex, and Ubc13-Uev1A; gel filtration separation of oligomeric forms

    PMID:15492226

    Open questions at the time
    • What triggers TIFA oligomerization in cells was unknown
    • Structural basis of oligomerization not resolved
    • TIFAB's inhibitory mechanism only partially characterized
  5. 2004 Medium

    Identification of TIFAB as a TIFA-binding negative regulator that lacks TRAF-binding capacity revealed the first endogenous brake on TIFA-mediated signaling.

    Evidence Co-immunoprecipitation and NF-κB reporter assays with TIFAB overexpression

    PMID:15047173

    Open questions at the time
    • TIFAB inhibitory mechanism (conformational vs. competitive) unclear
    • Structural basis of TIFA-TIFAB interaction not solved
    • Physiological contexts of TIFAB regulation unknown
  6. 2012 High

    Discovery that Thr9 phosphorylation drives FHA-mediated intermolecular oligomerization between TIFA dimers solved the long-standing question of how TIFA oligomerization is triggered.

    Evidence Phosphosite identification, NMR/biochemical analysis, size-exclusion chromatography, FHA-pThr9 binding assays, siRNA silencing

    PMID:22566686

    Open questions at the time
    • Identity of the Thr9 kinase(s) in different signaling contexts unknown
    • Structural visualization of the oligomeric assembly not achieved
    • Contribution of pThr9-independent oligomerization mechanisms not excluded
  7. 2015 High

    Crystal structures of TIFA and the FHA-pThr9 peptide complex provided the atomic-level explanation for why pThr9 binding can only occur between different dimers, rationalizing phosphorylation-dependent polymerization.

    Evidence X-ray crystallography, SAXS, functional mutagenesis

    PMID:26389808

    Open questions at the time
    • Full-length oligomeric structure not solved
    • In vivo stoichiometry of TIFAsomes unknown
    • Dynamics of assembly and disassembly not captured
  8. 2015 High

    A genome-wide RNAi screen identified TIFA as essential for the cytosolic innate immune response to bacterial HBP, establishing TIFA as a pattern recognition adaptor for a conserved Gram-negative metabolite.

    Evidence Genome-wide RNAi screen, HBP cytosolic delivery, NF-κB reporter, in vivo mouse model

    PMID:26068852

    Open questions at the time
    • The direct sensor/kinase upstream of TIFA for HBP not yet identified
    • Whether other bacterial metabolites activate TIFA unknown
    • Contribution of TIFA to adaptive immunity only partially explored
  9. 2016 High

    Identification of Akt as a Thr9 kinase linking disturbed hemodynamic flow to TIFA oligomerization and NLRP3 inflammasome assembly in endothelial cells demonstrated that TIFA integrates metabolic and mechanical stress signals beyond pathogen detection.

    Evidence Akt kinase assay, TIFA oligomerization assays, TIFA-caspase-1 co-IP, atheroprone flow model, hyperlipidemia mouse model

    PMID:27965388

    Open questions at the time
    • How TIFA physically bridges NLRP3 ASC specks not resolved
    • Whether TIFA directly interacts with NLRP3 components structurally unknown
    • Relative contribution of Akt vs. ALPK1 in different tissues not defined
  10. 2017 High

    Convergent studies identified ALPK1 as the kinase that phosphorylates TIFA at Thr9 in response to bacterial β-HBP/ADP-heptose delivered by T4SS and other secretion systems, completing the ALPK1→TIFA→TRAF6→NF-κB innate immune axis.

    Evidence Genome-wide RNAi screens, CRISPR knockout of ALPK1, recombinant protein technology, multiple Gram-negative bacterial pathogens (H. pylori, Shigella, Salmonella)

    PMID:28222186 PMID:28514661 PMID:28811347 PMID:28877472

    Open questions at the time
    • Direct in vitro kinase assay of ALPK1 on TIFA not reported in all studies
    • How ADP-heptose activates ALPK1 enzymatically not resolved
    • Whether additional kinases act on Thr9 in infection contexts not excluded
  11. 2018 High

    Discovery that TIFA translocates to damaged chromatin and promotes TRAF2-dependent NEMO ubiquitination extended TIFA function to DNA damage-induced NF-κB signaling, a context independent of pathogen detection.

    Evidence Nuclear fractionation, chromatin enrichment, TIFA T9A mutant, TRAF2 knockdown, NEMO ubiquitination assay

    PMID:29581234

    Open questions at the time
    • Kinase responsible for Thr9 phosphorylation in genotoxic stress not identified
    • Whether TIFA forms TIFAsome-like condensates on chromatin untested
    • Relationship to ATM/ATR signaling not explored
  12. 2018 High

    Crystal structures of the TRAF6-TIFA C-terminal peptide complex defined the salt-bridge network mediating TIFA-TRAF6 binding and enabled rational design of enhanced-affinity mutants.

    Evidence X-ray crystallography of TRAF6 TRAF domain with WT and S174Q/M179D TIFA peptides, binding assays

    PMID:30378729

    Open questions at the time
    • Full-length TIFA-TRAF6 complex structure not achieved
    • Whether enhanced-affinity mutants alter signaling output in cells not fully tested
    • Structural basis for TIFA-TRAF2 interaction not resolved
  13. 2021 High

    Dissection of TIFA's dual engagement of TRAF6 and TRAF2 revealed that TIFA-TRAF6 activates classical NF-κB via TAK1, while TIFA-TRAF2 triggers cIAP1 displacement and degradation to activate the alternative NF-κB pathway.

    Evidence Co-IP of TIFA-TRAF6-TAK1 and TIFA-TRAF2-cIAP1 complexes, TIFA knockout, proteasome inhibitor experiments

    PMID:34328245

    Open questions at the time
    • Whether the two complexes form in the same or different TIFAsomes unknown
    • Relative kinetics and stoichiometry of the two pathways not defined
    • Whether TIFA-TRAF2 function extends to non-infection contexts not tested
  14. 2024 High

    Structural resolution of the TIFA-TIFAB heterodimer revealed it as a pseudo-TIFA dimer lacking the Thr9 phosphosite and TRAF6-binding motif, providing the molecular basis for TIFAB's dominant-negative inhibition of TIFA signaling.

    Evidence X-ray crystallography of TIFA/TIFAB complex, biochemical binding assays, NF-κB activation assays, SEC

    PMID:38442163

    Open questions at the time
    • In vivo regulation of TIFAB expression and its physiological impact not characterized
    • Whether TIFAB competes with pThr9-mediated oligomerization under infection unclear
    • No structural data for TIFAB in the context of full-length oligomeric TIFA
  15. 2024 High

    Demonstration that pThr9-dependent TIFA oligomers undergo liquid-liquid phase separation to form functional condensates that concentrate TRAF6 and support K63-linked ubiquitin chain synthesis reframed TIFAsomes as biomolecular condensates.

    Evidence Phase separation assays, fluorescence microscopy, chemical LLPS inhibitor (compound 22), K63-ubiquitination assays in condensates

    PMID:38357697

    Open questions at the time
    • Whether LLPS occurs in vivo in physiological infection models not shown
    • Material properties (viscosity, aging) of TIFAsome condensates not characterized
    • Selectivity of chemical LLPS inhibitor for TIFA condensates vs. other condensates unknown
  16. 2025 Medium

    Identification of a novel TRAF2-binding motif (PxxE) in TIFA and demonstration that both TRAF2 and TRAF6 contribute to TIFA autophagic degradation established that TIFA turnover is an active signaling-coupled process.

    Evidence Mutagenesis of PxxE motif, autophagy flux assays, TRAF2/TRAF6 knockdown

    PMID:40696502

    Open questions at the time
    • Structural basis of PxxE-TRAF2 interaction not solved
    • Whether autophagy of TIFA serves signal termination or signal amplification not distinguished
    • Relationship to optineurin/TAX1BP1-mediated degradation pathway not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length structure of an active TIFAsome oligomer, whether TIFA condensates form in vivo during physiological infection, how different upstream kinases (ALPK1, Aurora A, Akt) are selected in different cellular contexts, and whether TIFA participates in additional innate sensing pathways beyond ADP-heptose.
  • No full-length oligomeric or condensate-state structure available
  • In vivo condensate formation not confirmed by live imaging
  • Context-dependent kinase selection mechanism 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 4 GO:0005634 nucleus 1 GO:0005694 chromosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
ALPK1IRAK1MYO6NEMOTAK1TIFABTRAF2TRAF6
Complex memberships
TIFAsome

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 T6BP (later called TIFA) was identified as a protein that specifically associates with TRAF6 via the coiled-coil region of T6BP interacting with the N-terminal ring finger and zinc finger domains of TRAF6. IL-1, but not TNF, induces TRAF6-T6BP complex formation in a ligand-dependent manner requiring IRAK. Yeast two-hybrid screen, co-immunoprecipitation, ligand-stimulation assays Proceedings of the National Academy of Sciences of the United States of America Medium 10920205
2002 T2BP (TIFA) was identified as a TRAF2-binding protein via a mammalian two-hybrid screen. The TRAF domain of TRAF2 is required for binding to T2BP, and almost the entire T2BP protein is needed for TRAF2 interaction. Overexpression of T2BP activates NF-κB and AP-1 in a dose-dependent manner. Mammalian two-hybrid screening, co-immunoprecipitation, NF-κB/AP-1 reporter assays Biochemical and biophysical research communications Medium 11798190
2003 TIFA was identified as an adaptor protein linking TRAF6 to IRAK-1 in IL-1 receptor signaling. TIFA binds TRAF6 constitutively and associates with IRAK-1 in an IL-1 stimulation-dependent manner. Mutations abolishing TRAF6 binding or FHA domain phosphopeptide binding prevented NF-κB and JNK activation. TIFA overexpression significantly enhanced the IRAK-1/TRAF6 interaction. Co-immunoprecipitation, transient transfection, NF-κB/JNK reporter assays, FHA domain mutagenesis The Journal of biological chemistry High 12566447
2004 TIFA activates IKK by promoting oligomerization and K63-linked polyubiquitination of TRAF6, leading to TAK1 and IKK activation. Only high-molecular-weight oligomeric forms of TIFA (not monomer/dimer) activate IKK. TIFA requires a functional TRAF6-binding site for this activity. This was reconstituted in vitro with purified TIFA, TRAF6, TAK1 complex, and Ubc13-Uev1A, independently of the proteasome. In vitro IKK reconstitution with purified proteins, crude cytosolic extract assays, gel filtration to separate oligomeric forms, ubiquitination assays, TRAF6-binding-defective mutant Proceedings of the National Academy of Sciences of the United States of America High 15492226
2004 TIFAB, a TIFA-related protein lacking TRAF family binding, was identified as a negative regulator of TIFA-mediated NF-κB activation. TIFAB binds TIFA but not TRAF proteins, and increases the amount of TRAF6 co-precipitated with TIFA, suggesting TIFAB inhibits TIFA-mediated TRAF6 activation possibly by inducing a conformational change in TIFA. Co-immunoprecipitation, transient transfection, NF-κB reporter assay Biochemical and biophysical research communications Medium 15047173
2005 Xenopus laevis homologs of TRAF6 (XTRAF6) and TIFA (XTIFA) were identified. Overexpression of XTIFA activated NF-κB by binding XTRAF6, and a mutation abolishing XTRAF6 binding abolished NF-κB activation, confirming conservation of the TIFA-TRAF6 signaling mechanism in vertebrate development. Xenopus overexpression, NF-κB reporter assay, binding-defective mutant Gene Medium 16023795
2006 ZCCHC11, a novel zinc finger protein, was identified as a TIFA-interacting partner. ZCCHC11L translocates from nucleus to cytoplasm in response to LPS and binds TIFA. ZCCHC11 functions as a negative regulator of TLR-mediated NF-κB activation in a TRAF6-dependent manner, as shown by overexpression and siRNA knockdown experiments. GST-TIFA affinity purification, mass spectrometry, co-immunoprecipitation, siRNA knockdown, NF-κB reporter assay, immunofluorescence Biochemical and biophysical research communications Medium 16643855
2007 TIFA (T6BP) was identified as a myosin VI binding partner by yeast two-hybrid screen, confirmed in vitro and in vivo. T6BP and myosin VI localize to the trans-Golgi complex and perinuclear vesicles. RNAi knockdown of T6BP reduced membrane ruffling, increased stress fibres and focal adhesions, upregulated constitutive secretion, and T6BP was found to inhibit NF-κB activation. Yeast two-hybrid screen, in vitro binding, co-immunoprecipitation, immunofluorescence, electron microscopy, RNAi knockdown, secretion assay Journal of cell science Medium 17635994
2012 TIFA contains a novel phosphorylation site at Thr9, and phosphorylated Thr9 (pThr9) binds the FHA domain of a different TIFA molecule, driving intermolecular oligomerization. Unphosphorylated TIFA exists as an intrinsic dimer; FHA-pThr9 binding occurs between different dimers. TIFA silencing attenuates TNF-α-mediated NF-κB downstream signaling, establishing a link between TNF-α stimulation and NF-κB activation. Phosphorylation site identification, FHA-pT binding assay, size-exclusion chromatography, NMR/biochemical analysis, siRNA silencing, NF-κB reporter assay Molecular and cellular biology High 22566686
2013 TIFA expression is upregulated after hypoxia-reoxygenation in a TLR4- and MyD88-dependent manner. Under these conditions, TIFA associates with TRAF6 constitutively and with IRAK-1 only after hypoxia-reoxygenation. siRNA knockdown of TIFA reduced NF-κB activation and HMGB1 upregulation/release, placing TIFA in a TLR4/MyD88-dependent feed-forward signaling loop. qRT-PCR, western blotting, co-immunoprecipitation, siRNA knockdown, EMSA, TLR4−/− and MyD88−/− cells Free radical biology & medicine Medium 23722163
2015 Crystal structures of TIFA revealed that the FHA domain forms an intrinsic dimer in solution, and the pThr9 peptide binds at a site that can only interact with a different dimer (not within the same dimer), providing the structural mechanism for phosphorylation-dependent TIFA oligomerization. This oligomerization is essential for NF-κB activation in immune responses. X-ray crystallography of TIFA and TIFA-pThr9 peptide complex, small angle X-ray scattering, functional mutagenesis Biochemistry High 26389808
2015 Cytosolic detection of the bacterial metabolite heptose-1,7-bisphosphate (HBP), a conserved Gram-negative LPS biosynthetic intermediate absent from eukaryotes, triggers TIFA-dependent NF-κB activation. A genome-wide RNAi screen identified TIFA as essential for this response. HBP induces phosphorylation-dependent TIFA oligomerization, activating innate and adaptive immune responses in vivo. Genome-wide RNAi screen, HBP cytosolic delivery assay, NF-κB reporter, in vivo mouse model, TIFA phosphorylation analysis Science High 26068852
2015 TIFA reconstitution in hepatocellular carcinoma cells promotes two independent apoptosis pathways (p53-dependent cell cycle arrest and caspase-8/caspase-3 activation). A non-oligomerizing TIFA mutant had minimal effect, demonstrating that TIFA oligomerization is required for its tumor-suppressive apoptotic function. TIFA reconstitution in HCC cell lines, non-oligomerizing mutant expression, caspase assays, p53 pathway analysis, xenograft mouse model, TUNEL staining Oncogenesis Medium 26501855
2016 TIFA is phosphorylated at Thr9 by Aurora A kinase, triggering NF-κB survival pathway activation in acute myeloid leukemia. Silencing TIFA decreased leukemic cell growth and chemoresistance by downregulating Bcl-2 and Bcl-XL. In vivo delivery of TIFA-inhibitory fragments potentiated myeloblast clearance in xenograft mice. Aurora A kinase assay for Thr9 phosphorylation, siRNA silencing in AML lines and primary patient cells, Bcl-2/Bcl-XL western blotting, xenograft mouse model Cancer research High 28069801
2016 TIFA acts as a crucial mediator of NLRP3 inflammasome in vascular endothelial cells, regulating both priming (signal 1) and activation (signal 2). For signal 1, TIFA is transactivated by SREBP2 and induces NF-κB to upregulate NLRP3 components. For signal 2, Akt phosphorylates TIFA at Thr9, enabling TIFA-TIFA homophilic oligomerization that facilitates higher-order NLRP3 assembly and TIFA-caspase-1 interaction. SREBP2 transactivation assay, Akt kinase assay, TIFA Thr9 phosphorylation, co-immunoprecipitation (TIFA-caspase-1), oligomerization assays, atheroprone flow model, hyperlipidemia mouse model Proceedings of the National Academy of Sciences of the United States of America High 27965388
2016 TIFA suppresses hepatocellular carcinoma via MALT1-dependent and MALT1-independent signaling. MALT1 competes with TIFA and its silencing enhances TIFA-induced apoptosis. Long-duration TIFA reconstitution activates JNK and p38 via TRAF6 binding: JNK activation drives apoptosis while p38 governs cell cycle arrest via p53-p21 signaling. MALT1 shRNA silencing, JNK/p38 activation assays, TRAF6 co-immunoprecipitation, caspase assays, in vitro and xenograft in vivo models Signal transduction and targeted therapy Medium 29263897
2017 In H. pylori-infected gastric epithelial cells, ALPK1 kinase phosphorylates TIFA in response to the T4SS-delivered bacterial metabolite β-HBP (D-glycero-β-D-manno-heptose 1,7-bisphosphate), leading to formation of large TIFA complexes (TIFAsomes) that include TRAF2. NF-κB activation, TIFA phosphorylation, and TIFAsome formation all depend on functional ALPK1, establishing ALPK1 as the upstream kinase in this innate immune axis. Genome-wide RNAi screen, CRISPR/Cas9 knockout, recombinant protein technology, immunofluorescence microscopy, immunoblotting, mass spectrometry, mutant H. pylori strains Cell reports High 28877472
2017 HBP delivered to the host cytosol via the H. pylori cag-T4SS activates the TIFA-dependent cytosolic surveillance pathway independently of NOD1, driving NF-κB-dependent inflammation within hours of infection and preceding NOD1 activation. CagA toxin contributes to NF-κB responses subsequent to TIFA and NOD1 activation, establishing sequential activation: TIFA → NOD1 → CagA. Genetic epistasis with TIFA and NOD1 knockdown/knockout, timed NF-κB activation assays, cag-T4SS mutant bacteria, HBP delivery assays mBio High 28811347
2017 TIFA threonine 9 and the FHA domain are required for TIFA oligomerization in both infected and bystander cells during Shigella and Salmonella infection. TIFA oligomerization triggers TRAF6 oligomerization and NF-κB activation. ALPK1 is the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to invasive and extracellular Gram-negative bacteria. Genome-wide RNAi screen, T9A and FHA domain mutants, NF-κB/IL-8 reporter assays, bacterial infection models, ALPK1 siRNA PLoS pathogens High 28222186
2017 TIFA senses HBP released during intracellular bacterial replication in the host cytosol, assembling into large signaling complexes to drive dynamic NF-κB activation proportional to bacterial proliferation rate. IECs lacking TIFA could not discriminate between proliferating and stagnant intracellular bacteria despite intact NOD1/2 pathways, defining TIFA as a rheostat for intracellular bacterial replication. TIFA-knockout IECs, Shigella intracellular replication assay, NF-κB activation kinetics, HBP detection assay Cell reports High 28514661
2018 TIFA undergoes nuclear translocation and accumulates on damaged chromatin following genotoxic stress. DNA damage induces TIFA phosphorylation at Thr9, and this pThr9-FHA interaction is required for chromatin enrichment. TIFA then partners with TRAF2 to stimulate ubiquitination of NEMO (whose sumoylation, phosphorylation, and ubiquitination relay DNA damage to NF-κB). TRAF2 knockdown suppressed TIFA-enhanced NEMO ubiquitination under genotoxic stress. Nuclear fractionation, chromatin immunoprecipitation, TIFA overexpression and T9A mutant, TRAF2 knockdown, NEMO ubiquitination assay, NF-κB target gene expression The Journal of biological chemistry High 29581234
2018 Direct binding between TIFA and the TRAF domain of TRAF6 was demonstrated biochemically, and the crystal structures of TRAF6-TRAF domain complexed with wild-type and S174Q/M179D mutant TIFA C-terminal peptides were solved. The structures revealed salt-bridge formation between TIFA residues 177-181 and TRAF6 binding-pocket residues. A rationally designed TIFA double mutant (S174Q/M179D) showed enhanced binding to endogenous full-length TRAF6. In vitro binding assays, X-ray crystallography of TRAF domain-TIFA peptide complexes, co-immunoprecipitation with full-length TRAF6 Chembiochem High 30378729
2020 H. pylori-induced DNA double-strand breaks occur co-transcriptionally in S-phase cells and depend on ALPK1/TIFA/NF-κB signaling triggered by β-ADP-heptose. DNA damage requires co-transcriptional RNA/DNA hybrids (R-loops) that form as a consequence of β-ADP-heptose/ALPK1/TIFA/NF-κB signaling, linking bacterial innate immune activation to replication stress. DNA damage markers (γH2AX), R-loop immunofluorescence (S9.6 antibody), ALPK1/TIFA pathway inhibition, gastric organoid primary cells, replication fork stalling assay Nature communications High 33037203
2020 Crystal structures of mouse TIFA and phosphomimetic mutants (T9D and T9E) confirmed the dimeric structure similar to human TIFA. Size-exclusion chromatography analysis of TIFA and TIFA-TRAF6 complexes suggested a model for the TIFA-TRAF6 signaling complex assembly wherein TIFA oligomers recruit TRAF6. X-ray crystallography, small angle X-ray scattering, size-exclusion chromatography, phosphomimetic mutagenesis Scientific reports High 32198460
2021 TIFA has dual functions in H. pylori-infected gastric epithelial cells: (1) TIFA-TRAF6 interaction enables TAK1 binding, activating classical NF-κB signaling; (2) TIFA-TRAF2 interaction causes transient displacement of cIAP1 from TRAF2 and proteasomal degradation of cIAP1, facilitating alternative NF-κB pathway activation. Both interactions contribute to TIFAsome formation. Co-immunoprecipitation (TIFA-TRAF6-TAK1 and TIFA-TRAF2-cIAP1 complexes), TIFA knockout, proteasome inhibitor experiments, classical and alternative NF-κB pathway reporters EMBO reports High 34328245
2022 TIFA expression in intestinal epithelial cells is required for NF-κB activation by ADP-heptose released from the commensal bacterium Akkermansia muciniphila, via the ALPK1/TIFA/TRAF6 axis. This signaling induces MUC2, BIRC3, and TNFAIP3 expression involved in intestinal barrier maintenance. Drug inhibitors, CRISPR gene editing (ALPK1, TIFA, TRAF6 KO), ADP-heptose characterization, NF-κB reporter, gene expression assays Gut microbes Medium 36036242
2022 TIFA promotes colorectal cancer cell proliferation via TRAF6 binding and oligomerization: mutants at the oligomerization site (T9A) or TRAF6-binding site (D6 deletion) abolished TIFA-mediated proliferation enhancement. The mechanism involves RSK and PRAS40 kinase activation downstream of TIFA. TIFA knockdown, T9A and D6 mutant overexpression, cell proliferation assays in vitro and xenograft in vivo, RSK/PRAS40 phosphorylation assays Cancer science Medium 35639239
2023 H. pylori promotes TIFA turnover in gastric epithelial cells via both proteasomal and lysosomal degradation pathways following ALPK1-dependent TIFA activation. H. pylori infection promotes TIFA interaction with free polyubiquitin and with autophagy/trafficking adaptors optineurin, TAX1BP1, and LAMP1, implicating selective autophagy in TIFA degradation. TRAF2, TRAF6, TAK1, and NEMO are not required for TIFA degradation. Proteasome and lysosome inhibitors, co-immunoprecipitation of TIFA with optineurin/TAX1BP1/LAMP1, H. pylori infection assays, western blotting for TIFA levels European journal of cell biology Medium 36965415
2024 TIFAB forms a stable heterodimer with monomeric TIFA (not the intrinsic TIFA dimer), inhibiting TIFA dimer formation and suppressing TIFA-TRAF6 signaling. Structural analysis showed the TIFA/TIFAB complex is a 'pseudo-TIFA dimer' lacking the phosphorylation site and TRAF6-binding motif contributed by TIFAB, preventing formation of the orderly phosphorylated TIFA oligomer required for NF-κB activation. X-ray crystallography of TIFA/TIFAB complex, biochemical binding assays, cell-based NF-κB activation assays, size-exclusion chromatography Proceedings of the National Academy of Sciences of the United States of America High 38442163
2024 ALPK1-induced TIFA phosphorylation at Thr9 drives liquid-liquid phase separation (LLPS) of TIFA, mediated by the pT9-FHA domain interaction and an intrinsically disordered region. TRAF6 is subsequently recruited into TIFA condensates, where K63-linked polyubiquitin chain synthesis occurs and downstream effectors are enriched and activated. Chemical inhibition of LLPS (compound 22) blocked the ALPK1-TIFA-TRAF6 pathway. Phase separation assays, fluorescence microscopy of condensates, chemical probe inhibitor, K63-ubiquitination assays in condensates, intrinsically disordered region analysis Research (Washington, D.C.) High 38357697
2024 IFN-γ licenses the ALPK1/TIFA pathway in human monocytes by upregulating TIFA expression; TIFA induction alone is sufficient to recapitulate the licensing effect of IFN-γ. This licensing was blocked by JAK inhibitors. B cells did not require IFN-γ for ALPK1/TIFA responsiveness. ADP-heptose stimulation of human mononuclear cell subsets, IFN-γ treatment, TIFA overexpression, JAK inhibitor blockade, NF-κB activation assays iScience Medium 39868044
2025 TRAF2 interacts with TIFA via two conserved sequence motifs, one of which (Pro159-Xaa-Xaa-Glu162) is a novel TRAF2-binding motif. ADP-heptose induces TIFA degradation by autophagy, and both TRAF2 and TRAF6 contribute to this autophagic degradation process. Mutagenesis of TIFA motifs, co-immunoprecipitation, autophagy flux assays, TRAF2/TRAF6 knockdown FEBS letters Medium 40696502
2025 NSUN3 stabilizes TIFA mRNA through m5C modification recognized by IGF2BP2, increasing TIFA expression. Knockdown of NSUN3 reduced TIFA expression and alleviated LPS-induced kidney injury, placing NSUN3 as an upstream regulator of TIFA at the post-transcriptional level. MeRIP-seq, methylation RNA immunoprecipitation-qPCR, actinomycin D mRNA stability assay, NSUN3 knockdown, TIFA western blotting Clinical and experimental pharmacology & physiology Medium 39924309
2025 METTL3-mediated m6A modification of TIFA mRNA is recognized by IGF2BP2 to enhance TIFA mRNA stability. Increased TIFA promotes NLRP3 transcription via NF-κB signaling, activating the NLRP3 inflammasome and Caspase-1, driving pyroptosis in tubular epithelial cells during ischemic AKI. MeRIP-seq, RNA-seq, m6A-RIP, METTL3 conditional KO mice, TIFA knockdown, NLRP3/Caspase-1/GSDMD western blot, pyroptosis assays Free radical biology & medicine High 41320097
2025 ALPK1 activation enhances STING pathway outputs including canonical NF-κB/interferon responses and noncanonical STING proton channel-dependent LC3B lipidation and NLRP3 inflammasome activation. Conversely, STING activation increases ALPK1 protein expression and triggers TIFA Thr9 phosphorylation, establishing bidirectional crosstalk between the ALPK1-TIFA and STING innate immune pathways. ALPK1 gain-of-function mutations, STING pathway reporters, LC3B lipidation assay, NLRP3 inflammasome activation, TIFA pThr9 immunoblot, eIF2α phosphorylation assay bioRxivpreprint Medium

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 1061 18978771
2008 IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nature medicine 962 18264110
2020 COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovascular research 943 32352535
2020 Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nature communications 826 32901017
2009 Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. The Journal of clinical investigation 807 19920355
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2011 Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 549 21600206
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2009 Circulating Th17, Th22, and Th1 cells are increased in psoriasis. The Journal of investigative dermatology 495 20032993
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2000 Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. Journal of immunology (Baltimore, Md. : 1950) 399 10657629
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2014 Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. Journal of immunology (Baltimore, Md. : 1950) 329 24610014
2014 IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 324 24816405
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2011 Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology (Baltimore, Md.) 259 21674558
2005 Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology 243 15765404
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2015 INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity. Science (New York, N.Y.) 126 26068852
2017 TIFA Signaling in Gastric Epithelial Cells Initiates the cag Type 4 Secretion System-Dependent Innate Immune Response to Helicobacter pylori Infection. mBio 118 28811347
2004 TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. Proceedings of the National Academy of Sciences of the United States of America 115 15492226
2017 ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria. PLoS pathogens 104 28222186
2020 The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress. Nature communications 89 33037203
2007 T6BP and NDP52 are myosin VI binding partners with potential roles in cytokine signalling and cell adhesion. Journal of cell science 80 17635994
2003 Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling. The Journal of biological chemistry 75 12566447
2022 Akkermansia muciniphila upregulates genes involved in maintaining the intestinal barrier function via ADP-heptose-dependent activation of the ALPK1/TIFA pathway. Gut microbes 62 36036242
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2002 T2BP, a novel TRAF2 binding protein, can activate NF-kappaB and AP-1 without TNF stimulation. Biochemical and biophysical research communications 55 11798190
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2016 Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA. Cancer research 48 28069801
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2023 Fusobacterium nucleatum promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation. Gut microbes 43 38126163
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2006 A novel Zinc finger protein, ZCCHC11, interacts with TIFA and modulates TLR signaling. Biochemical and biophysical research communications 41 16643855
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2013 TIFA upregulation after hypoxia-reoxygenation is TLR4- and MyD88-dependent and associated with HMGB1 upregulation and release. Free radical biology & medicine 31 23722163
2015 Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses. Biochemistry 29 26389808
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2004 TIFAB inhibits TIFA, TRAF-interacting protein with a forkhead-associated domain. Biochemical and biophysical research communications 20 15047173
2022 The potential biomarker TIFA regulates pyroptosis in sepsis-induced acute kidney injury. International immunopharmacology 19 36586274
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2018 TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 13 29975933
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2020 Nonhydrolyzable Heptose Bis- and Monophosphate Analogues Modulate Pro-inflammatory TIFA-NF-κB Signaling. Chembiochem : a European journal of chemical biology 9 32452604
2025 NSUN3 Aggravates Sepsis-Associated Acute Kidney Injury by Stabilising TIFA mRNA Through m5C. Clinical and experimental pharmacology & physiology 8 39924309
2024 ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses. Research (Washington, D.C.) 7 38357697
2024 TIFAB regulates the TIFA-TRAF6 signaling pathway involved in innate immunity by forming a heterodimer complex with TIFA. Proceedings of the National Academy of Sciences of the United States of America 6 38442163
2023 Helicobacter pylori regulates TIFA turnover in gastric epithelial cells. European journal of cell biology 6 36965415
2005 Identification and characterization of Xenopus laevis homologs of mammalian TRAF6 and its binding protein TIFA. Gene 6 16023795
2023 TIFA contributes to periodontitis in diabetic mice via activating the NF‑κB signaling pathway. Molecular medicine reports 4 38099344
2025 TIFA renders intestinal epithelial cells responsive to microbial ADP-heptose and drives colonic inflammation in mice. Mucosal immunology 3 39842611
2023 Inducing a Proinflammatory Response with Bioengineered Yeast Vacuoles with TLR2-Binding Peptides (VacT2BP) as a Drug Carrier for Daunorubicin Delivery. ACS applied materials & interfaces 3 37615983
2024 TIFA enhances glycolysis through E2F1 and promotes the progression of glioma. Cellular signalling 2 39481822
2024 IFN-γ licenses normal and pathogenic ALPK1/TIFA pathway in human monocytes. iScience 2 39868044
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2025 METTL3-mediated m6A modification of TIFA mRNA promotes tubular cell pyroptosis in acute kidney injury. Free radical biology & medicine 0 41320097