Affinage

TRAF3IP2

E3 ubiquitin ligase TRAF3IP2 · UniProt O43734

Length
574 aa
Mass
64.7 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAF3IP2 (Act1/CIKS) is a cytoplasmic adaptor and U-box E3 ubiquitin ligase that functions as the obligate membrane-proximal signal transducer for IL-17 family receptor signaling and additionally acts as a negative regulator of CD40/BAFF and STAT3 pathways in lymphocytes. Upon IL-17 stimulation, Act1 is recruited to IL-17R via heterotypic SEFIR domain interaction (mediated by the CC' loop/αC helix), then recruits TRAF6 through a conserved N-terminal motif and catalyzes K63-linked ubiquitination of TRAF6 at K124 via the Ubc13–Uev1A E2 complex, activating downstream TAK1/IKK/NF-κB and JNK/AP-1 cascades (PMID:17035243, PMID:19825828, PMID:22045852). Act1 also directly binds stem-loop structures in inflammatory mRNA 3′UTRs through its SEFIR domain, assembling distinct ribonucleoprotein complexes that prevent mRNA decay and promote translation, while its own turnover is governed by Hsp90 chaperoning, TBK1/IKKi-mediated inhibitory phosphorylation, and SCF(β-TrCP)-dependent K48-linked ubiquitination and degradation (PMID:29563620, PMID:23202271, PMID:22851696, PMID:22045853). Biallelic loss-of-function mutation (T536I) in the SEFIR domain abolishes IL-17R interaction and causes chronic mucocutaneous candidiasis in humans, while the FYN-TRAF3IP2 fusion drives NF-κB-dependent T-cell lymphomagenesis (PMID:24120361, PMID:33928261).

Mechanistic history

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

    Identification of TRAF3IP2/Act1 as a novel NF-κB- and JNK-activating adaptor established the gene as a signaling node upstream of IKK, resolving whether it was merely a scaffold or an active signal inducer.

    Evidence Molecular cloning, co-immunoprecipitation with NEMO/IKKγ, NF-κB and JNK reporter assays by two independent groups

    PMID:10962024 PMID:10962033

    Open questions at the time
    • Upstream receptor triggering Act1 was unknown
    • Enzymatic activity of Act1 itself not characterized
    • Homo-oligomerization shown but second regulatory step undefined
  2. 2002 High

    Demonstration that Act1 selectively binds TRAF6 (not other TRAFs) through its N-terminus and participates in CD40 signaling via TRAF3 placed it at the intersection of TNF-family and NF-κB pathways, narrowing the search for its functional partnerships.

    Evidence Yeast two-hybrid and co-immunoprecipitation of Act1 with TRAF6 and TRAF3; CD40-induced recruitment of endogenous Act1 in epithelial cells

    PMID:12089335 PMID:12459498

    Open questions at the time
    • Physiological receptor linking Act1 to innate immunity remained unknown
    • Whether Act1 had E3 ligase activity was not tested
  3. 2004 High

    Genetic evidence from Act1-deficient mice revealed an unexpected negative regulatory role in B cells downstream of CD40 and BAFF via TRAF3, resolving conflicting positive/negative functions into a cell-type-dependent model.

    Evidence Act1-KO mice and B-cell-specific conditional KO; Act1/CD40 and Act1/BAFF double-KO epistasis

    PMID:15485634

    Open questions at the time
    • Molecular mechanism of negative regulation in B cells was unclear
    • IL-17 receptor connection not yet established
  4. 2006 High

    Discovery that Act1 directly binds IL-17R via homotypic SEFIR domain interaction and is indispensable for IL-17-induced NF-κB activation identified the long-sought obligate adaptor connecting IL-17 family receptors to downstream inflammatory signaling.

    Evidence Co-immunoprecipitation of Act1 with IL-17R, Act1-deficient fibroblasts showing abolished IL-17 responses

    PMID:17035243

    Open questions at the time
    • Structural basis of SEFIR–SEFIR interaction unknown
    • E3 ligase activity of Act1 not yet recognized
  5. 2007 High

    In vivo validation using Act1-deficient mice in EAE and colitis models established that Act1-dependent recruitment of TRAF6 and TAK1 to IL-17R is required for inflammatory disease, cementing Act1 as a therapeutic target.

    Evidence Act1-KO primary cells plus EAE and dextran sulfate colitis in vivo models

    PMID:17277779

    Open questions at the time
    • Precise ubiquitination substrate and linkage type downstream of Act1 unknown
    • Role in IL-25 signaling not yet tested
  6. 2009 High

    Biochemical reconstitution showed Act1 is a U-box E3 ubiquitin ligase that catalyzes K63-linked ubiquitination of TRAF6 at K124, resolving whether Act1 was merely an adaptor or an active enzyme in IL-17 signaling.

    Evidence In vitro ubiquitination assay with Ubc13–Uev1A, U-box point mutations, TRAF6 K124R mutagenesis, reconstitution in Act1−/− MEFs

    PMID:19825828

    Open questions at the time
    • Whether Act1 ubiquitinates additional substrates beyond TRAF6 was unknown
    • Structural basis of U-box activity not determined
  7. 2009 High

    Extension of Act1's adaptor role to IL-25 (IL-17E) receptor signaling demonstrated that Act1 is a universal transducer for the entire IL-17 receptor family, broadening its function from Th17 to Th2 immunity.

    Evidence Act1-KO and epithelial-specific Act1-KO mice in IL-25-driven pulmonary eosinophilia models

    PMID:19155511 PMID:19155512

    Open questions at the time
    • Whether Act1 uses distinct downstream effectors for IL-25 versus IL-17A was unclear
  8. 2011 High

    Structural and peptide-decoy studies mapped the CC' loop of the Act1 SEFIR domain as the critical interface for IL-17RA binding, and identified a conserved N-terminal subdomain sufficient for TRAF6 interaction, providing a molecular framework for therapeutic intervention.

    Evidence SPR direct binding, deletion mutagenesis, cell-permeable CC' loop decoy peptide blocking pulmonary inflammation in mice

    PMID:21335551 PMID:22045852

    Open questions at the time
    • High-resolution co-crystal structure of Act1–IL-17RA complex not available
    • SEFIR domain structure of Act1 itself unsolved
  9. 2011 High

    Identification of SCF(β-TrCP)-mediated K48-linked ubiquitination and proteasomal degradation of Act1 upon persistent IL-17 stimulation revealed the signal-termination mechanism for IL-17R pathway desensitization.

    Evidence Co-immunoprecipitation with β-TrCP1/2, dominant-negative β-TrCP, siRNA, ubiquitination assays in HeLa cells

    PMID:22045853

    Open questions at the time
    • Phosphodegron on Act1 recognized by β-TrCP not precisely mapped
    • Kinase responsible for degron phosphorylation not identified
  10. 2012 High

    Discovery that TBK1/IKKi phosphorylate Act1 on multiple serine residues to inhibit TRAF6 binding established a negative feedback loop within IL-17 signaling, explaining how cells attenuate inflammatory output.

    Evidence In vitro kinase assays, site-directed Ser mutagenesis, co-IP showing reduced Act1–TRAF6 association

    PMID:22851696

    Open questions at the time
    • Temporal dynamics of phosphorylation-dependent versus degradation-dependent attenuation not resolved
  11. 2012 High

    Identification of Act1 as an Hsp90 client protein, with the psoriasis-associated D10N variant defective in Hsp90 binding, provided the first mechanism linking a TRAF3IP2 disease-associated variant to protein stability and global loss of function.

    Evidence Co-IP of Act1 with Hsp90, D10N fibroblast signaling assays, Act1-deficient mouse skin phenotype

    PMID:23202271

    Open questions at the time
    • Whether alternative isoform D19N fully compensates in all tissues was only partially resolved
  12. 2013 High

    Identification of a human biallelic T536I SEFIR domain mutation abolishing Act1–IL-17R interaction and causing chronic mucocutaneous candidiasis provided direct genetic proof that Act1 is essential for human anti-fungal immunity.

    Evidence Patient fibroblast signaling assays, co-IP of endogenous proteins, genetic mapping in affected kindred

    PMID:24120361

    Open questions at the time
    • Whether T536I affects Act1's RNA-binding or STAT3-inhibitory functions was not examined
  13. 2013 High

    Demonstration that Act1 mediates K63-linked ubiquitination of HuR to promote inflammatory mRNA stabilization revealed a post-transcriptional effector arm beyond NF-κB, expanding Act1's mechanistic repertoire.

    Evidence HuR-deficient cells, co-IP, polysome fractionation, HuR lung-epithelial deletion mouse model

    PMID:23772036

    Open questions at the time
    • Full repertoire of mRNA targets stabilized by Act1–HuR axis unknown
  14. 2018 High

    Discovery that Act1's SEFIR domain directly binds stem-loop structures (SBEs) in inflammatory mRNA 3′UTRs and assembles three distinct RNP complexes for nuclear stabilization, P-body decapping inhibition, and translational promotion established Act1 as a bona fide RNA-binding protein.

    Evidence RNA immunoprecipitation, RNA aptamer competition, SEFIR domain–RNA binding assays, in vivo aptamer-based inhibition in mouse inflammation models

    PMID:29563620

    Open questions at the time
    • Structural basis of SEFIR–RNA interaction unsolved
    • Full transcriptome-wide set of SBE-containing targets not defined
  15. 2018 High

    Demonstration that Act1 directly inhibits STAT3 in T and B cells independently of IL-17 receptors resolved the paradox of why Act1-KO but not IL-17R-KO mice develop autoimmunity, establishing a dual positive/negative regulatory logic.

    Evidence Mass spectrometry identifying Act1–STAT3 complex, STAT3 phosphorylation assays in Act1−/− and receptor-KO T and B cells, autoimmune disease models

    PMID:30013031

    Open questions at the time
    • Molecular mechanism of STAT3 inhibition (direct binding site, competition, or sequestration) not delineated
  16. 2021 High

    Discovery of the recurrent FYN-TRAF3IP2 oncogenic fusion in peripheral T-cell lymphomas demonstrated that constitutive Act1-driven NF-κB activation is sufficient for T-cell transformation, directly implicating the gene in cancer pathogenesis.

    Evidence RNA-seq fusion detection, hematopoietic progenitor transduction in mouse model, IKK inhibitor rescue in vitro and in vivo

    PMID:33928261 PMID:34140493

    Open questions at the time
    • Whether the fusion retains Act1's RNA-binding or STAT3-inhibitory functions is unknown
    • Frequency of FYN-TRAF3IP2 across broader lymphoma subtypes incompletely characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of the Act1 SEFIR domain and its interface with IL-17RA, the full transcriptome of SBE-containing mRNAs regulated by Act1, the molecular mechanism by which Act1 inhibits STAT3, and whether Act1's E3 ligase activity extends to substrates beyond TRAF6 and HuR.
  • No crystal or cryo-EM structure of Act1 itself
  • Transcriptome-wide CLIP-seq of Act1 RNA targets not performed
  • STAT3 inhibition mechanism not biochemically reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0016874 ligase activity 3 GO:0003723 RNA binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 4
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 3
Partners
DDX3XELAVL1HSP90IL17RANEMOSTAT3TRAF3TRAF6
Complex memberships
Act1–TRAF6 complexIL-17R signalosome (Act1–IL-17RA–IL-17RC)

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Act1/CIKS (TRAF3IP2) directly interacts with NEMO/IKKγ and activates IKK and SAPK/JNK kinases, functioning as an adaptor that connects upstream signals to NF-κB and AP-1 activation pathways. Molecular cloning, co-immunoprecipitation, reporter assays, dominant-negative kinase mutants Proceedings of the National Academy of Sciences of the United States of America High 10962024 10962033
2006 Act1 (TRAF3IP2) directly associates with IL-17 receptor via homotypic SEFIR domain interaction and is an essential membrane-proximal adaptor for IL-17R signaling, mediating NF-κB activation and inflammatory gene induction. Co-immunoprecipitation, Act1-deficient fibroblasts, cytokine/chemokine expression assays, NF-κB reporter assay The Journal of biological chemistry High 17035243
2007 After IL-17 stimulation, Act1 is recruited to IL-17R via the SEFIR domain, then recruits TAK1 and the E3 ubiquitin ligase TRAF6 to mediate downstream NF-κB activation. Act1 deficiency abolishes IL-17-induced inflammation in vivo. Co-immunoprecipitation, Act1-deficient primary astroglial and gut epithelial cells, in vivo EAE and colitis models Nature immunology High 17277779
2000 Act1 associates with and activates IκB kinase (IKK), leading to liberation of NF-κB from IκB, and also activates JNK. cDNA isolation using NF-κB-dependent selectable marker, co-immunoprecipitation, kinase assays Proceedings of the National Academy of Sciences of the United States of America High 10962024
2009 Act1 is a U-box E3 ubiquitin ligase that, through the Ubc13-Uev1A E2 complex, mediates K63-linked ubiquitination of TRAF6 at lysine-124. U-box mutations abolish this activity and impair IL-17-dependent signaling. In vitro ubiquitination assay, U-box point mutagenesis, Act1-/- MEF reconstitution, site-directed mutagenesis of TRAF6 K124 Science signaling High 19825828
2002 Act1 selectively interacts with TRAF6 (but not other TRAF family members) through its N-terminal domain, and this interaction mediates Act1-induced NF-κB activation; IL-1-induced NF-κB is inhibited by excess Act1. Co-immunoprecipitation, yeast two-hybrid, dominant-negative TRAF6, NF-κB reporter assay FEBS letters High 12459498
2002 Act1 is recruited to CD40 receptor in epithelial cells upon CD40L stimulation, interacts with TRAF3, and mediates CD40-induced NF-κB activation and protection from CD40L-induced apoptosis. Co-immunoprecipitation of endogenous Act1 with CD40, Act1 transfection into Act1-negative C33A cells, NF-κB reporter assay Proceedings of the National Academy of Sciences of the United States of America High 12089335
2004 Act1 functions as a negative regulator of CD40- and BAFF-mediated B cell survival; Act1-deficient B cells show enhanced IκB phosphorylation, NF-κB2 processing, and JNK/ERK/p38 activation upon CD40 and BAFF stimulation. Act1 is recruited to CD40 and BAFFR indirectly via TRAF3. Act1-deficient mice and B cell-specific Act1 KO, Act1/CD40 and Act1/BAFF double-KO epistasis, signaling assays Immunity High 15485634
2000 CIKS/Act1 forms homo-oligomers, interacts with NEMO/IKKγ, and is recruited to the IKK complex upon cell stimulation; oligomerization and IKK recruitment are necessary but not sufficient for NF-κB activation, indicating a second regulatory step. Co-immunoprecipitation, deletion mutagenesis, NF-κB reporter assay Proceedings of the National Academy of Sciences of the United States of America High 10962033
2011 Act1/CIKS is essential for all IL-17-induced immediate-early genes in primary fibroblasts. A novel N-terminal subdomain of CIKS is necessary and sufficient for interaction with TRAF6 and NF-κB activation; decoy peptides blocking CIKS-TRAF6 interaction inhibit IL-17 signaling. Act1-deficient primary mouse embryo fibroblasts, deletion mutagenesis, co-immunoprecipitation, NF-κB reporter, decoy peptide assay The Journal of biological chemistry High 21335551
2011 The CC' loop of the Act1 SEFIR domain directly binds IL-17RA and is required for Act1-IL-17RA interaction; deletion of the CC' loop abolishes this interaction. A cell-permeable CC' loop decoy peptide inhibits IL-17- and IL-25-induced pulmonary inflammation in mice. Deletion mutagenesis, surface plasmon resonance, co-immunoprecipitation, in vivo mouse lung inflammation model Science signaling High 22045852
2013 A biallelic T536I missense mutation in the Act1 SEFIR domain in humans abolishes homotypic Act1-IL-17R interaction without affecting Act1 homodimerization, causing failure to respond to IL-17A, IL-17F, and IL-17E, resulting in chronic mucocutaneous candidiasis. Patient fibroblast signaling assays, co-immunoprecipitation of endogenous proteins, genetic mapping Immunity High 24120361
2012 The psoriasis-associated Act1 D10N variant is defective in interaction with the molecular chaperone Hsp90, leading to global loss of Act1 function; Act1 is a client protein of Hsp90. Co-immunoprecipitation of Act1 with Hsp90, Act1-D10N fibroblast signaling assays, Act1-deficient mouse skin phenotype Nature immunology High 23202271
2010 The psoriasis-associated coding variant D10N (rs33980500) of TRAF3IP2/Act1 shows reduced binding to TRAF6 in functional assays, suggesting altered modulation of immunoregulatory signals. Functional binding assays (co-immunoprecipitation), genome-wide association study with functional follow-up Nature genetics Medium 20953186
2012 TBK1 and IKKi phosphorylate Act1 on serine residues (including Ser311 by IKKi and three additional Ser sites by TBK1), inhibiting Act1-TRAF6 association and consequently suppressing IL-17R-mediated NF-κB activation; TRAF6 (but not TRAF3) is required for IL-17-induced TBK1 activation and its association with Act1. In vitro kinase assays, site-directed mutagenesis of Ser sites, co-immunoprecipitation, NF-κB reporter Molecular and cellular biology High 22851696
2011 Persistent IL-17 stimulation induces phosphorylation-dependent Lys48-linked polyubiquitination and degradation of Act1 by SCF(β-TrCP) E3 ubiquitin ligase complexes (containing β-TrCP1 or β-TrCP2), providing a desensitization mechanism for IL-17R signaling. Co-immunoprecipitation, dominant-negative β-TrCP, siRNA knockdown, ubiquitination assays in HeLa cells Science signaling High 22045853
2018 Act1 binds and stabilizes inflammatory mRNAs (e.g., Cxcl1) through its SEFIR domain binding to a stem-loop structure (SEFIR-binding element, SBE) in the 3'UTR. Act1 assembles three distinct RNA-protein complexes (RNPs) that prevent mRNA decay in the nucleus, inhibit decapping in P bodies, and promote translation. RNA immunoprecipitation, RNA aptamer competition, Act1 SEFIR domain-RNA binding assays, fractionation, in vivo mouse inflammation models Nature immunology High 29563620
2013 HuR RNA-binding protein is required for IL-17-induced Act1-mediated mRNA stabilization of CXCL1 and CXCL5; Act1 mediates K63-linked polyubiquitination of HuR, which is required for HuR binding to CXCL1 mRNA and for mRNA stabilization. HuR-deficient cells, co-immunoprecipitation, sucrose gradient polysome fractionation, HuR lung epithelial deletion mouse model Journal of immunology High 23772036
2014 The SEFIR domain of IL-17RA has a 2.3 Å crystal structure; helix αC within the SEFIR domain is critical for interaction with Act1 and IL-17-stimulated gene expression, establishing that heterotypic SEFIR-SEFIR interaction via αC helix is the conserved mechanism for IL-17 signaling. X-ray crystallography (2.3 Å), mutagenesis of αC helix, gene expression assay Acta crystallographica. Section D, Biological crystallography High 24816115
2003 CIKS/Act1 forms homo-oligomers and requires a second level of regulation beyond NEMO/IKKγ binding for NF-κB activation; a deletion mutant that oligomerizes and binds NEMO but lacks the additional region fails to activate NF-κB. Co-immunoprecipitation, deletion mutagenesis, NF-κB reporter assay Biochemical and biophysical research communications Medium 12943667
2009 Act1 is an essential signaling molecule for IL-25 (IL-17E) receptor signaling; Act1 deficiency abolishes IL-25-induced Th2 cytokine expression and pulmonary eosinophilia, and Act1 in epithelial cells is required for both IL-17-induced neutrophilia and IL-25-induced eosinophilia. Act1-deficient mice, epithelial cell-specific Act1 knockout, allergic pulmonary inflammation model Journal of immunology High 19155511 19155512
2010 Act1 in neuroectoderm-derived CNS-resident cells (specifically astrocytes and NG2+ glia) is required for IL-17-mediated recruitment of lymphocytes, neutrophils, and macrophages in EAE; Act1 deficiency in astrocytes impairs IL-17-mediated inflammatory gene induction. Cell-type-specific conditional Act1 knockout mice, EAE model, inflammatory mediator expression assays Immunity High 20303295 23995070
2009 The Chlamydia pneumoniae inclusion membrane protein CP0236 binds directly to Act1, sequesters Act1 away from the IL-17 receptor upon IL-17A stimulation, and thereby inhibits NF-κB activation in infected cells. Yeast two-hybrid, co-immunoprecipitation of ectopic CP0236 with endogenous Act1, immunofluorescence localization, NF-κB activation assay Cellular microbiology Medium 19159390
2021 FYN-TRAF3IP2 is a recurrent oncogenic gene fusion in angioimmunoblastic T cell lymphoma and PTCL-NOS that leads to aberrant NF-κB signaling downstream of T cell receptor activation; expression in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice. RNA sequencing fusion discovery, hematopoietic progenitor transduction mouse model, IKK inhibitor treatment in vitro and in vivo Nature cancer High 33928261
2021 FYN-TRAF3IP2 and KHDRBS1-LCK fusions activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinical drugs targeting these pathways. RNA sequencing, ex vivo and in vivo experiments in PTCL models Nature communications Medium 34140493
2018 Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3; Act1 deficiency (but not Il17ra, Il17rc, or Il17rb deficiency) results in hyper IL-23- and IL-21-induced STAT3 activation. Mass spectrometry detected an Act1-STAT3 complex. Mass spectrometry (interactome), STAT3 activation assays in Act1-/- and single receptor KO T and B cells, in vivo autoimmune disease models Nature communications High 30013031
2014 Syk kinase is an upstream regulator in IL-17A signaling; Syk interacts with TRAF6 and Act1 under IL-17A stimulation, and Syk inhibition diminishes Act1-TRAF6 interaction and TRAF6 K63-linked polyubiquitination, reducing CCL20 expression in keratinocytes. Co-immunoprecipitation, siRNA knockdown, pharmacological Syk inhibition, ubiquitination assay, promoter activity assay The Journal of investigative dermatology Medium 25202827
2015 IL-17 stimulation promotes formation of a CIKS/Act1-DDX3X complex requiring the DDX3X helicase domain (but not its ATPase activity); this complex stabilizes Zc3h12a mRNA. IKKε, TRAF2, and TRAF5 are also required for this IL-17-induced mRNA stabilization. Co-immunoprecipitation, DDX3X knockdown, mRNA stability assays, direct RNA-binding assay Journal of immunology Medium 25710910
2014 TRAF3IP2 mediates oxLDL-induced endothelial cell death via Nox2/superoxide-dependent upregulation of TRAF3IP2, IKK/p65, and JNK/c-Jun activation; TRAF3IP2 knockdown attenuates this death and vasorelaxation impairment ex vivo. siRNA knockdown, Nox2 inhibition, ex vivo aortic ring relaxation, cell death assays Free radical biology & medicine Medium 24561578
2012 CIKS/TRAF3IP2 mediates angiotensin-II-induced IKK/NF-κB and JNK/AP-1 activation in cardiomyocytes, functioning as a scaffold protein binding to IKK and JNK; CIKS-null mice are protected from Ang-II-induced cardiac hypertrophy and fibrosis despite similar blood pressure increases. CIKS-null mice, co-immunoprecipitation (CIKS binding to IKK and JNK), siRNA, Ang-II infusion in vivo Journal of molecular and cellular cardiology High 22575763
2011 Act1 in IL-17 signaling promotes osteoclastogenesis by stimulating RANKL expression in osteoblastic cells; this requires both the E3 ligase U-box and the SEFIR domain of Act1. Act1-deficient mice are protected from ovariectomy-induced bone loss. Act1-/- mice, osteoblast-specific Act1 reconstitution with U-box and SEFIR domain mutants, RANKL expression assay, ovariectomy bone loss model Journal of cellular biochemistry High 22511335
2011 Act1 expression in T cells is required for IL-25-driven Th2 polarization (but not conventional IL-4-driven polarization), including induction of GATA-3 and GFI-1 transcription factors, eosinophilic airway infiltration, and airway hyperresponsiveness. T cell-specific Act1-deficient mice, IL-25 stimulation, Th2 differentiation assays, airway inflammation model Journal of immunology High 21856933
2022 IL-17A stimulation recruits MST1 to ACT1 in keratinocytes, reducing MST1-LATS1 interaction and leading to YAP dephosphorylation and activation of the YAP-AREG axis promoting keratinocyte proliferation. Co-immunoprecipitation (MST1 with ACT1), immunofluorescence, siRNA knockdown, HaCaT and primary keratinocyte assays The Journal of investigative dermatology Medium 35304250
2019 IL-17A induces Act1/FADD-dependent caspase-mediated apoptosis in retinal endothelial cells, contributing to retinal capillary degeneration in diabetes; IL-17A-/- mice show significantly less retinal capillary degeneration. IL-17A-/- diabetic mouse model, ex vivo retinal endothelial cell signaling assays, caspase assay Journal of diabetes and its complications Medium 31239234
2011 Act1 is an evolutionarily conserved signaling protein; zebrafish Act1 retains TRAF6 binding and NF-κB activation capacity in human cells, and a highly conserved N-terminal motif is critical for TRAF6 binding. The helix-loop-helix and Ufd2-box domains enabling JNK activation have more recent evolutionary origins in higher vertebrates. Evolutionary sequence analysis, zebrafish Act1 expression in human cells, co-immunoprecipitation, NF-κB and JNK reporter assays Journal of molecular evolution Medium 21643828
2021 The antisense lncRNA TRAF3IP2-AS1 regulates Act1 expression and IL-17A signaling by recruiting SRSF10, which downregulates IRF1, a transcriptional activator of Act1; a psoriasis-susceptible variant A4165G (rs13210247) of TRAF3IP2-AS1 is a gain-of-function mutant that increases Act1 expression. lncRNA knockdown/overexpression, SRSF10 siRNA, IRF1 ChIP, Act1 promoter reporter assay, mouse psoriasis and EAE models Journal of immunology Medium 33941656
2014 Human ACT1 undergoes alternative splicing producing two isoforms; both are Hsp90 client proteins, but ACT1-D19N has an additional Hsp90 binding site from the nine extra amino acids absent in ACT1-D10N. ACT1-D10N fails to transduce IL-17 signals, while ACT1-D19N is fully responsive. The two isoforms are differentially expressed in fibroblasts versus T cells. Co-immunoprecipitation with Hsp90, IL-17 signaling assays in ACT1(D10N/D10N) fibroblasts and T cells, isoform-specific expression analysis Journal of immunology Medium 25024377

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nature immunology 499 17277779
1997 Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC beta-lactamase, and the foss of an outer membrane protein. Antimicrobial agents and chemotherapy 366 9055993
1992 Systematic mutational analysis of the yeast ACT1 gene. Genetics 306 1427032
2010 Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nature genetics 298 20953186
2010 Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nature genetics 297 20953188
2006 Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. The Journal of biological chemistry 297 17035243
2010 Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 238 20303295
2013 An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity 229 24120361
2009 Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Science signaling 193 19825828
2013 Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nature neuroscience 180 23995070
2007 Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kappaB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 179 17982039
1997 Actin in the parasite Toxoplasma gondii is encoded by a single copy gene, ACT1 and exists primarily in a globular form. Cell motility and the cytoskeleton 154 9227855
2000 Act1, an NF-kappa B-activating protein. Proceedings of the National Academy of Sciences of the United States of America 145 10962024
1991 Construction of expression vectors based on the rice actin 1 (Act1) 5' region for use in monocot transformation. Molecular & general genetics : MGG 143 1753941
2000 CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Proceedings of the National Academy of Sciences of the United States of America 132 10962033
2011 IL-17-induced NF-kappaB activation via CIKS/Act1: physiologic significance and signaling mechanisms. The Journal of biological chemistry 125 21335551
1999 Phylogenetic analysis and rapid identification of Candida dubliniensis based on analysis of ACT1 intron and exon sequences. Microbiology (Reading, England) 121 10463153
1991 Analysis of rice Act1 5' region activity in transgenic rice plants. The Plant cell 118 1821763
2009 The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation. Journal of immunology (Baltimore, Md. : 1950) 114 19155512
2004 Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity 114 15485634
2009 The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. Journal of immunology (Baltimore, Md. : 1950) 113 19155511
2014 OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free radical biology & medicine 104 24561578
2018 IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nature immunology 101 29563620
2020 The SGLT2 inhibitor Empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/Caspase-1-dependent IL-1β and IL-18 secretion. Cellular signalling 96 33160017
2019 Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition. Cellular signalling 94 31862399
2012 IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. Journal of cellular biochemistry 90 22511335
2012 The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90. Nature immunology 90 23202271
2012 Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients. Cancer immunology, immunotherapy : CII 89 22744010
2013 HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization. Journal of immunology (Baltimore, Md. : 1950) 87 23772036
1996 Conserved expression of the Arabidopsis ACT1 and ACT 3 actin subclass in organ primordia and mature pollen. The Plant cell 86 8597657
2018 Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype. The Journal of investigative dermatology 85 30528823
2012 TRAF6-dependent Act1 phosphorylation by the IκB kinase-related kinases suppresses interleukin-17-induced NF-κB activation. Molecular and cellular biology 77 22851696
2016 IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via Act1 signaling. Experimental & molecular medicine 76 27980343
2022 Salidroside attenuates HALI via IL-17A-mediated ferroptosis of alveolar epithelial cells by regulating Act1-TRAF6-p38 MAPK pathway. Cell communication and signaling : CCS 74 36411467
2012 Epithelial cell-specific Act1 adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin(-)c-Kit(+) innate cell population. Immunity 61 22608496
2003 Occurrence of extended-spectrum and AmpC beta-lactamases in bloodstream isolates of Klebsiella pneumoniae: isolates harbor plasmid-mediated FOX-5 and ACT-1 AmpC beta-lactamases. Journal of clinical microbiology 61 12574281
2007 Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling. Cytokine 60 18061473
2012 IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 22699909
2008 Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome. European journal of immunology 57 18624351
2014 Syk mediates IL-17-induced CCL20 expression by targeting Act1-dependent K63-linked ubiquitination of TRAF6. The Journal of investigative dermatology 56 25202827
2021 Low expression of TRAF3IP2-AS1 promotes progression of NONO-TFE3 translocation renal cell carcinoma by stimulating N6-methyladenosine of PARP1 mRNA and downregulating PTEN. Journal of hematology & oncology 55 33741027
2017 Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice. Cardiovascular diabetology 55 28476142
2015 Targeting connexin 43 with α-connexin carboxyl-terminal (ACT1) peptide enhances the activity of the targeted inhibitors, tamoxifen and lapatinib, in breast cancer: clinical implication for ACT1. BMC cancer 53 25881004
2015 Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2. Cellular signalling 53 26148936
2013 Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling. Free radical biology & medicine 52 23453926
2014 Interleukin-17A promotes MUC5AC expression and goblet cell hyperplasia in nasal polyps via the Act1-mediated pathway. PloS one 51 24892823
2013 TRAF3IP2 gene and systemic lupus erythematosus: association with disease susceptibility and pericarditis development. Immunogenetics 50 23836313
2012 CIKS (Act1 or TRAF3IP2) mediates Angiotensin-II-induced Interleukin-18 expression, and Nox2-dependent cardiomyocyte hypertrophy. Journal of molecular and cellular cardiology 49 22575763
2002 Role of NF kappa B activator Act1 in CD40-mediated signaling in epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 49 12089335
2011 Persistent stimulation with interleukin-17 desensitizes cells through SCFβ-TrCP-mediated degradation of Act1. Science signaling 47 22045853
2022 IL-17A Promotes Psoriasis-Associated Keratinocyte Proliferation through ACT1-Dependent Activation of YAP-AREG Axis. The Journal of investigative dermatology 46 35304250
2011 A CC' loop decoy peptide blocks the interaction between Act1 and IL-17RA to attenuate IL-17- and IL-25-induced inflammation. Science signaling 46 22045852
1993 Screens for extragenic mutations that fail to complement act1 alleles identify genes that are important for actin function in Saccharomyces cerevisiae. Genetics 46 8243992
2012 TRAF3IP2 gene is associated with cutaneous extraintestinal manifestations in inflammatory bowel disease. Journal of Crohn's & colitis 44 22445837
2002 Chromosomal ampC genes in Enterobacter species other than Enterobacter cloacae, and ancestral association of the ACT-1 plasmid-encoded cephalosporinase to Enterobacter asburiae. FEMS microbiology letters 40 12023082
2012 CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction. Cellular signalling 39 23085260
2006 The actin gene ACT1 is required for phagocytosis, motility, and cell separation of Tetrahymena thermophila. Eukaryotic cell 39 16524910
2011 T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation. Journal of immunology (Baltimore, Md. : 1950) 38 21856933
2002 NF-kappaB activator Act1 associates with IL-1/Toll pathway adaptor molecule TRAF6. FEBS letters 38 12459498
2009 The connexin43 carboxyl-terminal peptide ACT1 modulates the biological response to silicone implants. Plastic and reconstructive surgery 37 19407614
2019 microRNA-340-5p inhibits hypoxia/reoxygenation-induced apoptosis and oxidative stress in cardiomyocytes by regulating the Act1/NF-κB pathway. Journal of cellular biochemistry 36 30989715
2018 Act1 is a negative regulator in T and B cells via direct inhibition of STAT3. Nature communications 36 30013031
2015 CIKS/DDX3X interaction controls the stability of the Zc3h12a mRNA induced by IL-17. Journal of immunology (Baltimore, Md. : 1950) 36 25710910
2009 A protein secreted by the respiratory pathogen Chlamydia pneumoniae impairs IL-17 signalling via interaction with human Act1. Cellular microbiology 36 19159390
2019 Diabetes induces IL-17A-Act1-FADD-dependent retinal endothelial cell death and capillary degeneration. Journal of diabetes and its complications 35 31239234
2012 New insight into the functions of the interleukin-17 receptor adaptor protein Act1 in psoriatic arthritis. Arthritis research & therapy 35 23116200
2002 The ACT-1 plasmid-encoded AmpC beta-lactamase is inducible: detection in a complex beta-lactamase background. The Journal of antimicrobial chemotherapy 35 11864960
2018 TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. Journal of molecular and cellular cardiology 34 29981796
2019 RECK suppresses interleukin-17/TRAF3IP2-mediated MMP-13 activation and human aortic smooth muscle cell migration and proliferation. Journal of cellular physiology 33 31074012
2014 Structure of the unique SEFIR domain from human interleukin 17 receptor A reveals a composite ligand-binding site containing a conserved α-helix for Act1 binding and IL-17 signaling. Acta crystallographica. Section D, Biological crystallography 33 24816115
2017 TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells. American journal of physiology. Heart and circulatory physiology 32 28971844
2019 IL-17 stimulates the expression of CCL2 in cardiac myocytes via Act1/TRAF6/p38MAPK-dependent AP-1 activation. Scandinavian journal of immunology 29 31630418
2017 Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling. The Journal of biological chemistry 29 28053087
2010 The adaptor protein CIKS/ACT1 is necessary for collagen-induced arthritis, and it contributes to the production of collagen-specific antibody. Arthritis and rheumatism 29 20662069
2000 Suppressors of mdm20 in yeast identify new alleles of ACT1 and TPM1 predicted to enhance actin-tropomyosin interactions. Genetics 29 11014803
2019 STAT4, TRAF3IP2, IL10, and HCP5 Polymorphisms in Sjögren's Syndrome: Association with Disease Susceptibility and Clinical Aspects. Journal of immunology research 28 30882006
2016 TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis. Molecular and cellular endocrinology 28 27040306
2013 TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation. Cellular signalling 28 23872479
2010 An atopic dermatitis-like skin disease with hyper-IgE-emia develops in mice carrying a spontaneous recessive point mutation in the Traf3ip2 (Act1/CIKS) gene. Journal of immunology (Baltimore, Md. : 1950) 28 20660351
2021 FYN-TRAF3IP2 induces NF-κB signaling-driven peripheral T cell lymphoma. Nature cancer 27 33928261
2019 MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling. American journal of physiology. Lung cellular and molecular physiology 27 30892082
2018 MiR-298 Exacerbates Ischemia/Reperfusion Injury Following Ischemic Stroke by Targeting Act1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 27 30021197
2021 Identification of a Long Noncoding RNA TRAF3IP2-AS1 as Key Regulator of IL-17 Signaling through the SRSF10-IRF1-Act1 Axis in Autoimmune Diseases. Journal of immunology (Baltimore, Md. : 1950) 26 33941656
2021 Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified. Nature communications 26 34140493
2017 Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses. The Journal of investigative dermatology 26 28274739
2014 TRAF5 and TRAF3IP2 gene polymorphisms are associated with Behçet's disease and Vogt-Koyanagi-Harada syndrome: a case-control study. PloS one 26 24416204
2012 Function of Act1 in IL-17 family signaling and autoimmunity. Advances in experimental medicine and biology 26 21948371
2007 A role for the cytoplasmic adaptor protein Act1 in mediating IL-17 signaling. Science's STKE : signal transduction knowledge environment 26 17684298
2006 Th1 bias in PBMC induced by multicycles of auto-CIKs infusion in malignant solid tumor patients. Cancer biotherapy & radiopharmaceuticals 26 16480328
2003 Multiple conserved 5' elements are required for high-level pollen expression of the Arabidopsis reproductive actin ACT1. Plant molecular biology 25 14682614
2021 Downregulation of Macrophage-Specific Act-1 Intensifies Periodontitis and Alveolar Bone Loss Possibly via TNF/NF-κB Signaling. Frontiers in cell and developmental biology 24 33748112
2012 CIKS/Act1-mediated signaling by IL-17 cytokines in context: implications for how a CIKS gene variant may predispose to psoriasis. Journal of immunology (Baltimore, Md. : 1950) 24 22581863
2016 Feasibility study of DCs/CIKs combined with thoracic radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Radiation oncology (London, England) 23 27097970
2003 Role of the adaptor protein CIKS in the activation of the IKK complex. Biochemical and biophysical research communications 23 12943667
1991 A chicken beta-actin gene can complement a disruption of the Saccharomyces cerevisiae ACT1 gene. Molecular and cellular biology 23 1986221
2019 Chronic Mucocutaneous Candidiasis in an Adolescent Boy Due to a Novel Mutation in TRAF3IP2. Journal of clinical immunology 22 31292894
2011 Evolution of vertebrate immunity: sequence and functional analysis of the SEFIR domain family member Act1. Journal of molecular evolution 22 21643828
2017 Upregulation of miR-215 exerts neuroprotection effects against ischemic injury via negative regulation of Act1/IL-17RA signaling. Neuroscience letters 20 29080697
2014 The differential regulation of human ACT1 isoforms by Hsp90 in IL-17 signaling. Journal of immunology (Baltimore, Md. : 1950) 20 25024377
2016 Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction. The Journal of biological chemistry 19 27466370