Affinage

Showing TRAF3IP2 — ACT1 is a alias.

TRAF3IP2

E3 ubiquitin ligase TRAF3IP2 · UniProt O43734

Length
574 aa
Mass
64.7 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 34 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

TRAF3IP2 (Act1/CIKS) is the essential membrane-proximal adaptor and signal transducer of the IL-17 receptor family, coupling IL-17/IL-25 receptor engagement to inflammatory gene expression in fibroblasts, epithelial cells, astrocytes, and CNS glia (PMID:17035243, PMID:17277779, PMID:19155512, PMID:19155511, PMID:20303295, PMID:23995070). Upon IL-17 stimulation, Act1 is recruited to IL-17RA through a heterotypic SEFIR-SEFIR interaction in which the Act1 CC' loop engages a composite surface formed by the IL-17RA CC' loop and helix αC (PMID:22045852, PMID:24816115), and it then recruits TRAF6 and TAK1 to activate IKK/NF-κB and JNK/AP-1 (PMID:10962024, PMID:12459498, PMID:17277779). Act1 itself is a U-box E3 ubiquitin ligase that, with the Ubc13-Uev1A E2, catalyzes Lys63-linked ubiquitination of TRAF6 at Lys-124, an activity required for downstream NF-κB signaling (PMID:19825828). Beyond transcriptional activation, Act1 binds a SEFIR-binding element stem-loop in the 3'-UTR of inflammatory mRNAs (e.g., Cxcl1) to assemble compartmentally distinct nuclear, P-body, and polysomal RNP complexes that prevent decay, block decapping, and promote translation, in part through ubiquitination of HuR and interaction with DDX3X (PMID:23772036, PMID:25710910, PMID:29563620). Act1 signaling is constrained by TBK1/IKKi-mediated phosphorylation that disrupts Act1-TRAF6 binding and by SCFβ-TrCP-mediated Lys48 ubiquitination and degradation (PMID:22045853, PMID:22851696), and its folding and function depend on the chaperone Hsp90 (PMID:23202271). Independently of IL-17 signaling, Act1 acts as a negative regulator: it attenuates CD40/BAFF-driven B cell survival via a TRAF3-dependent interaction (PMID:12089335, PMID:15485634, PMID:18061473, PMID:21948371) and directly inhibits STAT3 in T and B cells (PMID:30013031). Human SEFIR-domain (T536I) and TRAF-domain (D10N) variants cause loss or impairment of IL-17 responsiveness and underlie chronic mucocutaneous candidiasis-type immunodeficiency and psoriasis susceptibility (PMID:24120361, PMID:23202271, PMID:20953186), while the oncogenic FYN-TRAF3IP2 fusion drives NF-κB-dependent peripheral T-cell lymphoma downstream of TCR activation (PMID:33928261).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 High

    Established Act1/CIKS as a NEMO-binding activator of the IKK–NF-κB and JNK cascades, defining it as a signaling adaptor rather than an enzyme of unknown role.

    Evidence Reciprocal co-IP with NEMO, ectopic expression, NF-κB reporter and JNK assays with dominant-negative IKK in mammalian cells

    PMID:10962024 PMID:10962033

    Open questions at the time
    • The upstream receptor was unidentified; the IL-1-unresponsive cell line implicated an unknown component
    • No endogenous-level mechanism or substrate defined
  2. 2002 Medium

    Placed TRAF6 immediately downstream of Act1 and showed Act1 engages CD40 receptor signaling, beginning to map the adaptor into specific receptor pathways.

    Evidence Co-IP with domain mapping, dominant-negative TRAF6 epistasis, and endogenous CD40 recruitment with rescue in epithelial cells

    PMID:12089335 PMID:12459498

    Open questions at the time
    • TRAF6 selectivity established but biochemical mechanism of activation unknown
    • CD40 vs IL-1 pathway distinction not yet resolved
  3. 2004 High

    Revealed a context-dependent dual function: Act1 is a negative regulator of CD40/BAFF-mediated B cell survival, contrasting its activating role elsewhere.

    Evidence Genetic knockout with CD40-Act1 and BAFF-Act1 double-knockout epistasis and multi-pathway signaling immunoblots in B cells

    PMID:15485634

    Open questions at the time
    • Molecular basis for the inhibitory (vs activating) outcome not defined
    • Domain requirements distinguishing the two roles unknown
  4. 2007 High

    Identified Act1 as the essential, non-redundant adaptor for IL-17 (and later IL-25) receptor signaling in vivo via SEFIR-domain recruitment, defining its principal physiological pathway.

    Evidence Genetic KO mice, primary astroglial/epithelial cells, co-IP defining the IL-17R–Act1–TRAF6–TAK1 complex, EAE and colitis disease models

    PMID:17035243 PMID:17277779 PMID:19155511 PMID:19155512

    Open questions at the time
    • Structural basis of SEFIR-SEFIR specificity not yet resolved
    • Whether Act1 acts catalytically or only as scaffold unresolved at this stage
  5. 2009 High

    Demonstrated Act1 is itself a U-box E3 ligase that K63-ubiquitinates TRAF6 at K124, converting it from a passive scaffold to an active enzyme essential for IL-17-driven NF-κB.

    Evidence In vitro ubiquitination reconstitution with Ubc13-Uev1A, U-box and TRAF6-K124 mutagenesis, rescue of Act1-/- MEFs

    PMID:19825828

    Open questions at the time
    • Whether all Act1 functions require ligase activity not established
    • Regulation of the ligase activity in vivo undefined
  6. 2011 High

    Defined the structural and regulatory logic of the IL-17R interaction and its negative control, including CC'-loop SEFIR binding and β-TrCP-mediated degradation.

    Evidence SPR binding of CC' loop peptide, mutagenesis of both partners, decoy-peptide inhibition in vivo, and co-IP/siRNA mapping of SCFβ-TrCP degradation

    PMID:22045852 PMID:22045853

    Open questions at the time
    • Kinase generating the phosphodegron not identified in this work
    • Stoichiometry of degradative vs signaling pools unknown
  7. 2012 High

    Resolved how Act1 stability and signaling are gated by Hsp90 chaperoning and by TBK1/IKKi phosphorylation that uncouples Act1 from TRAF6, and linked the D10N variant to psoriasis.

    Evidence Co-IP of Act1-Hsp90 and Act1-TBK1, in vitro kinase assay with site mutagenesis, conditional KO mice and in vivo cytokine neutralization

    PMID:22851696 PMID:23202271

    Open questions at the time
    • How phosphorylation and degradation feedback are temporally coordinated unclear
    • Hsp90 client maturation steps not defined
  8. 2013 High

    Established Act1 as a post-transcriptional regulator that stabilizes inflammatory mRNAs via HuR, and confirmed human disease causation through the SEFIR-domain T536I mutation.

    Evidence HuR KO, Act1-HuR co-IP, polysome fractionation, mRNA decay assays; patient-derived fibroblasts/T cells with co-IP of mutant ACT1

    PMID:23772036 PMID:24120361

    Open questions at the time
    • Direct RNA-binding element on target mRNAs not yet mapped
    • Genotype–phenotype distinction between SEFIR and TRAF-domain mutations only partially defined
  9. 2015 Medium

    Extended the RNA-regulatory mechanism by showing Act1 partners with DDX3X (and TRAF2/TRAF5/IKKε) to selectively stabilize specific transcripts such as Zc3h12a.

    Evidence Co-IP of CIKS-DDX3X with helicase-domain requirement, DDX3X knockdown, RIP and mRNA stability assays

    PMID:25710910

    Open questions at the time
    • Single lab; transcript selectivity mechanism incompletely defined
    • Relationship between DDX3X and HuR pathways not integrated
  10. 2018 High

    Unified the RNA function into a structural model where Act1 binds a 3'-UTR SEFIR-binding element to assemble compartment-specific RNPs, and revealed a separable IL-17-independent role inhibiting STAT3.

    Evidence RIP, RNA structure mapping, polysome profiling, P-body imaging, aptamer therapy in vivo; mass spectrometry of Act1-STAT3 with comparative KO mice

    PMID:29563620 PMID:30013031

    Open questions at the time
    • How Act1 distributes between cytoplasmic signaling, RNP, and nuclear STAT3-inhibitory pools is unresolved
    • Mechanism of direct STAT3 inhibition not biochemically defined
  11. 2021 High

    Showed that genomic fusion of TRAF3IP2 to FYN constitutively drives NF-κB signaling and T-cell transformation, establishing an oncogenic gain-of-function for the adaptor.

    Evidence RNA-seq fusion identification, mouse hematopoietic progenitor transformation, Tet2-loss cooperation, IKK inhibitor treatment in vitro and in vivo

    PMID:33928261

    Open questions at the time
    • Molecular mechanism by which the FYN moiety activates Act1-NF-κB output not fully defined
    • Whether endogenous Act1 enzymatic functions are required for transformation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single adaptor is partitioned among its activating (IL-17R/TRAF6/NF-κB), post-transcriptional (RNP/HuR/DDX3X), and inhibitory (CD40/BAFF, STAT3) functions, and how its phosphorylation, ubiquitination, and chaperoning are integrated to dictate these outcomes, remains unresolved.
  • No unified model of Act1 pool partitioning across compartments
  • Regulatory hierarchy linking TBK1 phosphorylation, β-TrCP degradation, and Hsp90 chaperoning not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0060089 molecular transducer activity 3 GO:0003723 RNA binding 2 GO:0016874 ligase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 4 GO:0005886 plasma membrane 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3
Partners
DDX3XHSP90HUR/ELAVL1IL17RANEMO/IKBKGSTAT3TRAF3TRAF6
Complex memberships
IL-17 receptor signaling complex (IL-17RA–Act1–TRAF6–TAK1)SCFβ-TrCP E3 ligase complex (substrate)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Act1/CIKS was identified as a novel protein that directly interacts with NEMO/IKKγ in cells. When ectopically expressed, CIKS stimulates IKK and SAPK/JNK kinases and transactivates an NF-κB-dependent reporter, with NF-κB activation prevented by kinase-deficient IKK mutants. Co-immunoprecipitation, ectopic expression, NF-κB reporter assay, dominant-negative kinase mutants Proceedings of the National Academy of Sciences of the United States of America High 10962024 10962033
2000 Act1 associates with and activates IκB kinase (IKK), leading to liberation of NF-κB from its IκB complex, and also activates JNK. Act1 failed to activate NF-κB in an IL-1-unresponsive mutant cell line despite all known signaling components being present, suggesting interaction with an unknown component of IL-1 signaling. Co-immunoprecipitation, NF-κB reporter assay, JNK kinase assay, IL-1-unresponsive mutant cell line Proceedings of the National Academy of Sciences of the United States of America High 10962024
2002 Act1 interacts with TRAF6 specifically (not other TRAF family members) via its amino-terminal half, and Act1-mediated NF-κB activation is inhibited by a dominant-negative TRAF6 mutant in a dose-dependent manner, placing TRAF6 downstream of Act1 in IL-1/Toll-mediated signaling. Co-immunoprecipitation, dominant-negative TRAF6, NF-κB reporter assay FEBS letters Medium 12459498
2002 Endogenous Act1 is recruited to the CD40 receptor in epithelial cells upon CD40L stimulation, and Act1 interacts with TRAF3 (a CD40-associated component). Transfection of Act1 into Act1-negative cervical epithelial cells renders them sensitive to CD40L-induced NF-κB activation and protects them from CD40L-induced apoptosis. Co-immunoprecipitation of endogenous proteins, ectopic expression rescue, NF-κB reporter assay, apoptosis assay Proceedings of the National Academy of Sciences of the United States of America Medium 12089335
2003 CIKS/Act1 forms homo-oligomers, interacts with NEMO/IKKγ, and is recruited to the IKK complex upon cell stimulation. A deletion mutant that retains oligomerization and NEMO binding but lacks a second domain fails to activate NF-κB, indicating that recruitment to IKK is necessary but not sufficient for NF-κB activation. Co-immunoprecipitation, deletion mutagenesis, NF-κB reporter assay Biochemical and biophysical research communications Medium 12943667
2004 Act1 functions as a negative regulator of CD40- and BAFF-mediated B cell survival. Act1 deficiency leads to stronger IκB phosphorylation, processing of NF-κB2 (p100/p52), and activation of JNK, ERK, and p38 pathways in B cells. The phenotype is largely blocked in CD40-Act1 and BAFF-Act1 double-knockout mice, genetically placing Act1 downstream of CD40 and BAFFR. Genetic knockout, double-knockout epistasis, signaling pathway analysis by immunoblot Immunity High 15485634
2006 Act1 directly associates with IL-17 receptor (IL-17RA) likely via homotypic SEFIR domain interaction and acts as a membrane-proximal adaptor. Deficiency of Act1 in fibroblasts abrogates IL-17-induced cytokine and chemokine expression, C/EBPβ, C/EBPδ, and IκBζ induction, and NF-κB pathway activation. Co-immunoprecipitation, Act1-deficient fibroblasts, immunoblot/qPCR for downstream targets The Journal of biological chemistry High 17035243
2007 Act1 is essential for IL-17 receptor (IL-17R) signaling in vivo. After IL-17 stimulation, Act1 is recruited to IL-17R via SEFIR domain interaction, followed by recruitment of TAK1 and TRAF6 to mediate NF-κB activation. Act1-deficient primary astroglial and gut epithelial cells showed abolished IL-17-induced inflammatory gene expression, and Act1-deficient mice showed reduced EAE and DSS-induced colitis. Genetic knockout mouse, primary cell studies, co-immunoprecipitation, SEFIR domain analysis, in vivo disease models Nature immunology High 17277779
2007 Two independent signaling pathways are required for IL-17A-induced gene expression in human airway epithelial cells: (1) a JAK1-associated PI3K signaling axis independent of NF-κB, and (2) an Act1/TRAF6/TAK1-mediated NF-κB activation pathway. siRNA knockdown of Act1, TRAF6, or TAK1 reduced IL-17A-inducible gene expression and NF-κB activation. siRNA knockdown, PI3K inhibitor, JAK inhibitor, NF-κB DNA-binding assay, promoter activity assay Journal of immunology Medium 17982039
2009 Act1 is a U-box E3 ubiquitin ligase. Using the Ubc13-Uev1A E2 complex, Act1 mediates Lys63-linked ubiquitination of TRAF6, and this activity is essential for IL-17-mediated NF-κB signaling. Deletion and point mutations of the Act1 U-box abolished TRAF6 ubiquitination and impaired IL-17-dependent signaling and gene expression in Act1-/- MEFs. Lys-124 of TRAF6 was identified as a critical ubiquitination site. In vitro ubiquitination assay, U-box point mutagenesis, rescue of Act1-/- MEFs, immunoblot for K63-linked ubiquitin chains, site-directed mutagenesis of TRAF6-K124 Science signaling High 19825828
2009 Act1 is an essential signaling molecule for IL-25 (IL-17E) receptor signaling in addition to IL-17 receptor signaling. Act1 deficiency abolished IL-25-induced expression of IL-4, IL-5, IL-13, eotaxin-1, and pulmonary eosinophilia in mice. Act1-deficient mice, cytokine/chemokine expression assays, pulmonary inflammation model Journal of immunology High 19155511 19155512
2010 Act1 deficiency specifically in neuroectoderm-derived CNS-resident cells (neurons, astrocytes, oligodendrocytes) markedly reduced EAE severity. Act1-deficient astrocytes showed impaired IL-17-mediated inflammatory gene induction, identifying astrocytes as critical cellular targets of IL-17-Act1 signaling in CNS inflammation. Conditional cell-type-specific Act1 knockout mice, EAE model, gene expression analysis in primary astrocytes Immunity High 20303295
2011 CIKS/Act1 is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts. A novel N-terminal subdomain of CIKS is both necessary and sufficient for interaction with TRAF6 and for IL-17-mediated NF-κB activation. CIKS-deficient MEFs, domain deletion mutagenesis, Co-IP, NF-κB reporter assay The Journal of biological chemistry Medium 21335551
2011 Persistent IL-17 stimulation leads to Lys48-linked polyubiquitination and degradation of Act1 in a phosphorylation-dependent manner via SCFβ-TrCP E3 ligase complexes (containing β-TrCP1 or β-TrCP2), desensitizing IL-17R signaling. Dominant-negative β-TrCP or knockdown of β-TrCP1/2 markedly reduced IL-17-induced Act1 ubiquitination and degradation. Co-immunoprecipitation of Act1 with β-TrCP, dominant-negative β-TrCP, siRNA knockdown, ubiquitin linkage analysis Science signaling Medium 22045853
2011 The CC' loop of the Act1 SEFIR domain (not the BB' loop as in TIR domains) is required for heterotypic interaction with IL-17RA SEFIR domain. Deletion of the CC' loop from Act1 or IL-17RA abolished the Act1-IL-17RA interaction. Surface plasmon resonance confirmed direct binding of a CC' loop peptide to IL-17RA. A cell-permeable CC' loop decoy peptide inhibited IL-17- and IL-25-mediated signaling in vitro and in vivo. Co-immunoprecipitation, SEFIR domain deletion mutagenesis, surface plasmon resonance, cell-permeable peptide inhibition in vitro and in vivo Science signaling High 22045852
2012 Act1 is recruited to CD40 and BAFFR indirectly via TRAF3 through a TRAF-binding site in Act1, whereas Act1 interacts with IL-17R through its C-terminal SEFIR domain. These distinct domain requirements underlie the opposing roles of Act1 in B cell vs. T cell signaling. Domain interaction analysis, genetic knockout, double-knockout epistasis Cytokine / Advances in experimental medicine and biology Medium 18061473 21948371
2012 Act1 is a client protein of the molecular chaperone Hsp90. The psoriasis-associated D10N variant of Act1 is defective in its interaction with Hsp90, resulting in global loss of Act1 function. Act1-deficient mice develop spontaneous IL-22-dependent skin inflammation, revealing that loss of Act1 function in IL-17 signaling leads to hyperactive Th17 responses. Co-immunoprecipitation of Act1-Hsp90, Act1-deficient mice, conditional knockout, cytokine/antibody neutralization in vivo Nature immunology High 23202271
2012 TBK1 directly phosphorylates Act1 on three serine sites to suppress IL-17R-mediated NF-κB activation. IKKi also phosphorylates Act1 on the same sites redundantly. Phosphorylation of these sites inhibits Act1 association with TRAF6 and consequently NF-κB activation. TRAF6 (not TRAF3) is critical for IL-17-induced TBK1 activation, its association with Act1, and subsequent Act1 phosphorylation. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, siRNA knockdown, immunoblot for phosphorylation Molecular and cellular biology High 22851696
2012 Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells, not in neurons or mature oligodendrocytes. Deletion of Act1 in NG2+ glia resulted in markedly reduced EAE severity. IL-17 exhibited inhibitory effects on maturation and survival of oligodendrocyte lineage cells. Conditional cell-type-specific Act1 knockout mice (NG2-Cre, GFAP-Cre, Olig1-Cre, Syn1-Cre), EAE model, in vitro oligodendrocyte differentiation assays Nature neuroscience High 23995070
2013 A biallelic missense mutation (T536I) in ACT1, located in the SEFIR domain, abolished the homotypic interaction of ACT1 with IL-17 receptors (but not homodimerization), resulting in failure to respond to IL-17A, IL-17F, and IL-17E in patient fibroblasts and T cells. In contrast, the D10N variant in the TRAF-interacting domain impairs but does not abolish IL-17 responses. Patient-derived fibroblasts, Co-IP of mutant ACT1 with IL-17R, cytokine response assays, comparison of SEFIR vs. TRAF-domain mutations Immunity High 24120361
2013 HuR is required for IL-17-induced Act1-mediated CXCL1/CXCL5 mRNA stabilization. Act1-mediated polyubiquitination of HuR is required for HuR binding to CXCL1 mRNA, leading to mRNA stabilization. IL-17 induces co-shift of Act1 and HuR to polysomal fractions; HuR deficiency reduces translation-active chemokine mRNAs. HuR knockout in distal lung epithelium, Co-IP of Act1-HuR, sucrose gradient fractionation, mRNA decay assay, in vivo neutrophilia model Journal of immunology High 23772036
2013 Chlamydia pneumoniae inclusion membrane protein CP0236 interacts with Act1 in HeLa cells. C. pneumoniae infection causes Act1 to associate with the chlamydial inclusion membrane, sequestering it away from the IL-17 receptor, thereby inhibiting NF-κB activation in IL-17-stimulated infected cells. Yeast two-hybrid screen, co-immunoprecipitation of CP0236 with endogenous Act1, immunofluorescence localization Cellular microbiology Medium 19159390
2014 The crystal structure of the IL-17RA SEFIR domain at 2.3 Å resolution reveals that helix αC is critical for interaction with Act1 and IL-17-stimulated gene expression. The CC' loop region and helix αC form a composite ligand-binding surface for recruiting Act1, defining the structural basis for SEFIR-SEFIR interaction specificity. X-ray crystallography (2.3 Å resolution), structure-based mutagenesis, gene expression assays Acta crystallographica. Section D, Biological crystallography High 24816115
2014 The psoriasis-associated D10N variant of ACT1 shows reduced binding to TRAF6, suggesting altered modulation of immunoregulatory signals through TRAF interactions. Functional assays demonstrated this impaired binding is associated with reduced IL-17 signaling activity. Functional binding assay, variant protein expression, comparison of wild-type vs. D10N variant interaction with TRAF6 Nature genetics Medium 20953186
2014 Syk kinase is recruited to the IL-17R signaling complex (with TRAF6 and Act1) upon IL-17A stimulation. Syk acts upstream of TAK1. Syk siRNA or pharmacological inhibition diminished TRAF6-Act1 interaction and TRAF6 K63-polyubiquitination, placing Syk as an upstream regulator of Act1-TRAF6 interaction in IL-17 signaling. Co-immunoprecipitation, siRNA knockdown, kinase inhibitor, TRAF6 ubiquitination assay, CCL20 promoter activity The Journal of investigative dermatology Medium 25202827
2014 ACT1 has two human isoforms (D10N and D19N) due to alternative splicing. Both are Hsp90 client proteins, but ACT1-D19N has an additional 9 amino acids providing a second Hsp90 binding site absent in ACT1-D10N. ACT1-D10N is a non-functional dead protein for IL-17 signaling, whereas ACT1-D19N is fully responsive. The two isoforms are differentially expressed in fibroblasts vs. T cells. Hsp90 co-IP with isoform-specific constructs, IL-17 signaling functional assay, isoform expression analysis in primary cells Journal of immunology Medium 25024377
2015 IL-17-induced CIKS/Act1 interaction with the DEAD box protein DDX3X (requiring the DDX3X helicase domain but not its ATPase activity) controls the stability of Zc3h12a mRNA. DDX3X knockdown decreases IL-17-induced Zc3h12a mRNA stability without affecting other mRNAs. IKKε, TRAF2, and TRAF5 are also required for this stabilization. Co-immunoprecipitation of CIKS-DDX3X, DDX3X knockdown, mRNA stability assay, RIP (RNA immunoprecipitation) Journal of immunology Medium 25710910
2018 Act1 binds and stabilizes mRNAs encoding key inflammatory proteins via its SEFIR domain binding to a stem-loop structure (SEFIR-binding element, SBE) in the 3' UTR of Cxcl1 mRNA. mRNA-bound Act1 directs formation of three compartmentally distinct RNA-protein complexes (RNPs) that regulate: (1) preventing mRNA decay in the nucleus, (2) inhibiting mRNA decapping in P-bodies, and (3) promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization and inflammation in vivo. RNA immunoprecipitation, SEFIR domain mutagenesis, sucrose gradient polysome fractionation, P-body imaging, SBE aptamer inhibition in vitro and in vivo mouse models Nature immunology High 29563620
2018 Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry identified an Act1-STAT3 complex. Act1 deficiency (but not IL-17RA/RC/RB deficiency) results in hyperactivated IL-23- and IL-21-induced STAT3 activation in T and B cells, respectively, causing SLE- and Sjögren's-like diseases. Mass spectrometry identification of Act1-STAT3 complex, co-immunoprecipitation, conditional KO comparison (Act1 vs. IL-17R subunits), STAT3 phosphorylation assay, in vivo disease model Nature communications High 30013031
2021 The FYN-TRAF3IP2 gene fusion (identified in peripheral T-cell lymphoma) leads to aberrant NF-κB signaling downstream of T cell receptor activation. FYN-TRAF3IP2 expression in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with Tet2 loss. IκB kinase inhibitors delivered anti-lymphoma effects in vitro and in vivo. RNA-sequencing identification of fusion, mouse hematopoietic progenitor transformation assay, NF-κB signaling analysis, IKK inhibitor treatment in vitro and in vivo Nature cancer High 33928261
2012 CIKS/Act1 binds to IKK and JNK under basal conditions (functioning as a scaffold), and this association is enhanced by Angiotensin-II stimulation. CIKS-null cardiomyocytes lack Ang-II-induced IKK/NF-κB and JNK/AP-1 activation, IL-18 and MMP-9 induction, and hypertrophy both in vitro and in vivo, demonstrating CIKS is required for Ang-II-induced cardiac hypertrophy. Co-immunoprecipitation (CIKS/IKK/JNK), CIKS-null mice, Ang-II infusion model, cardiac function measurements Journal of molecular and cellular cardiology Medium 22575763
2022 IL-17A stimulates the recruitment of MST1 to ACT1 in keratinocytes, which leads to reduced MST1-LATS1 interaction and YAP dephosphorylation (activation), promoting AREG expression and keratinocyte proliferation. Co-immunoprecipitation of ACT1-MST1, YAP phosphorylation immunoblot, keratinocyte proliferation assay The Journal of investigative dermatology Medium 35304250
2011 A novel amino-terminal motif of Act1 is critical for binding to TRAF6 and activating NF-κB-dependent gene expression, conserved throughout vertebrate evolution. Zebrafish Act1 (lacking the helix-loop-helix and Ufd2-box domains present in higher vertebrates) cannot induce JNK phosphorylation or activate cytokine expression in human cells, but can still bind TRAF6 and activate NF-κB. Evolutionary sequence analysis, domain truncation, co-immunoprecipitation of zebrafish Act1 with human TRAF6, NF-κB reporter assay, JNK phosphorylation assay Journal of molecular evolution Medium 21643828
2019 Diabetes-induced retinal endothelial cell death occurs through an IL-17A/IL-17R → Act1/FADD signaling cascade causing caspase-mediated apoptosis. Act1 was shown to interact with FADD, identifying Act1 as a bridge between the IL-17 receptor complex and the apoptotic FADD/caspase pathway. IL-17A-/- mouse STZ diabetes model, retinal endothelial cell ex vivo studies, Act1/FADD signaling pathway analysis, capillary degeneration quantification Journal of diabetes and its complications Medium 31239234

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 504 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 300 20953186
2006 Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. The Journal of biological chemistry 299 17035243
2010 Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 240 20303295
2013 An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity 231 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 127 21335551
1999 Phylogenetic analysis and rapid identification of Candida dubliniensis based on analysis of ACT1 intron and exon sequences. Microbiology (Reading, England) 122 10463153
1991 Analysis of rice Act1 5' region activity in transgenic rice plants. The Plant cell 118 1821763
2004 Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity 115 15485634
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
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 105 24561578
2018 IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nature immunology 102 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 101 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 96 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
2018 Neutrophil Extracellular Traps Induce Human Th17 Cells: Effect of Psoriasis-Associated TRAF3IP2 Genotype. The Journal of investigative dermatology 87 30528823
2013 HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization. Journal of immunology (Baltimore, Md. : 1950) 87 23772036
2012 TRAF6-dependent Act1 phosphorylation by the IκB kinase-related kinases suppresses interleukin-17-induced NF-κB activation. Molecular and cellular biology 79 22851696
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 77 36411467
2016 IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via Act1 signaling. Experimental & molecular medicine 76 27980343
2012 Epithelial cell-specific Act1 adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin(-)c-Kit(+) innate cell population. Immunity 61 22608496
2007 Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling. Cytokine 61 18061473
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
2008 Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren's syndrome. European journal of immunology 58 18624351
2014 Syk mediates IL-17-induced CCL20 expression by targeting Act1-dependent K63-linked ubiquitination of TRAF6. The Journal of investigative dermatology 57 25202827
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
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 56 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 56 28476142
2015 Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2. Cellular signalling 54 26148936
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
2014 Interleukin-17A promotes MUC5AC expression and goblet cell hyperplasia in nasal polyps via the Act1-mediated pathway. PloS one 52 24892823
2013 Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling. Free radical biology & medicine 52 23453926
2013 TRAF3IP2 gene and systemic lupus erythematosus: association with disease susceptibility and pericarditis development. Immunogenetics 50 23836313
2022 IL-17A Promotes Psoriasis-Associated Keratinocyte Proliferation through ACT1-Dependent Activation of YAP-AREG Axis. The Journal of investigative dermatology 49 35304250
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
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
2018 Act1 is a negative regulator in T and B cells via direct inhibition of STAT3. Nature communications 37 30013031
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 TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. Journal of molecular and cellular cardiology 36 29981796
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
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
2016 TRAF3IP2 mediates aldosterone/salt-induced cardiac hypertrophy and fibrosis. Molecular and cellular endocrinology 29 27040306
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) 29 20660351
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
2019 MLN4924 protects against interleukin-17A-induced pulmonary inflammation by disrupting ACT1-mediated signaling. American journal of physiology. Lung cellular and molecular physiology 28 30892082
2013 TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation. Cellular signalling 28 23872479
2021 FYN-TRAF3IP2 induces NF-κB signaling-driven peripheral T cell lymphoma. Nature cancer 27 33928261
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) 27 33941656
2021 Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified. Nature communications 27 34140493
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
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 27 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
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 25 33748112
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) 24 27097970
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
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
2023 IL-23/IL-17 immune axis mediates the imiquimod-induced psoriatic inflammation by activating ACT1/TRAF6/TAK1/NF-κB pathway in macrophages and keratinocytes. The Kaohsiung journal of medical sciences 20 37098777
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
2010 The adaptor molecule Act1 regulates BAFF responsiveness and self-reactive B cell selection during transitional B cell maturation. Journal of immunology (Baltimore, Md. : 1950) 19 20543113
2020 TRAF3IP2 (TRAF3 Interacting Protein 2) Mediates Obesity-Associated Vascular Insulin Resistance and Dysfunction in Male Mice. Hypertension (Dallas, Tex. : 1979) 18 32829657

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