Affinage

UBASH3A

Ubiquitin-associated and SH3 domain-containing protein A · UniProt P57075

Round 2 corrected
Length
661 aa
Mass
74.1 kDa
Annotated
2026-04-28
130 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBASH3A (TULA/STS-2) is a lymphoid-enriched multi-domain adaptor protein that functions as a negative regulator of T cell receptor signaling and immune activation. Its SH3 domain mediates interactions with c-Cbl, CBL-B, PTPN22, dynamin, and NF-κB pathway components (TAK1, NEMO, non-degradative polyubiquitin chains), through which UBASH3A suppresses IKK/NF-κB activation, inhibits dynamin-dependent endocytosis, modulates TCR-CD3 complex synthesis and surface turnover, and cooperates with PTPN22 to set the TCR activation threshold (PMID:28607106, PMID:17382318, PMID:31659016, PMID:37240014). Its PGM/2H-phosphatase domain possesses weak, acid-dependent phosphatase activity (His366 as nucleophilic residue) that contributes modestly to ZAP-70 dephosphorylation—substantially less than its paralog UBASH3B/STS-1—while its UBA domain undergoes E3-independent monoubiquitination that limits its own ubiquitin-binding capacity and regulates receptor trafficking (PMID:19196006, PMID:19627098, PMID:21393235, PMID:17588522). Loss of UBASH3A in NOD mice and LEW.1W rats accelerates autoimmune diabetes development through a T cell-intrinsic mechanism, and type 1 diabetes risk alleles increase UBASH3A expression in stimulated CD4+ T cells, establishing UBASH3A as a causal immunoregulatory checkpoint gene for T1D (PMID:32694640, PMID:34205929, PMID:28607106).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 High

    Identification of UBASH3A as a novel lymphoid-restricted gene with a unique SH3–UBA–PGM domain architecture established the molecular foundation for its study as a potential immune signaling regulator.

    Evidence cDNA cloning, domain analysis, and tissue-restricted RT-PCR expression profiling

    PMID:11281453

    Open questions at the time
    • No function assigned; domain activities unknown
    • Expression at protein level in lymphocyte subsets not confirmed
  2. 2004 High

    Genetic ablation of Sts-1 and Sts-2 in mice revealed that the two paralogs cooperate to negatively regulate TCR signaling, with double-knockout T cells showing hyperphosphorylated ZAP-70, increased cytokine production, and susceptibility to autoimmunity, establishing the core physiological role of the family.

    Evidence Double-knockout mouse T cells with phospho-ZAP-70 immunoblotting, cytokine assays, and EAE autoimmune model

    PMID:14738763

    Open questions at the time
    • Individual contributions of Sts-1 vs Sts-2 not separated in the double KO
    • Mechanism of ZAP-70 regulation (direct dephosphorylation vs adaptor function) unresolved
  3. 2004 High

    Biochemical dissection showed that UBASH3A's SH3 domain binds c-Cbl and its UBA domain binds monoubiquitin, and that UBASH3A inhibits Cbl-mediated receptor downregulation and dynamin-dependent endocytosis, defining two key molecular interaction modes.

    Evidence Co-IP, mass spectrometry, EGFR trafficking assays, and endocytosis assays with multiple cargo types including dynamin rescue

    PMID:15107835 PMID:15159412 PMID:17382318

    Open questions at the time
    • Physiological significance of endocytosis inhibition in lymphocytes not demonstrated
    • Relative importance of Cbl-binding versus dynamin-sequestration in T cell context unclear
  4. 2006 High

    Discovery that UBASH3A undergoes E3-independent monoubiquitination—with its own UBA domain directly cooperating with Ub-charged E2 enzymes—revealed a self-regulatory switch: monoubiquitinated UBASH3A loses the ability to bind ubiquitinated targets in trans, tuning its adaptor activity.

    Evidence In vitro E3-independent ubiquitination reconstitution, FRET, siRNA, ubiquitin fusion constructs, and EGFR trafficking assays

    PMID:16429130 PMID:17588522

    Open questions at the time
    • Identity of E2 enzyme(s) responsible in T cells not defined
    • Dynamics of monoubiquitination/deubiquitination cycle in vivo unknown
  5. 2007 High

    Identification of AIF as a UBASH3A-interacting protein and demonstration that UBASH3A promotes caspase-independent apoptosis via AIF revealed a pro-apoptotic function distinct from its TCR-signaling role, while interaction with ABCE-1 and UBA-dependent inhibition of HIV-1 budding uncovered an antiviral function.

    Evidence Mass spectrometry interaction screens, AIF siRNA rescue of apoptosis, HIV-1 production assays with UBA domain mutants

    PMID:17709377 PMID:18006034

    Open questions at the time
    • Physiological relevance of AIF-mediated apoptosis in T cell homeostasis not confirmed in vivo
    • Anti-HIV activity studied only in overexpression systems
  6. 2009 High

    Crystal structures of the UBASH3A PGM domain in apo, substrate-bound, phospho-intermediate, and transition-state forms established that His366 is the catalytic nucleophile and identified five non-conserved residues (Gln372, Ala446, Glu481, Ser552, Ser582) whose divergence from UBASH3B explains the dramatically lower phosphatase activity of UBASH3A.

    Evidence X-ray crystallography of multiple catalytic intermediates, site-directed mutagenesis restoring activity, pH-rate profiling

    PMID:19196006 PMID:19627098

    Open questions at the time
    • Physiological substrate identity for UBASH3A phosphatase domain remains uncertain
    • Whether the weak phosphatase activity is biologically meaningful independent of the adaptor functions is unknown
  7. 2011 High

    Direct measurement confirmed that UBASH3A possesses weak but detectable phosphatase activity toward ZAP-70, and combinatorial peptide library screening showed no activity against a broad phosphotyrosyl panel, resolving the long-standing question of whether UBASH3A functions primarily as a phosphatase or as an adaptor.

    Evidence Combinatorial phosphopeptide library screen (negative result), T cell phospho-ZAP-70 assays, mutagenesis of specificity determinants

    PMID:20670933 PMID:21393235

    Open questions at the time
    • Whether UBASH3A contributes to ZAP-70 dephosphorylation in vivo through direct activity or by recruiting UBASH3B/Nrdp1 remains debated
  8. 2015 High

    Discovery that Nrdp1 E3 ligase mediates K33-linked polyubiquitination of ZAP-70 and promotes its dephosphorylation by both Sts-1 and Sts-2 provided a molecular link between ubiquitin signaling and phosphatase-mediated TCR signal termination.

    Evidence K33 polyubiquitination assays, co-IP of Nrdp1/ZAP-70/Sts proteins, Nrdp1 knockout mice, T cell activation assays

    PMID:26390156

    Open questions at the time
    • Whether UBASH3A's UBA domain directly recognizes K33-linked chains on ZAP-70 is not shown
    • Relative contribution of UBASH3A vs UBASH3B in Nrdp1-dependent dephosphorylation not quantified
  9. 2017 High

    Identification of UBASH3A as a suppressor of NF-κB/IKK signaling through novel interactions with non-degradative polyubiquitin chains, TAK1, and NEMO, combined with the finding that T1D risk alleles increase UBASH3A expression and reduce IL-2 production, established a distinct signaling axis beyond ZAP-70 dephosphorylation.

    Evidence siRNA/overexpression in primary human CD4+ T cells, IKK activity assays, co-IP with TAK1/NEMO/polyubiquitin, allele-specific expression

    PMID:28607106

    Open questions at the time
    • Whether TAK1/NEMO interaction is direct or ubiquitin-mediated is not fully resolved
    • Structural basis of SH3 domain recognition of TAK1/NEMO unknown
  10. 2019 High

    Demonstration that UBASH3A controls steady-state TCR-CD3 complex levels and surface turnover, and identification of CBL-B and ERAD pathway components as interactors, expanded the functional model beyond signal transduction to receptor homeostasis.

    Evidence Flow cytometry for surface TCR-CD3 upon UBASH3A modulation, mass spectrometry interactome, co-IP of CBL-B via SH3 domain

    PMID:31659016

    Open questions at the time
    • Whether UBASH3A promotes TCR-CD3 degradation through ERAD or endolysosomal pathways is unclear
    • Interactome not validated for all hits beyond CBL-B
  11. 2020 High

    UBASH3A knockout in NOD mice and LEW.1W rats accelerated autoimmune diabetes with increased β-cell autoreactive T cells, and adoptive transfer demonstrated a T cell-intrinsic protective mechanism, providing in vivo genetic proof that UBASH3A is a causal checkpoint gene for type 1 diabetes.

    Evidence Zinc-finger nuclease KO in NOD mice, germline KO in LEW.1W rats, diabetes incidence, insulitis scoring, adoptive transfer into Rag1−/− hosts

    PMID:32694640 PMID:34205929

    Open questions at the time
    • Which UBASH3A-dependent pathway (NF-κB suppression, TCR-CD3 turnover, ZAP-70 dephosphorylation, or apoptosis) is most critical for T1D protection is unresolved
    • Human validation of knockout phenotype not available
  12. 2023 Medium

    Physical interaction of UBASH3A with PTPN22 via the SH3 domain and cooperative effects of their T1D risk variants on IL-2 expression revealed functional epistasis between two major T1D susceptibility genes at the protein level.

    Evidence Co-IP in T cells, SH3 domain binding assays, RNA-seq of primary CD8+ T cells, genetic interaction analysis

    PMID:37240014

    Open questions at the time
    • Functional consequence of UBASH3A–PTPN22 interaction on phosphatase activity or substrate access not defined
    • Reciprocal co-IP not shown
    • Whether interaction occurs at the immunological synapse is unknown
  13. 2024 Medium

    Identification of UBASH3A as a tumor suppressor in erythroleukemia, acting downstream of FLI1/GATA2 to activate HSPA1B and suppress proliferation, extended UBASH3A's functional repertoire beyond lymphocyte regulation.

    Evidence ChIP and luciferase reporter for UBASH3A promoter, shRNA knockdown, RNA-seq, proliferation assays in erythroleukemic cells

    PMID:38461240

    Open questions at the time
    • Mechanism by which UBASH3A activates HSPA1B transcription is unknown
    • Tumor-suppressive role not validated in vivo
    • Whether this function involves the same domains as immune regulation is unstudied

Open questions

Synthesis pass · forward-looking unresolved questions
  • The relative contributions of UBASH3A's adaptor functions (NF-κB suppression, TCR-CD3 turnover, endocytosis inhibition) versus its weak phosphatase activity to T cell homeostasis and autoimmune disease protection remain to be dissected in vivo with domain-specific mutants.
  • No domain-specific knock-in models exist to separate adaptor from phosphatase function in vivo
  • No structural model of full-length UBASH3A or its multi-domain complexes
  • Therapeutic potential of modulating UBASH3A expression or activity in autoimmunity is untested

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 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AIFM1CBLCBLBDNM2NEMOPTPN22TAK1ZAP70

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 UBASH3A (also called TULA/STS-2) was identified as a novel gene on chromosome 21q22.3 encoding a 661-amino-acid protein with a unique combination of an SH3 domain, a ubiquitin-associated (UBA) domain, and a novel phosphoglycerate mutase-like domain containing a nuclear localization signal. Expression was found to be restricted to spleen, peripheral blood leukocytes, and bone marrow, suggesting lymphoid-specific expression. cDNA cloning, domain analysis, semi-quantitative RT-PCR across tissues Human genetics High 11281453
2004 Sts-2 (UBASH3A) and Sts-1 negatively regulate TCR signaling: T cells from Sts-1/2 double-knockout mice are hyperresponsive to TCR stimulation, exhibiting increased ZAP-70 phosphorylation (including ubiquitylated forms) and hyperactivation of downstream signaling proteins, leading to increased cytokine production and increased susceptibility to autoimmunity in an EAE mouse model. Double-knockout mouse generation, T cell stimulation assays, immunoblotting for phospho-ZAP-70, cytokine production assays, EAE model Immunity High 14738763
2004 TULA (UBASH3A/STS-2) binds directly to c-Cbl via its SH3 domain, binds mono-ubiquitin and EGFR/ubiquitin chimera via its UBA domain, and inhibits c-Cbl-mediated downregulation of EGFR in 293T cells. TULA overexpression in Jurkat T cells upregulates ZAP-70 kinase activity and NF-AT transcription factor activity, suggesting it counteracts c-Cbl-mediated suppression of protein tyrosine kinases by promoting ubiquitylation and degradation of c-Cbl. Affinity chromatography, mass spectrometry, co-immunoprecipitation, co-expression in 293T cells, Jurkat T-cell overexpression/knockdown assays Oncogene Medium 15107835
2004 TULA (UBASH3A/STS-2) and Sts-1 are recruited into activated EGFR complexes upon ligand stimulation, inhibit receptor internalization (reducing the number of EGFR-containing endocytic vesicles), block receptor degradation, and thereby prolong activation of mitogenic signaling pathways. The SH3 domain mediates Cbl binding; the UBA domain binds mono-ubiquitin and EGFR/Ub chimera; the PGM domain mediates Sts-1/2 oligomerization. Co-immunoprecipitation, dominant-negative interference, fluorescence microscopy, endocytosis assays, cell proliferation and transformation assays The Journal of biological chemistry High 15159412
2007 TULA (UBASH3A) inhibits clathrin-dependent endocytosis of transferrin and LDL, and clathrin-independent but dynamin-dependent endocytosis of CD59 and MHC-I, but does not affect dynamin-independent uptake of ricin. TULA co-immunoprecipitates and colocalizes with dynamin, and the inhibitory effect on endocytosis is counteracted by overexpression of dynamin, indicating that the SH3 domain of TULA sequesters dynamin via its proline-rich sequences. Endocytosis assays (Tf, LDL, CD59, MHC-I, ricin uptake), co-immunoprecipitation of TULA and dynamin, rescue experiments with dynamin overexpression, domain mapping Experimental cell research High 17382318
2007 TULA (UBASH3A) promotes T cell apoptosis independently of TCR/CD3 signaling and caspase activity. Mass spectrometry identified apoptosis-inducing factor (AIF) as a TULA-interacting protein; RNAi knockdown of AIF abolishes the apoptotic effect of TULA. Subcellular localization and functional analysis of TULA mutants indicate that TULA enhances AIF-mediated caspase-independent apoptosis, likely by facilitating AIF interactions with co-factors. Mass spectrometry-based protein interaction analysis, siRNA knockdown of AIF, apoptosis assays (caspase-independent), subcellular localization, TULA mutant analysis The Journal of biological chemistry High 17709377
2007 TULA (UBASH3A/STS-2) proteins bind to ABCE-1 (also known as RLI/HP68, a host factor for HIV-1 assembly) as identified by mass spectrometry, and substantially inhibit production of both sub-genomic and full-length HIV-1 viral particles. The anti-HIV-1 effect requires the UBA domain of TULA, and ABCE-1 appears to recruit TULA to sites of HIV-1 assembly where it disrupts ubiquitylation-dependent steps of the HIV-1 life cycle. Mass spectrometry identification of TULA-associated proteins, HIV-1 production assays, UBA domain deletion mutants, co-localization studies Virology Medium 18006034
2006 Sts-2 (UBASH3A) undergoes monoubiquitination via an intramolecular mechanism: the UBA domain of Sts-2 binds to the attached ubiquitin moiety, preventing Sts-2 from binding in trans to ubiquitinated targets. Permanent monoubiquitination (mimicked by ubiquitin fusion to the C-terminus) impairs the ability of Sts-2 to regulate trafficking of ubiquitinated receptors. The in vivo monoubiquitination site of Sts-2 was mapped, and its mutation enhances Sts-2-mediated effects on EGFR downregulation. Monoubiquitination site mapping, ubiquitin fusion constructs, co-immunoprecipitation, EGFR trafficking assays Nature cell biology High 16429130
2007 Sts-2 (UBASH3A), in contrast to Sts-1, stabilizes EGFR in a signaling-competent (phosphorylated) state: Sts-2 UBA domain contributes to receptor stabilization, but the PGM domain of Sts-2 lacks the dephosphorylation activity toward EGFR that Sts-1 PGM possesses. Thus Sts-1 and Sts-2 inhibit EGFR degradation via mechanistically distinct pathways. Domain swap and deletion experiments, EGFR phosphorylation and degradation assays, comparison of Sts-1 and Sts-2 PGM phosphatase activity toward EGFR FEBS letters Medium 17880946
2007 Sts-2 (UBASH3A) undergoes E3-independent monoubiquitination: the UBA domain directly cooperates with Ub-charged E2 enzymes to promote monoubiquitination in the absence of E3 ligases. FRET and siRNA studies confirmed that Ub-loaded E2 and Sts-2 interact in cells and that E2 enzymes are essential for their monoubiquitination in vivo. E3-independent ubiquitination assays in vitro, FRET, siRNA knockdown, in vivo ubiquitination assays Molecular cell High 17588522
2008 TULA (UBASH3A/STS-2) has negligible phosphatase activity toward tyrosine-phosphorylated Syk compared to TULA-2. Overexpression of TULA increases Syk tyrosine phosphorylation in cells co-transfected with Syk, suggesting TULA acts as a dominant-negative inhibitor of TULA-2-dependent Syk dephosphorylation. Thus TULA and TULA-2 exert opposing effects on Syk phosphorylation. In vitro phosphatase assays with Syk substrate, co-transfection overexpression in cells, immunoblotting for phospho-Syk, dominant-negative mutant analysis Journal of cellular biochemistry Medium 18189269
2009 The crystal structure of the PGM (2H-phosphatase) domain of Sts-2 (UBASH3A) was solved in apo, tungstate-bound, and phosphate-bound forms, showing strong structural similarity to Sts-1 PGM including conservation of all catalytic residues. The active site shows pH optimum at 5.0 (acid-dependent phosphatase). Non-conserved residues Gln372, Ala446, Glu481, Ser552, and Ser582 account for the reduced activity relative to Sts-1: mutating these to Sts-1 equivalents substantially increases Sts-2 PGM activity. X-ray crystallography (apo, tungstate-bound, phosphate-bound structures), phosphatase kinetics, site-directed mutagenesis Biochemistry High 19196006
2009 Crystal structures of the Sts-2 (UBASH3A) PGM domain in its phosphorylated form and bound to vanadate (transition-state analogue) reveal that His366 is the nucleophilic residue transiently phosphorylated during catalysis. The V-NE2 bond length (2.25 Å) indicates a partially associative reaction mechanism. Glu476 plays a role in activating a uniquely positioned water molecule for dephosphorylation. X-ray crystallography of phospho-intermediate and VO3-bound transition state analogue, bond length analysis Biochemistry High 19627098
2010 TULA-1 (UBASH3A) showed no detectable phosphatase activity toward any phosphotyrosyl peptides in a combinatorial library screen, in contrast to TULA-2 which showed activity toward two peptide classes. This establishes that UBASH3A lacks significant intrinsic phosphatase activity against the substrates tested. Combinatorial phosphotyrosyl peptide library screening, kinetic analysis of representative peptide substrates The Journal of biological chemistry High 20670933
2011 Sts-2 (UBASH3A) regulates the level of tyrosine phosphorylation on ZAP-70 in T cells. The PGM domain of Sts-2 has clear but weak phosphatase activity detectable with appropriate substrates. Residues Glu-481, Ser-552, and Ser-582 are specificity determinants: a triple mutant converting these to their Sts-1 counterparts substantially increases Sts-2 phosphatase activity, suggesting the two homologs cooperate independently to set the TCR activation threshold. T cell phosphorylation assays, in vitro phosphatase activity with new substrates, site-directed mutagenesis of active site residues The Journal of biological chemistry High 21393235
2015 Nrdp1 E3 ligase mediates K33-linked polyubiquitination of ZAP-70 and promotes its dephosphorylation by Sts-1 and Sts-2 (UBASH3A), thereby terminating early TCR signaling in CD8+ T cells. Nrdp1 physically interacts with ZAP-70 and with both Sts proteins, linking K33-ubiquitin modification of ZAP-70 to Sts-mediated dephosphorylation. K33 polyubiquitination assays, co-immunoprecipitation, Nrdp1 knockout mice, T cell activation assays, ZAP-70 phosphorylation analysis Nature immunology High 26390156
2017 UBASH3A attenuates NF-κB signaling downstream of TCR stimulation by specifically suppressing activation of the IκB kinase (IKK) complex. Novel interactions of UBASH3A with non-degradative polyubiquitin chains, TAK1, and NEMO were identified, suggesting an ubiquitin-dependent mechanism of NF-κB pathway regulation. T1D risk alleles at rs11203203 and rs80054410 increase UBASH3A expression in primary CD4+ T cells upon TCR stimulation, resulting in reduced IKK activation and decreased IL-2 gene expression. siRNA knockdown and overexpression in primary human CD4+ T cells, IKK complex activity assays, co-immunoprecipitation of UBASH3A with polyubiquitin chains/TAK1/NEMO, IL-2 production assays, allele-specific expression studies Diabetes High 28607106
2017 Human Sts-2 (UBASH3A) histidine phosphatase domain (Sts-2HP) crystal structure was solved to 2.4 Å with sulfate bound; steady-state kinetics confirm that Sts-2HP has significantly lower phosphatase activity than Sts-1HP (human proteins behave similarly to mouse). The PHPS1 inhibitor (known SHP-1 inhibitor) inhibits Sts-1 with Ki = 1.05 μM, and human Sts-1 shows robust phosphatase activity against ZAP-70 in a cell-based assay. X-ray crystallography of human Sts-2HP, steady-state kinetic analysis, inhibitor testing, cell-based ZAP-70 dephosphorylation assay Biochemistry High 28759203
2018 UBASH3A noncoding variant rs1893592 plays a novel role in T1D: its minor allele is associated with reduced overall UBASH3A mRNA levels and increased proportion of an intron-9-retaining, non-functional transcript in primary CD4+ T cells upon TCR stimulation. This reduction in UBASH3A protein leads to increased IL-2 secretion, demonstrating that noncoding variants regulate UBASH3A expression and thereby T cell function. Haplotype analysis, allele-specific expression assays, RNA-seq in primary human CD4+ T cells, IL-2 secretion assays, splice-form quantification European journal of human genetics Medium 29491471
2019 UBASH3A regulates TCR-CD3 complex synthesis and turnover: modulation of UBASH3A levels in unstimulated Jurkat cells alters total cellular CD3 chain amounts and cell-surface TCR-CD3 levels (but not CD28 levels). Upon TCR engagement, UBASH3A enhances downmodulation of surface TCR-CD3. Mass spectrometry and protein-protein interaction studies reveal novel associations between UBASH3A and components of ER-associated protein degradation (ERAD), cell motility, endocytosis, and endocytic recycling pathways. The SH3 domain of UBASH3A mediates binding to CBL-B, an E3 ubiquitin ligase that negatively regulates CD28-mediated signaling. UBASH3A modulation (overexpression/knockdown) in Jurkat cells, flow cytometry for surface TCR-CD3 and CD28, mass spectrometry interactome, co-immunoprecipitation, SH3 domain binding assays Journal of immunology High 31659016
2020 UBASH3A deficiency in NOD mice accelerates type 1 diabetes development in both sexes, is associated with increased β-cell autoreactive T cells in spleen and pancreatic lymph nodes, and promotes salivary gland inflammation in females. Adoptive transfer of UBASH3A-deficient splenic T cells into NOD.Rag1-/- mice was sufficient to promote T1D development, establishing that UBASH3A's protective effect is T cell-intrinsic. Zinc-finger nuclease-mediated knockout in NOD mice, diabetes incidence monitoring, insulitis scoring, flow cytometry for autoreactive T cells, adoptive transfer experiments Scientific reports High 32694640
2022 In rheumatoid arthritis CD4+ T cells, UBASH3A transcription is suppressed via epigenetic dysregulation of a super-enhancer: BACH2 (a silencing transcription factor) accumulates at UBASH3A loci while MED1/BRD4 (SE-defining factors) are reduced. Knockdown of enhancer RNAs (eRNA_1, eRNA_3) reduces UBASH3A mRNA. UBASH3A overexpression in RA patient CD4+ T cells significantly inhibits TCR-stimulated IL-6 production. ChIP for BACH2, MED1, BRD4 at UBASH3A loci, locked nucleic acid-mediated eRNA knockdown, RT-PCR, western blotting, UBASH3A overexpression in CD4+ T cells, cytometric bead array for IL-6 Inflammation and regeneration Medium 36324153
2023 UBASH3A physically interacts with PTPN22 in T cells via its SH3 domain, as demonstrated by co-immunoprecipitation. This interaction is not altered by the T1D risk coding variant rs2476601 in PTPN22. RNA-seq analysis of T1D cases shows that UBASH3A and PTPN22 transcript levels have a cooperative effect on IL-2 expression in primary CD8+ T cells, and the two T1D risk variants rs11203203 (UBASH3A) and rs2476601 (PTPN22) interact statistically to jointly affect T1D risk. Co-immunoprecipitation in T cells, SH3 domain binding assays, RNA-seq analysis of primary CD8+ T cells, genetic interaction analysis International journal of molecular sciences Medium 37240014
2024 FLI1 indirectly inhibits UBASH3A transcription via GATA2, thereby promoting erythroleukemia cell growth. UBASH3A knockdown in erythroleukemic cells increased proliferation, associated with dramatic induction of HSP70 gene HSPA1B; knockdown of HSPA1B accelerated leukemic cell proliferation, suggesting UBASH3A acts as a tumor suppressor in erythroleukemia partly by activating HSPA1B expression. Overexpression of UBASH3A across cancers is associated with good prognosis. ChIP analysis and luciferase assays for UBASH3A promoter, lentivirus-shRNA knockdown, RNA-seq, MTT proliferation assays, flow cytometry for apoptosis BMC cancer Medium 38461240
2021 Germline knockout of Ubash3a in LEW.1W rats (which carry RT1B/Du MHC but are normally T1D-resistant) renders these rats relatively susceptible to autoimmune diabetes, demonstrating that UBASH3A provides a critical immunoregulatory checkpoint downstream of the T cell receptor that protects against autoimmunity even in the context of a susceptible MHC haplotype. Germline Ubash3a knockout in LEW.1W rats, diabetes incidence monitoring, Tcrb-V13S1A1 knockout comparison, in silico structural modeling of TCR-MHC interaction Genes Medium 34205929

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 1778 24390342
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
2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature genetics 1382 19430480
2010 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature genetics 1018 20453842
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 787 18854154
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. The New England journal of medicine 566 19073967
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2010 Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. The New England journal of medicine 304 20410501
2011 Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS genetics 297 21383967
2006 Regulation of ubiquitin-binding proteins by monoubiquitination. Nature cell biology 271 16429130
2011 Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS genetics 215 21829393
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
1994 Tula virus: a newly detected hantavirus carried by European common voles. Journal of virology 176 7966573
2004 Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Immunity 152 14738763
2008 Proteomic analysis of exosomes from human neural stem cells by flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry. Journal of proteome research 148 18570454
2009 Charting the molecular network of the drug target Bcr-Abl. Proceedings of the National Academy of Sciences of the United States of America 137 19380743
2007 E3-independent monoubiquitination of ubiquitin-binding proteins. Molecular cell 128 17588522
2008 Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. Diabetes 121 18840781
2004 Suppressors of T-cell receptor signaling Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases. The Journal of biological chemistry 119 15159412
2007 Tula and Puumala hantavirus NSs ORFs are functional and the products inhibit activation of the interferon-beta promoter. Journal of medical virology 117 17705180
1996 Isolation and characterization of Tula virus, a distinct serotype in the genus Hantavirus, family Bunyaviridae. The Journal of general virology 117 9000098
2010 Electron cryotomography of Tula hantavirus suggests a unique assembly paradigm for enveloped viruses. Journal of virology 111 20219926
2007 Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes. The EMBO journal 105 17599067
2004 Identification of NPM-ALK interacting proteins by tandem mass spectrometry. Oncogene 92 14968112
1999 Recombination in Tula hantavirus evolution: analysis of genetic lineages from Slovakia. Journal of virology 87 9847372
2015 K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation. Nature immunology 82 26390156
1996 Inhibition of puumala and tula hantaviruses in Vero cells by MxA protein. Virology 82 8862399
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
1995 Genetic variation in Tula hantaviruses: sequence analysis of the S and M segments of strains from Central Europe. Virus research 79 8837887
2004 TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin. Oncogene 78 15107835
2011 Sts-2 is a phosphatase that negatively regulates zeta-associated protein (ZAP)-70 and T cell receptor signaling pathways. The Journal of biological chemistry 68 21393235
2021 Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy. Acta pharmaceutica Sinica. B 66 35256949
2010 A novel histidine tyrosine phosphatase, TULA-2, associates with Syk and negatively regulates GPVI signaling in platelets. Blood 61 20585042
2023 Cross-linking mass spectrometry discovers, evaluates, and corroborates structures and protein-protein interactions in the human cell. Proceedings of the National Academy of Sciences of the United States of America 60 37071682
2019 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. Nature communications 60 31515488
2005 Tula hantavirus triggers pro-apoptotic signals of ER stress in Vero E6 cells. Virology 57 15708603
1997 Puumala virus and two genetic variants of Tula virus are present in Austrian rodents. Journal of medical virology 57 9334930
2017 UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-κB Signaling. Diabetes 55 28607106
2013 Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers. Pediatric diabetes 53 25075402
2008 TULA proteins regulate activity of the protein tyrosine kinase Syk. Journal of cellular biochemistry 52 18189269
2001 Isolation and characterization of the UBASH3A gene on 21q22.3 encoding a potential nuclear protein with a novel combination of domains. Human genetics 50 11281453
2010 Determination of the substrate specificity of protein-tyrosine phosphatase TULA-2 and identification of Syk as a TULA-2 substrate. The Journal of biological chemistry 49 20670933
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