{"gene":"UBASH3A","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2004,"finding":"Sts-1 and Sts-2 (UBASH3A/STS-2 and its paralog) negatively regulate TCR signaling by suppressing ZAP-70 phosphorylation and activation; T cells from Sts-1/Sts-2 double-knockout mice are hyperresponsive to TCR stimulation with increased ZAP-70 phosphorylation, elevated cytokine production, and increased susceptibility to autoimmunity in a mouse EAE model.","method":"Genetic knockout (double KO mice), T cell stimulation assays, phosphorylation analysis, cytokine production measurement, EAE model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple defined cellular phenotypes, replicated across multiple readouts in a peer-reviewed study","pmids":["14738763"],"is_preprint":false},{"year":2004,"finding":"TULA (UBASH3A/STS-2) binds to c-Cbl via its SH3 domain and to ubiquitin via its UBA domain; TULA inhibits c-Cbl-mediated downregulation of EGF receptor and upregulates ZAP-70 activity and NF-AT transcription factor activity in Jurkat T cells; the inhibitory effect on c-Cbl appears to involve TULA-induced ubiquitylation and degradation of c-Cbl.","method":"Affinity chromatography, mass spectrometry identification, co-expression in 293T cells, functional assays in Jurkat cells, modulation of TULA concentration","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification plus functional co-expression assays, single lab, multiple orthogonal methods","pmids":["15107835"],"is_preprint":false},{"year":2004,"finding":"Sts-2 (UBASH3A) contains an SH3 domain that interacts with Cbl, a UBA domain that binds directly to mono-ubiquitin or EGFR/Ub chimera, and a phosphoglycerate mutase (PGM) domain that mediates oligomerization; ligand-induced recruitment of Sts-2 into activated EGFR complexes inhibits receptor internalization, reduces EGFR-containing endocytic vesicles, and blocks receptor degradation, leading to prolonged mitogenic signaling.","method":"Co-immunoprecipitation, domain binding assays, endocytosis assays, fluorescence microscopy, dominant-negative interference","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, functional endocytosis assays with multiple readouts, consistent with independent findings in PMID:15107835","pmids":["15159412"],"is_preprint":false},{"year":2001,"finding":"UBASH3A encodes a 661-amino-acid protein containing SH3, UBA, and a novel domain with a nuclear localization signal; it is expressed primarily in spleen, peripheral blood leukocytes, and bone marrow; the gene spans 40 kb and is divided into 15 exons.","method":"cDNA cloning, RT-PCR expression analysis, sequence/domain analysis, genomic characterization","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization of gene/protein structure and tissue expression, single lab but multiple methods","pmids":["11281453"],"is_preprint":false},{"year":2009,"finding":"The PGM/2H-phosphatase domain of Sts-2 (UBASH3A) is an acid-dependent phosphatase with a crystal structure remarkably similar to Sts-1; the catalytic mechanism involves a transiently phosphorylated nucleophilic histidine; non-conserved active site residues Gln372, Ala446, Glu481, Ser552, and Ser582 account for the substantially lower activity of Sts-2 compared to Sts-1.","method":"X-ray crystallography (apo, tungstate-bound, phosphate-bound structures), active site mutagenesis, enzymatic activity assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures combined with mutagenesis and in vitro enzymatic assays in a single rigorous study","pmids":["19196006"],"is_preprint":false},{"year":2009,"finding":"The phosphorylated intermediate and vanadate transition-state analogue structures of the Sts-2 PGM domain confirm His366 as the nucleophilic catalytic residue; the reaction mechanism is partially associative; Glu476 activates a uniquely positioned water molecule; the active site conformation does not change during dephosphorylation.","method":"X-ray crystallography of phosphorylated and VO3-bound enzyme forms","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures of catalytic intermediates providing direct mechanistic insight","pmids":["19627098"],"is_preprint":false},{"year":2011,"finding":"Sts-2 (UBASH3A) regulates tyrosine phosphorylation levels in T cells including on ZAP-70; the PGM domain of Sts-2 has clear but weak phosphatase activity; residues Glu-481, Ser-552, and Ser-582 are specificity determinants — mutation of these three residues to their Sts-1 counterparts substantially increases Sts-2(PGM) phosphatase activity.","method":"In vitro phosphatase assays with new phosphorylated substrates, active site mutagenesis, cell-based phosphorylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution combined with mutagenesis and cell-based assays, single lab but rigorous multi-method approach","pmids":["21393235"],"is_preprint":false},{"year":2008,"finding":"TULA (UBASH3A/STS-2) has negligible phosphatase activity compared to TULA-2 (STS-1); overexpression of TULA increases Syk tyrosine phosphorylation in cells, acting as a dominant-negative inhibitor of endogenous TULA-2-mediated Syk dephosphorylation rather than as a direct phosphatase.","method":"In vivo and in vitro phosphorylation assays, dominant-negative overexpression, co-transfection experiments","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo assays combined, single lab, multiple approaches","pmids":["18189269"],"is_preprint":false},{"year":2010,"finding":"TULA-1 (UBASH3A/STS-2) showed no detectable phosphatase activity toward any phosphotyrosyl peptides in a combinatorial library screen, confirming that its intrinsic enzymatic activity is negligible. TULA-2 (STS-1) showed clear substrate selectivity with two substrate classes.","method":"Combinatorial phosphotyrosyl peptide library screening, kinetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic combinatorial library screen with kinetic validation, rigorous negative result for UBASH3A phosphatase activity","pmids":["20670933"],"is_preprint":false},{"year":2007,"finding":"TULA (UBASH3A) inhibits clathrin-dependent endocytosis (transferrin, LDL uptake) and clathrin-independent but dynamin-dependent endocytosis (CD59, MHC-I) by co-immunoprecipitating with and functionally sequestering dynamin via its SH3 domain binding proline-rich sequences in dynamin; overexpression of dynamin counteracted TULA-mediated inhibition of these pathways but did not rescue EGFR endocytosis (which operates via a distinct Cbl/ubiquitination mechanism).","method":"Endocytosis assays (transferrin, LDL, CD59, MHC-I, ricin uptake), co-immunoprecipitation, colocalization microscopy, dynamin overexpression rescue experiments","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, co-localization, functional rescue experiments with multiple cargo types","pmids":["17382318"],"is_preprint":false},{"year":2017,"finding":"UBASH3A attenuates NF-κB signal transduction upon TCR stimulation in human T cells by specifically suppressing activation of the IκB kinase (IKK) complex; UBASH3A interacts with non-degradative polyubiquitin chains, TAK1, and NEMO, suggesting ubiquitin-dependent regulation of the NF-κB pathway; T1D risk alleles at rs11203203 and rs80054410 increase UBASH3A expression in primary CD4+ T cells upon TCR stimulation, thereby inhibiting NF-κB and reducing IL-2 expression.","method":"Protein-protein interaction studies (Co-IP), ubiquitin-binding assays, siRNA knockdown, TCR stimulation assays, IL-2 expression analysis in primary human CD4+ T cells","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction studies, functional knockdown/overexpression with defined molecular phenotypes, primary human T cells","pmids":["28607106"],"is_preprint":false},{"year":2019,"finding":"UBASH3A regulates TCR-CD3 complex synthesis and turnover in T cells: modulation of UBASH3A levels in Jurkat cells alters total cellular CD3 chains and cell-surface TCR-CD3 complexes (but not CD28 levels); upon TCR engagement, UBASH3A enhances TCR-CD3 downmodulation from the cell surface; mass spectrometry revealed novel UBASH3A associations with components of ER-associated protein degradation, cell motility, endocytosis, and endocytic recycling pathways; the SH3 domain of UBASH3A mediates binding to CBL-B E3 ubiquitin ligase.","method":"Modulation of UBASH3A expression in Jurkat cells, flow cytometry for surface receptor levels, mass spectrometry, protein-protein interaction studies, domain-mapping experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MS, Co-IP, flow cytometry, gain/loss of function) in a single focused study","pmids":["31659016"],"is_preprint":false},{"year":2007,"finding":"TULA (UBASH3A) binds to ABCE-1 (RLI/HP68), a host factor of HIV-1 assembly, as identified by mass spectrometry; TULA proteins substantially inhibit production of both sub-genomic and full-length HIV-1 viral particles in a UBA domain-dependent manner; ABCE-1 recruits TULA to HIV-1 assembly sites where it interferes with late steps of HIV-1 life cycle.","method":"Mass spectrometry identification of TULA-associated proteins, HIV-1 production assays, UBA domain deletion mutant analysis","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification plus functional assays with domain mutants, single lab","pmids":["18006034"],"is_preprint":false},{"year":2017,"finding":"The histidine phosphatase domains of human Sts-1 and Sts-2 were crystallized; Sts-2HP has significantly lower phosphatase activity than Sts-1HP in steady-state kinetic assays; Sts-1HP is a functional surrogate for full-length Sts-1; the SHP-1 inhibitor PHPS1 inhibits Sts-1 with Ki = 1.05 μM; human Sts-1 has robust phosphatase activity against ZAP-70 in cell-based assays.","method":"X-ray crystallography (Sts-1HP apo and sulfate-bound to 2.5/1.9 Å; Sts-2HP sulfate-bound to 2.4 Å), steady-state kinetics, cell-based ZAP-70 phosphatase assay, inhibitor testing","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures combined with kinetics and cell-based functional assays, single lab","pmids":["28759203"],"is_preprint":false},{"year":2014,"finding":"Deletion of either or both TULA-family members (TULA/UBASH3A and TULA-2) in mice leads to exacerbated T-cell responses and inflammation in TNBS-induced colitis; both single and double KO exacerbate inflammation, with double KO having a greater effect; the mechanism involves regulation of ZAP-70 phosphorylation in T cells.","method":"Single and double knockout mice, TNBS-induced colitis model, T-cell activation assays, TCR signaling analysis (ZAP-70 phosphorylation)","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo and ex vivo functional readouts, single lab","pmids":["25047644"],"is_preprint":false},{"year":2017,"finding":"STS-2 (UBASH3A) KO mice immunized with collagen develop arthritis more frequently than WT mice; STS-2 KO CD4+ T cells show increased IL-2 production upon TCR stimulation; STS-2 KO Tregs normally suppress T cell proliferation, suggesting the pro-arthritis phenotype is mediated by enhanced IL-2 production from effector T cells rather than impaired Treg function.","method":"Collagen-induced arthritis model in KO mice, intracellular cytokine staining, co-culture Treg suppression assays","journal":"Modern rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined cellular phenotype and mechanistic follow-up, single lab","pmids":["28972439"],"is_preprint":false},{"year":2020,"finding":"UBASH3A deficiency in NOD mice accelerates type 1 diabetes development and enhances salivary gland inflammation; adoptive transfer of UBASH3A-deficient splenic T cells into NOD.Rag1−/− mice was sufficient to promote T1D development, demonstrating that the UBASH3A effect is T cell-intrinsic.","method":"Zinc-finger nuclease-mediated KO in NOD mice, insulitis scoring, diabetes incidence monitoring, adoptive T cell transfer, flow cytometry","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vivo disease phenotype confirmed by adoptive transfer establishing T cell-intrinsic mechanism","pmids":["32694640"],"is_preprint":false},{"year":2022,"finding":"In CD4+ T cells from rheumatoid arthritis patients, UBASH3A transcription is suppressed via epigenetic regulation of a super-enhancer, involving accumulation of the silencing transcription factor BACH2 and absence of MED1/BRD4 at UBASH3A loci; knockdown of enhancer RNAs (eRNA_1 and eRNA_3) reduces UBASH3A mRNA; overexpression of UBASH3A in RA CD4+ T cells significantly inhibits TCR-induced IL-6 production.","method":"ChIP analysis, locked nucleic acid-mediated eRNA knockdown, RT-PCR/western blotting, UBASH3A plasmid overexpression, cytometric bead array for cytokines","journal":"Inflammation and regeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional gain/loss-of-function experiments, single lab, multiple orthogonal methods","pmids":["36324153"],"is_preprint":false},{"year":2023,"finding":"UBASH3A physically interacts with PTPN22 via its SH3 domain in T cells; this interaction is not altered by the T1D risk coding variant rs2476601 in PTPN22; UBASH3A and PTPN22 transcript levels exert a cooperative effect on IL2 expression in human primary CD8+ T cells.","method":"Co-immunoprecipitation (SH3 domain-mediated), domain mapping, RNA-seq analysis of primary T cells, statistical interaction analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus transcriptomic functional evidence, single lab","pmids":["37240014"],"is_preprint":false},{"year":2024,"finding":"UBASH3A knockdown in erythroleukemic cells increases proliferation, associated with induction of HSPA1B (HSP70); UBASH3A acts as a tumor suppressor in erythroleukemia in part through activation of HSPA1B; FLI1 indirectly inhibits UBASH3A transcription via GATA2; UBASH3A is transcriptionally distinct from UBASH3B in the context of FLI1-driven leukemia.","method":"shRNA knockdown, luciferase promoter assays, ChIP, RNAseq, MTT proliferation assays, flow cytometry apoptosis assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD, promoter assays, ChIP, functional readouts) in a single study, single lab","pmids":["38461240"],"is_preprint":false},{"year":2024,"finding":"CD6 regulates UBASH3A expression in CD4+ T cells during murine coronavirus infection; CD6-deficient mice showed reduced infection-induced upregulation of UBASH3A in lymph nodes, associated with intensified TCR signal strength and greater T cell activation, suggesting that CD6 suppresses T cell activation in part by promoting UBASH3A expression.","method":"CD6 KO mouse model, gene expression analysis, TCR signal strength measurement, T cell activation assays","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, indirect evidence (expression correlation in KO context), single lab, no direct mechanistic manipulation of UBASH3A","pmids":[],"is_preprint":true},{"year":2018,"finding":"A non-coding T1D-associated variant rs1893592 in UBASH3A affects disease risk; its minor allele is associated with reduced overall UBASH3A mRNA levels and increased proportion of a low-abundance intron-9-retaining transcript that cannot produce full-length protein; this reduction leads to increased IL-2 secretion upon TCR stimulation in primary CD4+ T cells.","method":"Haplotype analysis, allele-specific expression in primary human CD4+ T cells, RNA-seq, TCR stimulation assays, IL-2 measurement","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional variant characterization in primary human T cells with multiple molecular readouts, single lab","pmids":["29491471"],"is_preprint":false}],"current_model":"UBASH3A (STS-2/TULA) is a lymphoid multi-domain adaptor/phosphatase protein that negatively regulates T cell activation by: (1) suppressing ZAP-70 phosphorylation and TCR-induced NF-κB signaling through interactions with polyubiquitin chains, TAK1, and NEMO at the IKK complex; (2) binding CBL-B (via its SH3 domain) and dynamin to inhibit receptor endocytosis and TCR-CD3 turnover; (3) binding ubiquitin via its UBA domain; and (4) acting as a weak phosphatase (negligible intrinsic enzymatic activity compared to its paralog TULA-2/STS-1) whose regulatory effects are instead largely mediated by protein-protein interactions — including with PTPN22 via its SH3 domain — that modulate proximal TCR signaling and IL-2 production."},"narrative":{"mechanistic_narrative":"UBASH3A (STS-2/TULA) is a lymphoid-enriched multi-domain adaptor that negatively regulates proximal T cell receptor signaling and dampens T cell activation [PMID:14738763, PMID:11281453]. It restrains TCR-proximal kinases — suppressing ZAP-70 phosphorylation in T cells, with loss of UBASH3A producing hyperresponsive T cells, elevated cytokine output, and increased autoimmune susceptibility [PMID:14738763, PMID:21393235]. The protein is built from an SH3 domain that engages CBL-family E3 ligases (c-Cbl and CBL-B) and the phosphatase PTPN22, a UBA domain that binds mono- and poly-ubiquitin, and a histidine-phosphatase (PGM/2H) domain that oligomerizes [PMID:15159412, PMID:31659016, PMID:37240014]. Although the PGM domain adopts a catalytically competent fold using a nucleophilic histidine (His366), its intrinsic phosphatase activity is negligible relative to its paralog STS-1/TULA-2, a difference traced to non-conserved active-site residues; consequently UBASH3A acts largely through protein-protein interactions rather than direct catalysis, and can behave as a dominant-negative against STS-1-mediated Syk/ZAP-70 dephosphorylation [PMID:19196006, PMID:21393235, PMID:20670933, PMID:18189269]. Mechanistically, UBASH3A attenuates TCR-induced NF-κB signaling by suppressing IKK complex activation through interactions with non-degradative polyubiquitin chains, TAK1, and NEMO, thereby lowering IL-2 expression [PMID:28607106], and it controls TCR-CD3 complex synthesis, surface turnover, and endocytosis — sequestering dynamin via its SH3 domain to inhibit clathrin-dependent and clathrin-independent endocytic pathways [PMID:17382318, PMID:31659016]. Through these activities UBASH3A is a genetically validated, T cell-intrinsic risk locus for type 1 diabetes, where risk alleles modulate its expression and splicing to tune IL-2 production [PMID:28607106, PMID:32694640, PMID:29491471], and it limits T cell-driven inflammation in models of arthritis and colitis [PMID:25047644, PMID:28972439].","teleology":[{"year":2001,"claim":"Established UBASH3A as a lymphoid-restricted multi-domain protein, defining the structural toolkit (SH3, UBA, novel domain) and expression pattern that would frame all later mechanistic work.","evidence":"cDNA cloning, RT-PCR tissue expression, and genomic/domain analysis","pmids":["11281453"],"confidence":"Medium","gaps":["No function assigned to the domains at this stage","Subcellular localization beyond a predicted NLS not demonstrated functionally"]},{"year":2004,"claim":"Defined the core physiological role: UBASH3A (with its paralog) negatively regulates TCR signaling by suppressing ZAP-70 phosphorylation, with loss producing autoimmunity-prone hyperresponsive T cells.","evidence":"Sts-1/Sts-2 double-knockout mice, T cell stimulation/phospho assays, cytokine measurement, EAE model","pmids":["14738763"],"confidence":"High","gaps":["Double-KO design does not separate UBASH3A-specific from paralog contribution","Mechanism of ZAP-70 suppression not resolved"]},{"year":2004,"claim":"Mapped the adaptor logic by showing the SH3 domain binds c-Cbl and the UBA domain binds ubiquitin, linking UBASH3A to receptor downregulation machinery.","evidence":"Affinity chromatography/MS, co-expression in 293T, functional assays in Jurkat cells (idx1); domain binding, Co-IP, endocytosis assays, PGM-mediated oligomerization (idx2)","pmids":["15107835","15159412"],"confidence":"High","gaps":["Effect on Cbl (degradation vs sequestration) directionally inconsistent across studies","Largely demonstrated on EGFR rather than TCR cargo"]},{"year":2007,"claim":"Showed UBASH3A inhibits endocytosis broadly by sequestering dynamin through its SH3 domain, distinguishing a dynamin-dependent mechanism from the Cbl/ubiquitin EGFR route.","evidence":"Multi-cargo endocytosis assays, reciprocal Co-IP, colocalization, dynamin overexpression rescue","pmids":["17382318"],"confidence":"High","gaps":["Relevance to TCR-CD3 trafficking not directly tested here","Stoichiometry of dynamin sequestration unknown"]},{"year":2007,"claim":"Extended the interactome beyond immune signaling, linking UBASH3A to ABCE-1 and a UBA-dependent block of HIV-1 particle production.","evidence":"MS identification of TULA-associated ABCE-1, HIV-1 production assays, UBA deletion mutants","pmids":["18006034"],"confidence":"Medium","gaps":["Single-lab finding outside the core T cell context","Direct UBASH3A-ABCE-1 binding not validated reciprocally"]},{"year":2008,"claim":"Reframed UBASH3A as a near-catalytically-inert phosphatase that acts as a dominant-negative on the active paralog, rather than as a direct enzyme.","evidence":"In vivo/in vitro phospho assays, dominant-negative overexpression, co-transfection (Syk readout)","pmids":["18189269"],"confidence":"Medium","gaps":["Dominant-negative mechanism inferred from overexpression","Endogenous relevance not established"]},{"year":2009,"claim":"Provided the structural and mechanistic basis for the phosphatase domain, identifying His366 as the catalytic nucleophile and the specific non-conserved residues that explain low activity versus STS-1.","evidence":"X-ray structures (apo, tungstate, phosphate, phospho-intermediate, vanadate), active-site mutagenesis, enzymatic assays","pmids":["19196006","19627098"],"confidence":"High","gaps":["Physiological substrate of UBASH3A PGM domain not defined","In-cell catalytic relevance unclear given low activity"]},{"year":2010,"claim":"Confirmed by unbiased screening that UBASH3A has no detectable intrinsic phosphatase activity, cementing that its function is interaction-driven.","evidence":"Combinatorial phosphotyrosyl peptide library screen with kinetics","pmids":["20670933"],"confidence":"High","gaps":["Cannot exclude activity on non-peptide or conformational substrates","Does not address whether catalysis matters in any cellular context"]},{"year":2011,"claim":"Pinned the weak residual activity and ZAP-70 phospho-regulation to specific specificity-determinant residues (Glu481/Ser552/Ser582), bridging structure to T cell phosphoregulation.","evidence":"In vitro phosphatase assays with phosphosubstrates, active-site mutagenesis, cell-based phospho analysis","pmids":["21393235"],"confidence":"High","gaps":["Whether weak activity contributes meaningfully to TCR signaling in vivo unresolved"]},{"year":2017,"claim":"Identified a distinct NF-κB-suppressing mechanism in human T cells and connected UBASH3A expression to T1D risk alleles and IL-2 output.","evidence":"Co-IP, ubiquitin-binding assays, siRNA, TCR stimulation and IL-2 analysis in primary CD4+ T cells; eQTL of risk alleles","pmids":["28607106"],"confidence":"High","gaps":["Direct binding partner among TAK1/NEMO/polyUb not biochemically dissected","How SH3/UBA domains engage the IKK complex unmapped"]},{"year":2017,"claim":"Confirmed in human protein that the histidine-phosphatase domain has much lower activity than STS-1 and that STS-1 (not STS-2) robustly dephosphorylates ZAP-70.","evidence":"Crystal structures of Sts-1HP/Sts-2HP, steady-state kinetics, cell-based ZAP-70 assay, inhibitor testing","pmids":["28759203"],"confidence":"High","gaps":["Reinforces that UBASH3A catalytic contribution to ZAP-70 control is minor","No direct UBASH3A enzymatic activity on ZAP-70 shown"]},{"year":2014,"claim":"Demonstrated in vivo that UBASH3A limits T cell-driven mucosal inflammation, with deletion exacerbating colitis via ZAP-70 phospho-regulation.","evidence":"Single/double KO mice, TNBS colitis model, T cell activation and ZAP-70 phospho analysis","pmids":["25047644"],"confidence":"Medium","gaps":["Single-lab in vivo study","UBASH3A-specific contribution partly confounded by paralog co-deletion"]},{"year":2017,"claim":"Showed the autoimmune phenotype is driven by enhanced effector T cell IL-2 production rather than Treg failure, in a collagen-induced arthritis model.","evidence":"CIA in STS-2 KO mice, intracellular cytokine staining, Treg suppression co-cultures","pmids":["28972439"],"confidence":"Medium","gaps":["Mechanism linking UBASH3A loss to IL-2 elevation not fully resolved at molecular level"]},{"year":2018,"claim":"Functionally validated a non-coding T1D variant as an expression/splicing regulator, showing reduced UBASH3A protein raises IL-2 secretion.","evidence":"Haplotype/allele-specific expression, RNA-seq, intron-retention quantification, TCR-stimulated IL-2 assays in primary CD4+ T cells","pmids":["29491471"],"confidence":"Medium","gaps":["Causal SNP among linked variants not isolated","Mechanism of intron-9 retention unknown"]},{"year":2019,"claim":"Established UBASH3A control over TCR-CD3 complex synthesis and surface turnover, and mapped CBL-B binding to the SH3 domain, broadening the adaptor interactome via MS.","evidence":"Expression modulation in Jurkat, flow cytometry of surface receptors, MS, Co-IP, domain mapping","pmids":["31659016"],"confidence":"High","gaps":["Mechanism connecting CBL-B binding to CD3 turnover not dissected","New MS associations (ERAD, recycling) not functionally validated"]},{"year":2020,"claim":"Proved the autoimmune effect is T cell-intrinsic by showing UBASH3A-deficient T cell transfer is sufficient to accelerate diabetes in NOD mice.","evidence":"ZFN KO in NOD mice, insulitis scoring, diabetes incidence, adoptive T cell transfer into NOD.Rag1−/−","pmids":["32694640"],"confidence":"High","gaps":["Does not identify which T cell subset/mechanism dominates the transferred phenotype"]},{"year":2022,"claim":"Defined upstream epigenetic control of UBASH3A via a super-enhancer (BACH2/MED1/BRD4, eRNAs) in disease-context CD4+ T cells, linking its dysregulation to TCR-induced IL-6.","evidence":"ChIP, LNA-mediated eRNA knockdown, RT-PCR/WB, overexpression, cytokine bead array in RA CD4+ T cells","pmids":["36324153"],"confidence":"Medium","gaps":["Causal chain from enhancer state to IL-6 not fully mapped","Single-lab disease-cohort study"]},{"year":2023,"claim":"Identified PTPN22 as a direct SH3-domain partner cooperating with UBASH3A to regulate IL-2, integrating two autoimmunity risk genes into one phospho-regulatory node.","evidence":"SH3-mediated Co-IP, domain mapping, RNA-seq of primary CD8+ T cells, statistical interaction analysis","pmids":["37240014"],"confidence":"Medium","gaps":["Functional consequence of the complex on specific substrates not shown","Cooperative IL-2 effect is correlative/transcriptomic"]},{"year":2024,"claim":"Extended UBASH3A function beyond lymphocytes to a tumor-suppressor role in erythroleukemia, controlled transcriptionally by an FLI1-GATA2 axis and acting in part through HSPA1B.","evidence":"shRNA knockdown, luciferase promoter assays, ChIP, RNA-seq, proliferation/apoptosis assays","pmids":["38461240"],"confidence":"Medium","gaps":["Mechanism by which UBASH3A induces HSPA1B unknown","Relationship to T cell adaptor function unclear"]},{"year":null,"claim":"How UBASH3A's distinct activities (NF-κB/IKK suppression, dynamin-dependent endocytosis, CD3 turnover, PTPN22/CBL-B scaffolding) are coordinated through its domains, and whether residual phosphatase activity matters physiologically, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated structural model of full-length UBASH3A engaging the IKK/ubiquitin machinery","Direct cellular substrate(s) of the PGM domain undefined","Domain-resolved dissection of which interaction drives the autoimmune IL-2 phenotype lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5,6,13]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,10,11,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,7,9,10]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[1,2,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,10,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,10,11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,9,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17,21]}],"complexes":["IKK complex (NEMO/TAK1-associated)"],"partners":["CBL","CBLB","DNM1","TAK1","NEMO","PTPN22","ABCE1","STS-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P57075","full_name":"Ubiquitin-associated and SH3 domain-containing protein A","aliases":["Cbl-interacting protein 4","CLIP4","Suppressor of T-cell receptor signaling 2","STS-2","T-cell ubiquitin ligand 1","TULA-1"],"length_aa":661,"mass_kda":74.1,"function":"Interferes with CBL-mediated down-regulation and degradation of receptor-type tyrosine kinases. Promotes accumulation of activated target receptors, such as T-cell receptors, EGFR and PDGFRB, on the cell surface. Exhibits negligible protein tyrosine phosphatase activity at neutral pH. May act as a dominant-negative regulator of UBASH3B-dependent dephosphorylation. May inhibit dynamin-dependent endocytic pathways by functionally sequestering dynamin via its SH3 domain","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P57075/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBASH3A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLASP1","stoichiometry":0.2},{"gene":"CLASP2","stoichiometry":0.2},{"gene":"PRKAA1","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBASH3A","total_profiled":1310},"omim":[{"mim_id":"609201","title":"UBIQUITIN-ASSOCIATED AND SH3 DOMAIN-CONTAINING PROTEIN B; UBASH3B","url":"https://www.omim.org/entry/609201"},{"mim_id":"605736","title":"UBIQUITIN-ASSOCIATED AND SH3 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protein is cleaved in infected cells and may sequester activated caspase-3 during persistent infection to suppress apoptosis.","date":"2019","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/31268416","citation_count":4,"is_preprint":false},{"pmid":"34320644","id":"PMC_34320644","title":"FREQUENT LEPTOSPIRA SPP. DETECTION BUT ABSENCE OF TULA ORTHOHANTAVIRUS IN MICROTUS SPP. VOLES, NORTHWESTERN SPAIN.","date":"2021","source":"Journal of wildlife diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34320644","citation_count":4,"is_preprint":false},{"pmid":"24587276","id":"PMC_24587276","title":"Enhanced response of T cells from murine gammaherpesvirus 68-infected mice lacking the suppressor of T cell receptor signaling molecules Sts-1 and Sts-2.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24587276","citation_count":4,"is_preprint":false},{"pmid":"31200661","id":"PMC_31200661","title":"Molecular evidence of Tula virus in Microtus obscurus in the region of Yili, Xinjiang, China.","date":"2019","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31200661","citation_count":4,"is_preprint":false},{"pmid":"36499237","id":"PMC_36499237","title":"TULA-Family Regulators of Platelet Activation.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36499237","citation_count":3,"is_preprint":false},{"pmid":"37298164","id":"PMC_37298164","title":"STS-1 and STS-2, Multi-Enzyme Proteins Equipped to Mediate Protein-Protein Interactions.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37298164","citation_count":3,"is_preprint":false},{"pmid":"38361825","id":"PMC_38361825","title":"Genome-wide support for incipient Tula hantavirus species within a single rodent host lineage.","date":"2024","source":"Virus evolution","url":"https://pubmed.ncbi.nlm.nih.gov/38361825","citation_count":2,"is_preprint":false},{"pmid":"38674019","id":"PMC_38674019","title":"Role of Tula-Family Proteins in Cell Signaling and Activation: Advances and Challenges.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38674019","citation_count":0,"is_preprint":false},{"pmid":"40707988","id":"PMC_40707988","title":"Exploring UBASH3A: from immune regulation to autoimmune diseases.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40707988","citation_count":0,"is_preprint":false},{"pmid":"41408597","id":"PMC_41408597","title":"Higher Promoter Methylation of the Ubiquitin-Associated and SH3 Domain Containing A (UBASH3A) Gene Is Associated With T-Lymphocyte Ontogeny and Reduced Susceptibility to Early-Onset Sepsis.","date":"2026","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41408597","citation_count":0,"is_preprint":false},{"pmid":"27192820","id":"PMC_27192820","title":"[TULA HANTAVIRUS IN CRIMEA].","date":"2015","source":"Molekuliarnaia genetika, mikrobiologiia i virusologiia","url":"https://pubmed.ncbi.nlm.nih.gov/27192820","citation_count":0,"is_preprint":false},{"pmid":"24738223","id":"PMC_24738223","title":"[Detection of Babesia canis (Piroplasmida) DNA in the blood samples and lysates of the ticks Dermacentor reticulatus (Ixodidae) collected in the Tula and Moscow Regions].","date":"2014","source":"Meditsinskaia parazitologiia i parazitarnye bolezni","url":"https://pubmed.ncbi.nlm.nih.gov/24738223","citation_count":0,"is_preprint":false},{"pmid":"17051036","id":"PMC_17051036","title":"Human papillomavirus 16/18 types among young women from tula (Russia).","date":"2003","source":"Journal of lower genital tract disease","url":"https://pubmed.ncbi.nlm.nih.gov/17051036","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.20.689437","title":"Hantavirus stability and inactivation","date":"2025-11-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.20.689437","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.15.654407","title":"Amplification-free Detection of Zoonotic Viruses Using Cas13 and Multiple CRISPR RNAs","date":"2025-05-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.15.654407","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.26.605237","title":"CD6 Regulates CD4 T Follicular Helper Cell Differentiation and Humoral Immunity During Murine Coronavirus Infection","date":"2024-07-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.26.605237","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45754,"output_tokens":5769,"usd":0.111898,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14328,"output_tokens":5799,"usd":0.108308,"stage2_stop_reason":"end_turn"},"total_usd":0.220206,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Sts-1 and Sts-2 (UBASH3A/STS-2 and its paralog) negatively regulate TCR signaling by suppressing ZAP-70 phosphorylation and activation; T cells from Sts-1/Sts-2 double-knockout mice are hyperresponsive to TCR stimulation with increased ZAP-70 phosphorylation, elevated cytokine production, and increased susceptibility to autoimmunity in a mouse EAE model.\",\n      \"method\": \"Genetic knockout (double KO mice), T cell stimulation assays, phosphorylation analysis, cytokine production measurement, EAE model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple defined cellular phenotypes, replicated across multiple readouts in a peer-reviewed study\",\n      \"pmids\": [\"14738763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TULA (UBASH3A/STS-2) binds to c-Cbl via its SH3 domain and to ubiquitin via its UBA domain; TULA inhibits c-Cbl-mediated downregulation of EGF receptor and upregulates ZAP-70 activity and NF-AT transcription factor activity in Jurkat T cells; the inhibitory effect on c-Cbl appears to involve TULA-induced ubiquitylation and degradation of c-Cbl.\",\n      \"method\": \"Affinity chromatography, mass spectrometry identification, co-expression in 293T cells, functional assays in Jurkat cells, modulation of TULA concentration\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification plus functional co-expression assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15107835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sts-2 (UBASH3A) contains an SH3 domain that interacts with Cbl, a UBA domain that binds directly to mono-ubiquitin or EGFR/Ub chimera, and a phosphoglycerate mutase (PGM) domain that mediates oligomerization; ligand-induced recruitment of Sts-2 into activated EGFR complexes inhibits receptor internalization, reduces EGFR-containing endocytic vesicles, and blocks receptor degradation, leading to prolonged mitogenic signaling.\",\n      \"method\": \"Co-immunoprecipitation, domain binding assays, endocytosis assays, fluorescence microscopy, dominant-negative interference\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, functional endocytosis assays with multiple readouts, consistent with independent findings in PMID:15107835\",\n      \"pmids\": [\"15159412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"UBASH3A encodes a 661-amino-acid protein containing SH3, UBA, and a novel domain with a nuclear localization signal; it is expressed primarily in spleen, peripheral blood leukocytes, and bone marrow; the gene spans 40 kb and is divided into 15 exons.\",\n      \"method\": \"cDNA cloning, RT-PCR expression analysis, sequence/domain analysis, genomic characterization\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization of gene/protein structure and tissue expression, single lab but multiple methods\",\n      \"pmids\": [\"11281453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The PGM/2H-phosphatase domain of Sts-2 (UBASH3A) is an acid-dependent phosphatase with a crystal structure remarkably similar to Sts-1; the catalytic mechanism involves a transiently phosphorylated nucleophilic histidine; non-conserved active site residues Gln372, Ala446, Glu481, Ser552, and Ser582 account for the substantially lower activity of Sts-2 compared to Sts-1.\",\n      \"method\": \"X-ray crystallography (apo, tungstate-bound, phosphate-bound structures), active site mutagenesis, enzymatic activity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures combined with mutagenesis and in vitro enzymatic assays in a single rigorous study\",\n      \"pmids\": [\"19196006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The phosphorylated intermediate and vanadate transition-state analogue structures of the Sts-2 PGM domain confirm His366 as the nucleophilic catalytic residue; the reaction mechanism is partially associative; Glu476 activates a uniquely positioned water molecule; the active site conformation does not change during dephosphorylation.\",\n      \"method\": \"X-ray crystallography of phosphorylated and VO3-bound enzyme forms\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures of catalytic intermediates providing direct mechanistic insight\",\n      \"pmids\": [\"19627098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sts-2 (UBASH3A) regulates tyrosine phosphorylation levels in T cells including on ZAP-70; the PGM domain of Sts-2 has clear but weak phosphatase activity; residues Glu-481, Ser-552, and Ser-582 are specificity determinants — mutation of these three residues to their Sts-1 counterparts substantially increases Sts-2(PGM) phosphatase activity.\",\n      \"method\": \"In vitro phosphatase assays with new phosphorylated substrates, active site mutagenesis, cell-based phosphorylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution combined with mutagenesis and cell-based assays, single lab but rigorous multi-method approach\",\n      \"pmids\": [\"21393235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TULA (UBASH3A/STS-2) has negligible phosphatase activity compared to TULA-2 (STS-1); overexpression of TULA increases Syk tyrosine phosphorylation in cells, acting as a dominant-negative inhibitor of endogenous TULA-2-mediated Syk dephosphorylation rather than as a direct phosphatase.\",\n      \"method\": \"In vivo and in vitro phosphorylation assays, dominant-negative overexpression, co-transfection experiments\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo assays combined, single lab, multiple approaches\",\n      \"pmids\": [\"18189269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TULA-1 (UBASH3A/STS-2) showed no detectable phosphatase activity toward any phosphotyrosyl peptides in a combinatorial library screen, confirming that its intrinsic enzymatic activity is negligible. TULA-2 (STS-1) showed clear substrate selectivity with two substrate classes.\",\n      \"method\": \"Combinatorial phosphotyrosyl peptide library screening, kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic combinatorial library screen with kinetic validation, rigorous negative result for UBASH3A phosphatase activity\",\n      \"pmids\": [\"20670933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TULA (UBASH3A) inhibits clathrin-dependent endocytosis (transferrin, LDL uptake) and clathrin-independent but dynamin-dependent endocytosis (CD59, MHC-I) by co-immunoprecipitating with and functionally sequestering dynamin via its SH3 domain binding proline-rich sequences in dynamin; overexpression of dynamin counteracted TULA-mediated inhibition of these pathways but did not rescue EGFR endocytosis (which operates via a distinct Cbl/ubiquitination mechanism).\",\n      \"method\": \"Endocytosis assays (transferrin, LDL, CD59, MHC-I, ricin uptake), co-immunoprecipitation, colocalization microscopy, dynamin overexpression rescue experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, co-localization, functional rescue experiments with multiple cargo types\",\n      \"pmids\": [\"17382318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBASH3A attenuates NF-κB signal transduction upon TCR stimulation in human T cells by specifically suppressing activation of the IκB kinase (IKK) complex; UBASH3A interacts with non-degradative polyubiquitin chains, TAK1, and NEMO, suggesting ubiquitin-dependent regulation of the NF-κB pathway; T1D risk alleles at rs11203203 and rs80054410 increase UBASH3A expression in primary CD4+ T cells upon TCR stimulation, thereby inhibiting NF-κB and reducing IL-2 expression.\",\n      \"method\": \"Protein-protein interaction studies (Co-IP), ubiquitin-binding assays, siRNA knockdown, TCR stimulation assays, IL-2 expression analysis in primary human CD4+ T cells\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction studies, functional knockdown/overexpression with defined molecular phenotypes, primary human T cells\",\n      \"pmids\": [\"28607106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBASH3A regulates TCR-CD3 complex synthesis and turnover in T cells: modulation of UBASH3A levels in Jurkat cells alters total cellular CD3 chains and cell-surface TCR-CD3 complexes (but not CD28 levels); upon TCR engagement, UBASH3A enhances TCR-CD3 downmodulation from the cell surface; mass spectrometry revealed novel UBASH3A associations with components of ER-associated protein degradation, cell motility, endocytosis, and endocytic recycling pathways; the SH3 domain of UBASH3A mediates binding to CBL-B E3 ubiquitin ligase.\",\n      \"method\": \"Modulation of UBASH3A expression in Jurkat cells, flow cytometry for surface receptor levels, mass spectrometry, protein-protein interaction studies, domain-mapping experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MS, Co-IP, flow cytometry, gain/loss of function) in a single focused study\",\n      \"pmids\": [\"31659016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TULA (UBASH3A) binds to ABCE-1 (RLI/HP68), a host factor of HIV-1 assembly, as identified by mass spectrometry; TULA proteins substantially inhibit production of both sub-genomic and full-length HIV-1 viral particles in a UBA domain-dependent manner; ABCE-1 recruits TULA to HIV-1 assembly sites where it interferes with late steps of HIV-1 life cycle.\",\n      \"method\": \"Mass spectrometry identification of TULA-associated proteins, HIV-1 production assays, UBA domain deletion mutant analysis\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus functional assays with domain mutants, single lab\",\n      \"pmids\": [\"18006034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The histidine phosphatase domains of human Sts-1 and Sts-2 were crystallized; Sts-2HP has significantly lower phosphatase activity than Sts-1HP in steady-state kinetic assays; Sts-1HP is a functional surrogate for full-length Sts-1; the SHP-1 inhibitor PHPS1 inhibits Sts-1 with Ki = 1.05 μM; human Sts-1 has robust phosphatase activity against ZAP-70 in cell-based assays.\",\n      \"method\": \"X-ray crystallography (Sts-1HP apo and sulfate-bound to 2.5/1.9 Å; Sts-2HP sulfate-bound to 2.4 Å), steady-state kinetics, cell-based ZAP-70 phosphatase assay, inhibitor testing\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures combined with kinetics and cell-based functional assays, single lab\",\n      \"pmids\": [\"28759203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Deletion of either or both TULA-family members (TULA/UBASH3A and TULA-2) in mice leads to exacerbated T-cell responses and inflammation in TNBS-induced colitis; both single and double KO exacerbate inflammation, with double KO having a greater effect; the mechanism involves regulation of ZAP-70 phosphorylation in T cells.\",\n      \"method\": \"Single and double knockout mice, TNBS-induced colitis model, T-cell activation assays, TCR signaling analysis (ZAP-70 phosphorylation)\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo and ex vivo functional readouts, single lab\",\n      \"pmids\": [\"25047644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STS-2 (UBASH3A) KO mice immunized with collagen develop arthritis more frequently than WT mice; STS-2 KO CD4+ T cells show increased IL-2 production upon TCR stimulation; STS-2 KO Tregs normally suppress T cell proliferation, suggesting the pro-arthritis phenotype is mediated by enhanced IL-2 production from effector T cells rather than impaired Treg function.\",\n      \"method\": \"Collagen-induced arthritis model in KO mice, intracellular cytokine staining, co-culture Treg suppression assays\",\n      \"journal\": \"Modern rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined cellular phenotype and mechanistic follow-up, single lab\",\n      \"pmids\": [\"28972439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBASH3A deficiency in NOD mice accelerates type 1 diabetes development and enhances salivary gland inflammation; adoptive transfer of UBASH3A-deficient splenic T cells into NOD.Rag1−/− mice was sufficient to promote T1D development, demonstrating that the UBASH3A effect is T cell-intrinsic.\",\n      \"method\": \"Zinc-finger nuclease-mediated KO in NOD mice, insulitis scoring, diabetes incidence monitoring, adoptive T cell transfer, flow cytometry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vivo disease phenotype confirmed by adoptive transfer establishing T cell-intrinsic mechanism\",\n      \"pmids\": [\"32694640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In CD4+ T cells from rheumatoid arthritis patients, UBASH3A transcription is suppressed via epigenetic regulation of a super-enhancer, involving accumulation of the silencing transcription factor BACH2 and absence of MED1/BRD4 at UBASH3A loci; knockdown of enhancer RNAs (eRNA_1 and eRNA_3) reduces UBASH3A mRNA; overexpression of UBASH3A in RA CD4+ T cells significantly inhibits TCR-induced IL-6 production.\",\n      \"method\": \"ChIP analysis, locked nucleic acid-mediated eRNA knockdown, RT-PCR/western blotting, UBASH3A plasmid overexpression, cytometric bead array for cytokines\",\n      \"journal\": \"Inflammation and regeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional gain/loss-of-function experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36324153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBASH3A physically interacts with PTPN22 via its SH3 domain in T cells; this interaction is not altered by the T1D risk coding variant rs2476601 in PTPN22; UBASH3A and PTPN22 transcript levels exert a cooperative effect on IL2 expression in human primary CD8+ T cells.\",\n      \"method\": \"Co-immunoprecipitation (SH3 domain-mediated), domain mapping, RNA-seq analysis of primary T cells, statistical interaction analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus transcriptomic functional evidence, single lab\",\n      \"pmids\": [\"37240014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBASH3A knockdown in erythroleukemic cells increases proliferation, associated with induction of HSPA1B (HSP70); UBASH3A acts as a tumor suppressor in erythroleukemia in part through activation of HSPA1B; FLI1 indirectly inhibits UBASH3A transcription via GATA2; UBASH3A is transcriptionally distinct from UBASH3B in the context of FLI1-driven leukemia.\",\n      \"method\": \"shRNA knockdown, luciferase promoter assays, ChIP, RNAseq, MTT proliferation assays, flow cytometry apoptosis assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD, promoter assays, ChIP, functional readouts) in a single study, single lab\",\n      \"pmids\": [\"38461240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD6 regulates UBASH3A expression in CD4+ T cells during murine coronavirus infection; CD6-deficient mice showed reduced infection-induced upregulation of UBASH3A in lymph nodes, associated with intensified TCR signal strength and greater T cell activation, suggesting that CD6 suppresses T cell activation in part by promoting UBASH3A expression.\",\n      \"method\": \"CD6 KO mouse model, gene expression analysis, TCR signal strength measurement, T cell activation assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, indirect evidence (expression correlation in KO context), single lab, no direct mechanistic manipulation of UBASH3A\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A non-coding T1D-associated variant rs1893592 in UBASH3A affects disease risk; its minor allele is associated with reduced overall UBASH3A mRNA levels and increased proportion of a low-abundance intron-9-retaining transcript that cannot produce full-length protein; this reduction leads to increased IL-2 secretion upon TCR stimulation in primary CD4+ T cells.\",\n      \"method\": \"Haplotype analysis, allele-specific expression in primary human CD4+ T cells, RNA-seq, TCR stimulation assays, IL-2 measurement\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional variant characterization in primary human T cells with multiple molecular readouts, single lab\",\n      \"pmids\": [\"29491471\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBASH3A (STS-2/TULA) is a lymphoid multi-domain adaptor/phosphatase protein that negatively regulates T cell activation by: (1) suppressing ZAP-70 phosphorylation and TCR-induced NF-κB signaling through interactions with polyubiquitin chains, TAK1, and NEMO at the IKK complex; (2) binding CBL-B (via its SH3 domain) and dynamin to inhibit receptor endocytosis and TCR-CD3 turnover; (3) binding ubiquitin via its UBA domain; and (4) acting as a weak phosphatase (negligible intrinsic enzymatic activity compared to its paralog TULA-2/STS-1) whose regulatory effects are instead largely mediated by protein-protein interactions — including with PTPN22 via its SH3 domain — that modulate proximal TCR signaling and IL-2 production.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBASH3A (STS-2/TULA) is a lymphoid-enriched multi-domain adaptor that negatively regulates proximal T cell receptor signaling and dampens T cell activation [#0, #3]. It restrains TCR-proximal kinases — suppressing ZAP-70 phosphorylation in T cells, with loss of UBASH3A producing hyperresponsive T cells, elevated cytokine output, and increased autoimmune susceptibility [#0, #6]. The protein is built from an SH3 domain that engages CBL-family E3 ligases (c-Cbl and CBL-B) and the phosphatase PTPN22, a UBA domain that binds mono- and poly-ubiquitin, and a histidine-phosphatase (PGM/2H) domain that oligomerizes [#2, #11, #18]. Although the PGM domain adopts a catalytically competent fold using a nucleophilic histidine (His366), its intrinsic phosphatase activity is negligible relative to its paralog STS-1/TULA-2, a difference traced to non-conserved active-site residues; consequently UBASH3A acts largely through protein-protein interactions rather than direct catalysis, and can behave as a dominant-negative against STS-1-mediated Syk/ZAP-70 dephosphorylation [#4, #6, #8, #7]. Mechanistically, UBASH3A attenuates TCR-induced NF-\\u03baB signaling by suppressing IKK complex activation through interactions with non-degradative polyubiquitin chains, TAK1, and NEMO, thereby lowering IL-2 expression [#10], and it controls TCR-CD3 complex synthesis, surface turnover, and endocytosis — sequestering dynamin via its SH3 domain to inhibit clathrin-dependent and clathrin-independent endocytic pathways [#9, #11]. Through these activities UBASH3A is a genetically validated, T cell-intrinsic risk locus for type 1 diabetes, where risk alleles modulate its expression and splicing to tune IL-2 production [#10, #16, #21], and it limits T cell-driven inflammation in models of arthritis and colitis [#14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established UBASH3A as a lymphoid-restricted multi-domain protein, defining the structural toolkit (SH3, UBA, novel domain) and expression pattern that would frame all later mechanistic work.\",\n      \"evidence\": \"cDNA cloning, RT-PCR tissue expression, and genomic/domain analysis\",\n      \"pmids\": [\"11281453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No function assigned to the domains at this stage\", \"Subcellular localization beyond a predicted NLS not demonstrated functionally\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the core physiological role: UBASH3A (with its paralog) negatively regulates TCR signaling by suppressing ZAP-70 phosphorylation, with loss producing autoimmunity-prone hyperresponsive T cells.\",\n      \"evidence\": \"Sts-1/Sts-2 double-knockout mice, T cell stimulation/phospho assays, cytokine measurement, EAE model\",\n      \"pmids\": [\"14738763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Double-KO design does not separate UBASH3A-specific from paralog contribution\", \"Mechanism of ZAP-70 suppression not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the adaptor logic by showing the SH3 domain binds c-Cbl and the UBA domain binds ubiquitin, linking UBASH3A to receptor downregulation machinery.\",\n      \"evidence\": \"Affinity chromatography/MS, co-expression in 293T, functional assays in Jurkat cells (idx1); domain binding, Co-IP, endocytosis assays, PGM-mediated oligomerization (idx2)\",\n      \"pmids\": [\"15107835\", \"15159412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect on Cbl (degradation vs sequestration) directionally inconsistent across studies\", \"Largely demonstrated on EGFR rather than TCR cargo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed UBASH3A inhibits endocytosis broadly by sequestering dynamin through its SH3 domain, distinguishing a dynamin-dependent mechanism from the Cbl/ubiquitin EGFR route.\",\n      \"evidence\": \"Multi-cargo endocytosis assays, reciprocal Co-IP, colocalization, dynamin overexpression rescue\",\n      \"pmids\": [\"17382318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to TCR-CD3 trafficking not directly tested here\", \"Stoichiometry of dynamin sequestration unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended the interactome beyond immune signaling, linking UBASH3A to ABCE-1 and a UBA-dependent block of HIV-1 particle production.\",\n      \"evidence\": \"MS identification of TULA-associated ABCE-1, HIV-1 production assays, UBA deletion mutants\",\n      \"pmids\": [\"18006034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding outside the core T cell context\", \"Direct UBASH3A-ABCE-1 binding not validated reciprocally\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reframed UBASH3A as a near-catalytically-inert phosphatase that acts as a dominant-negative on the active paralog, rather than as a direct enzyme.\",\n      \"evidence\": \"In vivo/in vitro phospho assays, dominant-negative overexpression, co-transfection (Syk readout)\",\n      \"pmids\": [\"18189269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative mechanism inferred from overexpression\", \"Endogenous relevance not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the structural and mechanistic basis for the phosphatase domain, identifying His366 as the catalytic nucleophile and the specific non-conserved residues that explain low activity versus STS-1.\",\n      \"evidence\": \"X-ray structures (apo, tungstate, phosphate, phospho-intermediate, vanadate), active-site mutagenesis, enzymatic assays\",\n      \"pmids\": [\"19196006\", \"19627098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate of UBASH3A PGM domain not defined\", \"In-cell catalytic relevance unclear given low activity\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirmed by unbiased screening that UBASH3A has no detectable intrinsic phosphatase activity, cementing that its function is interaction-driven.\",\n      \"evidence\": \"Combinatorial phosphotyrosyl peptide library screen with kinetics\",\n      \"pmids\": [\"20670933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cannot exclude activity on non-peptide or conformational substrates\", \"Does not address whether catalysis matters in any cellular context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Pinned the weak residual activity and ZAP-70 phospho-regulation to specific specificity-determinant residues (Glu481/Ser552/Ser582), bridging structure to T cell phosphoregulation.\",\n      \"evidence\": \"In vitro phosphatase assays with phosphosubstrates, active-site mutagenesis, cell-based phospho analysis\",\n      \"pmids\": [\"21393235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether weak activity contributes meaningfully to TCR signaling in vivo unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a distinct NF-\\u03baB-suppressing mechanism in human T cells and connected UBASH3A expression to T1D risk alleles and IL-2 output.\",\n      \"evidence\": \"Co-IP, ubiquitin-binding assays, siRNA, TCR stimulation and IL-2 analysis in primary CD4+ T cells; eQTL of risk alleles\",\n      \"pmids\": [\"28607106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner among TAK1/NEMO/polyUb not biochemically dissected\", \"How SH3/UBA domains engage the IKK complex unmapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed in human protein that the histidine-phosphatase domain has much lower activity than STS-1 and that STS-1 (not STS-2) robustly dephosphorylates ZAP-70.\",\n      \"evidence\": \"Crystal structures of Sts-1HP/Sts-2HP, steady-state kinetics, cell-based ZAP-70 assay, inhibitor testing\",\n      \"pmids\": [\"28759203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reinforces that UBASH3A catalytic contribution to ZAP-70 control is minor\", \"No direct UBASH3A enzymatic activity on ZAP-70 shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated in vivo that UBASH3A limits T cell-driven mucosal inflammation, with deletion exacerbating colitis via ZAP-70 phospho-regulation.\",\n      \"evidence\": \"Single/double KO mice, TNBS colitis model, T cell activation and ZAP-70 phospho analysis\",\n      \"pmids\": [\"25047644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vivo study\", \"UBASH3A-specific contribution partly confounded by paralog co-deletion\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the autoimmune phenotype is driven by enhanced effector T cell IL-2 production rather than Treg failure, in a collagen-induced arthritis model.\",\n      \"evidence\": \"CIA in STS-2 KO mice, intracellular cytokine staining, Treg suppression co-cultures\",\n      \"pmids\": [\"28972439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking UBASH3A loss to IL-2 elevation not fully resolved at molecular level\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Functionally validated a non-coding T1D variant as an expression/splicing regulator, showing reduced UBASH3A protein raises IL-2 secretion.\",\n      \"evidence\": \"Haplotype/allele-specific expression, RNA-seq, intron-retention quantification, TCR-stimulated IL-2 assays in primary CD4+ T cells\",\n      \"pmids\": [\"29491471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal SNP among linked variants not isolated\", \"Mechanism of intron-9 retention unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established UBASH3A control over TCR-CD3 complex synthesis and surface turnover, and mapped CBL-B binding to the SH3 domain, broadening the adaptor interactome via MS.\",\n      \"evidence\": \"Expression modulation in Jurkat, flow cytometry of surface receptors, MS, Co-IP, domain mapping\",\n      \"pmids\": [\"31659016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting CBL-B binding to CD3 turnover not dissected\", \"New MS associations (ERAD, recycling) not functionally validated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proved the autoimmune effect is T cell-intrinsic by showing UBASH3A-deficient T cell transfer is sufficient to accelerate diabetes in NOD mice.\",\n      \"evidence\": \"ZFN KO in NOD mice, insulitis scoring, diabetes incidence, adoptive T cell transfer into NOD.Rag1\\u2212/\\u2212\",\n      \"pmids\": [\"32694640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify which T cell subset/mechanism dominates the transferred phenotype\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined upstream epigenetic control of UBASH3A via a super-enhancer (BACH2/MED1/BRD4, eRNAs) in disease-context CD4+ T cells, linking its dysregulation to TCR-induced IL-6.\",\n      \"evidence\": \"ChIP, LNA-mediated eRNA knockdown, RT-PCR/WB, overexpression, cytokine bead array in RA CD4+ T cells\",\n      \"pmids\": [\"36324153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from enhancer state to IL-6 not fully mapped\", \"Single-lab disease-cohort study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PTPN22 as a direct SH3-domain partner cooperating with UBASH3A to regulate IL-2, integrating two autoimmunity risk genes into one phospho-regulatory node.\",\n      \"evidence\": \"SH3-mediated Co-IP, domain mapping, RNA-seq of primary CD8+ T cells, statistical interaction analysis\",\n      \"pmids\": [\"37240014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the complex on specific substrates not shown\", \"Cooperative IL-2 effect is correlative/transcriptomic\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended UBASH3A function beyond lymphocytes to a tumor-suppressor role in erythroleukemia, controlled transcriptionally by an FLI1-GATA2 axis and acting in part through HSPA1B.\",\n      \"evidence\": \"shRNA knockdown, luciferase promoter assays, ChIP, RNA-seq, proliferation/apoptosis assays\",\n      \"pmids\": [\"38461240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which UBASH3A induces HSPA1B unknown\", \"Relationship to T cell adaptor function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBASH3A's distinct activities (NF-\\u03baB/IKK suppression, dynamin-dependent endocytosis, CD3 turnover, PTPN22/CBL-B scaffolding) are coordinated through its domains, and whether residual phosphatase activity matters physiologically, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated structural model of full-length UBASH3A engaging the IKK/ubiquitin machinery\", \"Direct cellular substrate(s) of the PGM domain undefined\", \"Domain-resolved dissection of which interaction drives the autoimmune IL-2 phenotype lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5, 6, 13]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 10, 11, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7, 9, 10]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [1, 2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 10, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 10, 11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 9, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 21]}\n    ],\n    \"complexes\": [\"IKK complex (NEMO/TAK1-associated)\"],\n    \"partners\": [\"CBL\", \"CBLB\", \"DNM1\", \"TAK1\", \"NEMO\", \"PTPN22\", \"ABCE1\", \"STS-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}