{"gene":"UXT","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2002,"finding":"ART-27 (UXT) was identified as a coactivator that interacts predominantly with the AR N-terminal region containing AF-1a (AR residues 153-336), localizes to the nucleus, and increases AR transcriptional activity when overexpressed. ART-27 interacts with AR in nuclear extracts from LNCaP cells in a ligand-independent manner. Native ART-27 is part of a multiprotein complex as shown by velocity gradient sedimentation of HeLa nuclear extracts.","method":"Yeast two-hybrid, co-immunoprecipitation from nuclear extracts, overexpression in mammalian cells, LexA fusion transcriptional assays, velocity gradient sedimentation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods (Y2H, nuclear extract Co-IP, sedimentation, transcriptional assays), replicated by subsequent studies","pmids":["11854421"],"is_preprint":false},{"year":2004,"finding":"ART-27 (UXT) expression in LNCaP prostate cancer cells inhibits androgen-mediated cellular proliferation while enhancing androgen-mediated transcription of the PSA gene, establishing a growth-suppressive and differentiation-promoting function for ART-27 as an AR cofactor.","method":"Regulated expression (inducible overexpression) in LNCaP cells with proliferation and PSA transcription readouts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gain-of-function in defined cell line with two orthogonal phenotypic readouts (proliferation and PSA transcription), single lab","pmids":["14711828"],"is_preprint":false},{"year":2005,"finding":"Naturally occurring AR mutations from prostate cancer (AR P340L) and androgen insensitivity syndrome (AR E2K) show reduced transcriptional responses to ART-27 coactivation. AR E2K shows reduced ART-27 protein association by co-immunoprecipitation, while AR P340L shows increased ART-27 association despite reduced transcriptional activation, indicating that aberrant AR–ART-27 physical interaction interferes with normal coactivator function.","method":"Transcriptional reporter assays, co-immunoprecipitation, AR mutation analysis","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP combined with functional transcriptional assays using specific point mutants, single lab","pmids":["15919721"],"is_preprint":false},{"year":2005,"finding":"UXT localizes to centrosomes and is associated with gamma-tubulin. Overexpression of UXT disrupts centrosome structure, and siRNA-mediated knockdown of UXT leads to cell death, establishing UXT as a centrosomal component essential for cell viability.","method":"Immunofluorescence, co-immunoprecipitation with gamma-tubulin, siRNA knockdown, overexpression studies","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (knockdown lethality, overexpression centrosome disruption), single lab, two orthogonal methods","pmids":["16221885"],"is_preprint":false},{"year":2007,"finding":"UXT (specifically the V2 isoform) is expressed predominantly in the nucleus and interacts specifically with NF-κB inside the nucleus. UXT is recruited to the NF-κB enhanceosome upon stimulation and forms a dynamic complex with NF-κB. RNAi knockdown of UXT impairs NF-κB transcriptional activity, attenuates NF-κB-dependent gene expression, and sensitizes cells to TNF-alpha-induced apoptosis.","method":"Yeast two-hybrid, co-immunoprecipitation, RNAi knockdown, reporter assays, chromatin immunoprecipitation-like enhanceosome recruitment assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, RNAi + gene expression, apoptosis assay), replicated in subsequent studies","pmids":["17620405"],"is_preprint":false},{"year":2007,"finding":"UXT interacts with the EVI1 transcriptional repressor through EVI1's repressor domain (Rp). Enforced UXT expression suppresses EVI1-induced cell transformation in Rat1 fibroblasts. Evi1 mutants lacking the UXT-binding site (Evi1Δ706-707) produce larger transformation colonies, indicating that endogenous UXT inhibits EVI1 biological activity.","method":"Yeast two-hybrid, colony formation assay, Evi1 deletion mutants, Rat1 fibroblast transformation assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus functional transformation assay with deletion mutants demonstrating domain specificity, single lab","pmids":["17635584"],"is_preprint":false},{"year":2007,"finding":"When overexpressed, GFP-tagged UXT localizes progressively from extranuclear cytosol to punctate cytosolic dots to perinuclear aggregates, coinciding with aggregation of mitochondria and LRPPRC, leading to mitochondrial aggregation and cell death. UXT was identified as a component of mitochondria-associated LRPPRC complex.","method":"GFP-UXT overexpression, fluorescence microscopy, co-localization with mitochondria and LRPPRC","journal":"In vitro cellular & developmental biology. Animal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression artifact possible, co-localization without biochemical confirmation of interaction","pmids":["17554592"],"is_preprint":false},{"year":2011,"finding":"UXT-V1 isoform localizes in the cytoplasm (in contrast to nuclear V2) and is a component of the TNF receptor signaling complex. UXT-V1 binds TRAF2 and prevents TRADD from recruiting FADD, thereby blocking formation of the apoptotic complex II. UXT-V1 is a short-half-life protein whose degradation facilitates complex II formation in response to TNF treatment.","method":"Subcellular fractionation, co-immunoprecipitation, siRNA knockdown, cycloheximide chase, apoptosis assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, Co-IP, knockdown, protein stability assay), clear mechanistic model with specific binding partner identification","pmids":["21307340"],"is_preprint":false},{"year":2011,"finding":"UXT-V1 is a novel TRAF3-binding protein that facilitates the interaction between TRAF3 and MAVS on mitochondria. The N-terminal TRAF-binding motif of UXT-V1 binds the C-terminal TRAF domain of TRAF3. UXT-V1 knockdown impairs virus-induced activation of NF-κB and IRF3, attenuates IFN-β induction, and blocks TRAF3 and TRADD recruitment to mitochondria upon virus infection.","method":"Co-immunoprecipitation, siRNA knockdown, reporter assays, mitochondrial fractionation, domain mapping","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-level binding mapped, multiple orthogonal methods (Co-IP, fractionation, knockdown with functional readouts), single lab","pmids":["22131337"],"is_preprint":false},{"year":2012,"finding":"EBV BGLF4 kinase phosphorylates UXT at Thr3. This phosphorylation interferes with the interaction between UXT and NF-κB, reducing NF-κB enhanceosome activity and downregulating NF-κB-dependent gene expression. Knockdown of UXT in EBV-positive NA cells induced spontaneous lytic cycle, demonstrating UXT is required for maintenance of EBV latency. Wild-type but not phosphorylation-deficient UXT enhanced lytic protein expression.","method":"In vitro kinase assay, site-directed mutagenesis (Thr3), co-immunoprecipitation, reporter assays, lentiviral shRNA knockdown","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay establishing phosphorylation site, mutagenesis of phosphosite with functional validation, multiple biological readouts","pmids":["22933289"],"is_preprint":false},{"year":2013,"finding":"VHL interacts with UXT as identified by yeast two-hybrid and confirmed by GST pull-down and co-immunoprecipitation. UXT recruits VHL to the nucleus. VHL associates with the DNA-binding domain and hinge domain of AR and induces AR ubiquitination. VHL interaction with AR activates AR transactivation upon DHT treatment; VHL knockdown inhibits AR ubiquitination and decreases AR transcriptional activation.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, ubiquitination assay, AR reporter assay, siRNA knockdown","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (Y2H, pull-down, Co-IP, ubiquitination, reporter), single lab","pmids":["23961993"],"is_preprint":false},{"year":2013,"finding":"UXT interacts with SARM via yeast two-hybrid analysis. The two UXT isoforms have opposing effects on SARM-induced apoptosis: UXT-V1 co-expressed with SARM reduces caspase 8 activity, while UXT-V2 strongly increases caspase 8 activity and enhances SARM-induced apoptosis by activating the extrinsic pathway and depolarizing mitochondria.","method":"Yeast two-hybrid, caspase 8 activity assay, mitochondrial membrane potential assay, overexpression of isoforms","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H plus functional isoform comparison with enzymatic readout, single lab, limited binding confirmation","pmids":["24021647"],"is_preprint":false},{"year":2013,"finding":"UXT associates with Foxp3 in the nucleus of human regulatory T cells, interacting with the proline-rich domain in the N-terminus of Foxp3. UXT knockdown in Treg cells results in a less-suppressive phenotype, affects nuclear localization stability of Foxp3, and downregulates Foxp3-related gene expression.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, suppression functional assays, immunofluorescence","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus functional knockdown phenotype, single lab","pmids":["24136450"],"is_preprint":false},{"year":2015,"finding":"UXT attenuates Notch signaling by binding to promoters of Notch-responsive genes and specifically interacting with the transactivation domain of the Notch intracellular domain (NICD), thereby impairing the interaction between NICD and the transcription factor RBP-Jκ. UXT knockdown in zebrafish results in shorter intersegmental vessels, loss of tip cell behavior, and impaired endothelial cell migration and division; blockade of Notch signaling rescues these defects.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (promoter binding), siRNA/morpholino knockdown in zebrafish, reporter assays, rescue experiments","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, in vivo knockdown with rescue), mechanistic pathway placement via epistasis","pmids":["25617435"],"is_preprint":false},{"year":2015,"finding":"UXT binds MDMX and suppresses basal p53 activity. UXT-mediated p53 inhibition results in NF-κB activation leading to induction of glycolysis. UXT acts as an oncogene promoting cell proliferation in vitro and tumor progression in vivo in sarcoma cells.","method":"Co-immunoprecipitation (UXT–MDMX interaction), pathway reporter screen, siRNA knockdown, overexpression, xenograft tumor model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding partner, functional knockdown/OE with pathway readouts, single lab","pmids":["25974965"],"is_preprint":false},{"year":2016,"finding":"EZH1 physically interacts with UXT, and also with SUZ12 but not EED. Knockdown of EZH1 or SUZ12 impairs NF-κB target gene transcriptional activation induced by TNFα, similar to UXT knockdown. EZH1 and SUZ12 regulate recruitment of p65 and RNA Pol II to NF-κB target genes without affecting H3K27 methylation or p65 nuclear translocation, acting synergistically with UXT.","method":"Co-immunoprecipitation, siRNA knockdown, chromatin immunoprecipitation with next-generation sequencing, reporter assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP-seq plus functional knockdown, single lab, multiple orthogonal methods","pmids":["27127229"],"is_preprint":false},{"year":2017,"finding":"UXT was identified as a LOX-PP interacting protein. UXT associates with estrogen receptor alpha (ER) and decreases ER transcriptional activity and target gene expression. LOX-PP interaction relocalizes UXT to the cytoplasm, promotes UXT ubiquitination, and decreases UXT stability via proteasomal degradation, releasing repression of ER transcriptional activity.","method":"Yeast two-hybrid, co-immunoprecipitation (UXT–ER, UXT–LOX-PP), proteasome inhibitor rescue, subcellular fractionation, ER reporter assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, proteasome inhibitor rescue, reporter assays), single lab","pmids":["28106301"],"is_preprint":false},{"year":2018,"finding":"Constitutive deletion of Uxt in mice is embryonic lethal. Conditional knockout of Uxt in the male germline results in a Sertoli cell-only phenotype during the first wave of spermatogenesis, manifesting between 6 and 7 days post-partum before meiotic entry. Gene expression analysis revealed that Uxt deletion downregulates transcription of genes governing SSC self-renewal, differentiation, and meiosis.","method":"Conditional knockout mouse model, histology, gene expression analysis (RNA-seq), immunofluorescence","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with defined phenotype, gene expression analysis revealing mechanism, consistent with known transcriptional cofactor role","pmids":["29649254"],"is_preprint":false},{"year":2018,"finding":"In prostate cells, URI is tightly bound to UXT; together they form a multiprotein complex acting as transcriptional repressors. URI regulates KAP1 through PP2A phosphatase activity, and the URI/UXT complex interacts with AR, KAP1, and PP2A.","method":"Co-immunoprecipitation, protein complex characterization","journal":"Advances in experimental medicine and biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review chapter describing interactions without original experimental detail in abstract, single context","pmids":["30484154"],"is_preprint":false},{"year":2019,"finding":"Prostate-specific conditional knockout of Uxt in mice led to a hyperplastic phenotype with prostate secretion fluid blockage and PIN by 4–6 months; doubly mutant Uxt/Pten mice developed more aggressive PIN. UXT depletion in prostate cancer cells increased retroelement expression (LINE-1, Alu) and retrotransposition activity, and accumulated DNA damage.","method":"Prostate-specific conditional knockout mouse, tissue microarray, retrotransposition assay, DNA damage markers","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with multiple phenotypic readouts, functional assays in cells, single lab","pmids":["30774773"],"is_preprint":false},{"year":2020,"finding":"Conditional knockout of Uxt in Sertoli cells results in smaller testes, loss of germ cells in a subset of seminiferous tubules, and reduced transcription of genes involved in tight junctions of the blood-testis barrier (BTB). Tracer experiments and electron microscopy confirmed that the BTB is permeable in Sertoli-specific UXT KO animals.","method":"Sertoli cell-specific conditional knockout, gene expression analysis, tracer permeability assay, electron microscopy","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with structural (EM) and functional (tracer) validation of BTB permeability, multiple orthogonal methods","pmids":["32678429"],"is_preprint":false},{"year":2020,"finding":"Conditional knockout of Uxt in mice leads to retinal degeneration resembling retinitis pigmentosa, including progressive reduction of photoreceptors, increased apoptotic cells, and impaired ERG responses. Mechanistically, UXT suppresses photoreceptor apoptotic cell death by inhibiting autophagy through regulation of MTOR activity; UXT KO leads to enhanced autophagic flux and apoptosis.","method":"Conditional knockout mouse, ERG, TUNEL assay, autophagic flux measurement, MTOR activity assay, RNA-seq","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with multiple orthogonal functional readouts (ERG, TUNEL, autophagic flux, MTOR activity), single lab","pmids":["32744119"],"is_preprint":false},{"year":2020,"finding":"SCF(Fbxo7) E3 ubiquitin ligase mediates polyubiquitination of UXT-V2 (with both K48 and K63 linkages), promoting its proteasomal degradation. The Ubl domain of Fbxo7 contributes to interaction with UXT-V2. UXT-V1 also interacts with and is ubiquitinated by Fbxo7. FBXO7 knockdown causes UXT-V2 accumulation and enhanced NF-κB reporter activity; Fbxo7-ΔF-box overexpression protects UXT-V2 from degradation.","method":"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, cycloheximide chase, ubiquitin chain restriction analysis, siRNA knockdown, reporter assay","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstitution plus in vivo validation, domain mapping, multiple orthogonal methods including chain linkage analysis","pmids":["33010352"],"is_preprint":false},{"year":2021,"finding":"UXT was identified as an interacting protein of p62/SQSTM1 via yeast two-hybrid. UXT binds both protein aggregates and the LB domain of p62, and forms oligomers that increase p62 clustering, promoting efficient targeting to protein aggregates and clearance via autophagy (aggrephagy). Ectopic expression of human UXT delays SOD1(A4V)-induced motor neuron degeneration in Xenopus; disruption of the UXT–p62 interaction suppresses this protection.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro aggregate binding assay, Xenopus in vivo model, UXT–p62 interaction disruption mutants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Y2H plus Co-IP plus in vitro binding plus in vivo rescue with interaction-disrupting mutants, multiple orthogonal methods","pmids":["33782410"],"is_preprint":false},{"year":2021,"finding":"UXT was identified as a novel TSG101 interaction partner associated with TSG101-containing cytoplasmic vesicles by co-immunoprecipitation. UXT depletion promoted TSG101 vesicle–lysosome association and elevated autophagic carrier flux, enhancing CEP55 degradation through the lysosome pathway upon TSG101 overexpression. UXT plays a role in late endosome/autophagosome–lysosome fusion.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, lysosome inhibitor experiments","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus knockdown phenotype, single lab, limited mechanistic follow-up","pmids":["33486193"],"is_preprint":false},{"year":2021,"finding":"UXT interacts with DNMT3b (confirmed by co-immunoprecipitation) and inhibits lncRNA MEG3 expression by recruiting DNMT3b to the MEG3 imprinting control region, promoting hypermethylation. This negatively regulates the MEG3/p53 axis to promote breast cancer cell proliferation and tumor growth in a DNMT3b-dependent manner.","method":"Co-immunoprecipitation, methylation-specific PCR, RNA immunoprecipitation, xenograft tumor model, siRNA knockdown","journal":"Molecular therapy oncolytics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS-PCR for methylation plus xenograft, multiple orthogonal methods, single lab","pmids":["35229028"],"is_preprint":false},{"year":2022,"finding":"UXT interacts with STING1 upon DNA mimic or cGAMP stimulation and promotes STING1 degradation through selective macroautophagy. UXT facilitates the interaction between SQSTM1/p62 and STING1 to enhance autophagic degradation of STING1. In vivo, UXT deficiency leads to enhanced cGAS-STING1 signaling in a DNA-virus infection mouse model and a TMPD-induced murine lupus model.","method":"Co-immunoprecipitation, autophagy inhibitor experiments, conditional knockout mouse models (DNA-virus infection, TMPD-lupus), PBMC functional assays, RNA-seq","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, multiple in vivo mouse models, human PBMC validation, multiple orthogonal methods, single lab with comprehensive mechanistic characterization","pmids":["35543189"],"is_preprint":false},{"year":2023,"finding":"UXT acts as a repressor of SENP1 expression. MYB upregulates SENP1 while inhibiting UXT expression. By repressing SENP1, UXT affects the global SUMO landscape; reduced UXT leads to increased SENP1 activity, decreased SUMOylation of MYB targets, and autoactivation of MYB. UXT was identified as a novel SENP1 interaction partner by mapping of SENP1 interaction partners.","method":"RNA-seq after MYB knockdown/rescue with SUMO mutants, interactome mapping of SENP1, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction partner identification without deep biochemical characterization of UXT–SENP1 mechanism in abstract, single lab","pmids":["37468105"],"is_preprint":false},{"year":2025,"finding":"UXT forms hexameric and higher-order oligomeric structures (via β-hairpin-mediated assembly of hexamers) that are essential for its function as an autophagy adaptor. The high-order oligomer of UXT is required for efficient clearance of SOD1(A4V) aggregates both in vitro and in vivo. Disruption of high-order oligomerization abolishes UXT's ability to promote aggregate clearance.","method":"In silico structural homology modeling, in vitro aggregate clearance assays, in vivo Xenopus model with oligomerization-disrupting mutants","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural modeling plus in vitro and in vivo functional validation with mutants, single lab","pmids":["40092611"],"is_preprint":false},{"year":2025,"finding":"UXT-V2 restricts HSV-2 replication by facilitating K48-linked ubiquitination of the viral glycoprotein B (gB), targeting it for proteasomal degradation. UXT-V2 interacts with gB and recruits the E3 ligase TRIM21 to ubiquitinate gB. This anti-viral function is independent of UXT-V2's role in NF-κB regulation.","method":"Knockout/overexpression of UXT-V2, co-immunoprecipitation (UXT-V2–gB, UXT-V2–TRIM21), ubiquitination assay (K48 linkage), proteasome inhibitor rescue, viral replication assay","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding partners, ubiquitination assay with linkage specificity, KO plus OE with viral replication readout, single lab","pmids":["40907749"],"is_preprint":false}],"current_model":"UXT (ART-27) is a prefoldin-like chaperone/coactivator that functions in multiple cellular compartments: in the nucleus it acts as a transcriptional cofactor for AR (via AF-1a binding), NF-κB (as an essential enhanceosome component regulated by EBV BGLF4-mediated phosphorylation at Thr3 and by SCF(Fbxo7)-mediated proteasomal degradation), Foxp3 in Tregs, and the Notch repressor pathway (by directly binding NICD and blocking RBP-Jκ activation); in the cytoplasm, its V1 isoform joins the TNF receptor signaling complex by binding TRAF2 to prevent FADD recruitment and complex II formation, and its V1 isoform also facilitates MAVS–TRAF3 complex assembly on mitochondria for antiviral signaling; in the autophagy pathway, UXT forms high-order oligomers that act as an adaptor bridging ubiquitinated protein aggregates to p62/SQSTM1 for aggrephagy, and separately promotes autophagic degradation of STING1 via SQSTM1 to dampen innate immune signaling; additionally, UXT-V2 recruits TRIM21 to direct K48-ubiquitination and proteasomal degradation of HSV-2 glycoprotein B; and in vivo, UXT is essential for spermatogenesis, blood-testis barrier integrity, and retinal photoreceptor survival through regulation of MTOR-dependent autophagy."},"narrative":{"mechanistic_narrative":"UXT (ART-27) is a small prefoldin-like protein that functions as a context-dependent transcriptional cofactor and chaperone-adaptor, partitioning between the nucleus and cytoplasm in two isoforms (nuclear V2, cytoplasmic V1) to regulate hormone signaling, innate immunity, and selective autophagy [PMID:11854421, PMID:17620405, PMID:21307340]. In the nucleus it was first defined as an androgen receptor coactivator binding the AR N-terminal AF-1a region and enhancing AR-driven transcription while suppressing androgen-mediated proliferation [PMID:11854421, PMID:14711828], and it more broadly modulates transcription factor activity by interacting with NF-κB as an essential, recruitable enhanceosome component [PMID:17620405], with Foxp3 to stabilize regulatory T cell suppressive function [PMID:24136450], and with the Notch intracellular domain to block NICD–RBP-Jκ activation [PMID:25617435]. Its activity as an NF-κB cofactor is tuned by post-translational control: EBV BGLF4 kinase phosphorylates UXT at Thr3 to disrupt the UXT–NF-κB interaction and maintain viral latency [PMID:22933289], and SCF(Fbxo7) ubiquitinates UXT-V2 to drive its proteasomal turnover [PMID:33010352]. In the cytoplasm, UXT-V1 enters TNF receptor signaling by binding TRAF2 to prevent FADD recruitment and apoptotic complex II formation [PMID:21307340], and bridges TRAF3 to MAVS on mitochondria to enable antiviral IFN-β induction [PMID:22131337]. UXT also acts as a selective autophagy adaptor, forming β-hairpin-mediated higher-order oligomers that cluster ubiquitinated aggregates with p62/SQSTM1 for aggrephagy [PMID:33782410, PMID:40092611] and directing SQSTM1-dependent autophagic degradation of STING1 to dampen cGAS-STING innate signaling [PMID:35543189]. In vivo, conditional Uxt deletion is embryonic lethal and demonstrates essential roles in spermatogenesis and blood-testis-barrier integrity [PMID:29649254, PMID:32678429] and in photoreceptor survival via MTOR-dependent restraint of autophagy [PMID:32744119].","teleology":[{"year":2002,"claim":"Established UXT as a nuclear androgen receptor coactivator, defining its founding identity as a transcriptional cofactor rather than an orphan protein.","evidence":"Y2H, nuclear-extract Co-IP, transcriptional reporter assays and velocity gradient sedimentation in LNCaP/HeLa cells","pmids":["11854421"],"confidence":"High","gaps":["Identity of the multiprotein complex members unresolved","Mechanism by which UXT enhances AR transactivation not defined"]},{"year":2004,"claim":"Showed UXT functionally rewires AR output, suppressing proliferation while enhancing differentiation gene transcription, implying a growth-suppressive coactivator role.","evidence":"Inducible overexpression in LNCaP cells with proliferation and PSA transcription readouts","pmids":["14711828"],"confidence":"Medium","gaps":["Single cell line","Endogenous-level confirmation lacking"]},{"year":2005,"claim":"Connected disease-associated AR mutations to altered UXT physical binding, linking the AR–UXT interface to androgen-pathology phenotypes; concurrently placed UXT at centrosomes as essential for viability.","evidence":"AR point-mutant Co-IP and reporter assays; immunofluorescence, gamma-tubulin Co-IP and siRNA in mammalian cells","pmids":["15919721","16221885"],"confidence":"Medium","gaps":["Whether centrosomal and nuclear pools are the same functional protein unclear","Cause of knockdown lethality not mechanistically defined"]},{"year":2007,"claim":"Defined the nuclear V2 isoform as a recruitable NF-κB enhanceosome component required for NF-κB transcription and survival, and extended cofactor reach to the EVI1 repressor.","evidence":"Y2H, Co-IP, RNAi with gene-expression and apoptosis readouts; transformation assays with Evi1 deletion mutants","pmids":["17620405","17635584"],"confidence":"High","gaps":["Molecular basis of enhanceosome recruitment unresolved","How UXT discriminates among transcription factors unknown"]},{"year":2011,"claim":"Resolved isoform-specific cytoplasmic functions, showing UXT-V1 binds TRAF2 to block apoptotic complex II and binds TRAF3 to assemble the MAVS antiviral signalosome on mitochondria.","evidence":"Subcellular fractionation, Co-IP, domain mapping, siRNA knockdown and reporter assays","pmids":["21307340","22131337"],"confidence":"High","gaps":["Structural detail of TRAF-binding motif engagement limited","Coordination between V1 and V2 functions unaddressed"]},{"year":2012,"claim":"Identified a phosphoswitch (BGLF4 at Thr3) controlling the UXT–NF-κB interaction, establishing post-translational regulation of UXT cofactor activity and its requirement for EBV latency.","evidence":"In vitro kinase assay, Thr3 mutagenesis with functional validation, shRNA knockdown in EBV-positive cells","pmids":["22933289"],"confidence":"High","gaps":["Host kinases acting on Thr3 not identified","Structural consequence of phosphorylation unmapped"]},{"year":2013,"claim":"Expanded the cofactor repertoire and assigned in vivo pathway roles: UXT stabilizes Foxp3 in Tregs, recruits VHL to modulate AR ubiquitination, and represses Notch signaling to control angiogenesis.","evidence":"Co-IP with domain mapping, ChIP, ubiquitination assays, zebrafish knockdown with Notch-blockade rescue, SARM caspase assays","pmids":["24136450","23961993","25617435","24021647"],"confidence":"Medium","gaps":["Whether these interactions are direct or complex-mediated varies by study","Tissue-specific selectivity among partners unexplained"]},{"year":2015,"claim":"Implicated UXT as a tumor-context oncogene through MDMX binding and p53 suppression, contrasting with its growth-suppressive AR-cofactor role.","evidence":"Co-IP, pathway reporter screen, knockdown/overexpression and xenograft in sarcoma cells","pmids":["25974965"],"confidence":"Medium","gaps":["Reconciliation with growth-suppressive AR role not addressed","Directness of UXT–MDMX effect on p53 unclear"]},{"year":2016,"claim":"Placed UXT within a chromatin cofactor module with EZH1/SUZ12 that controls p65 and Pol II recruitment to NF-κB targets independent of H3K27 methylation.","evidence":"Co-IP, siRNA knockdown, ChIP-seq and reporter assays","pmids":["27127229"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the UXT–EZH1–SUZ12 complex undefined","Whether complex assembles before or after NF-κB activation unknown"]},{"year":2017,"claim":"Demonstrated cytoplasmic relocalization and proteasomal turnover as a regulatory mode releasing UXT-mediated repression of ER, broadening UXT's nuclear receptor regulation beyond AR.","evidence":"Y2H, Co-IP, proteasome inhibitor rescue, fractionation and ER reporter assays","pmids":["28106301"],"confidence":"Medium","gaps":["E3 ligase mediating LOX-PP-driven degradation not identified","Physiological context of ER repression unclear"]},{"year":2018,"claim":"Provided the first in vivo essentiality evidence: Uxt is embryonic lethal and required cell-autonomously in the germline for spermatogonial transcription programs.","evidence":"Constitutive and germline-conditional knockout mice with histology and RNA-seq","pmids":["29649254"],"confidence":"High","gaps":["Direct transcriptional targets driving the spermatogenesis phenotype not pinpointed","Which UXT partner mediates the germline role unknown"]},{"year":2019,"claim":"Linked UXT loss to prostate neoplasia and genome instability via derepression of retroelements, connecting UXT to suppression of transposon activity.","evidence":"Prostate-specific conditional knockout mice, retrotransposition assays and DNA-damage markers","pmids":["30774773"],"confidence":"Medium","gaps":["Mechanism by which UXT restrains LINE-1/Alu undefined","Relationship to its transcriptional cofactor activity unresolved"]},{"year":2020,"claim":"Defined tissue-level physiological roles: Sertoli-cell UXT maintains blood-testis-barrier integrity, and retinal UXT preserves photoreceptors by restraining autophagy through MTOR.","evidence":"Sertoli- and retina-conditional knockout mice with EM, tracer permeability, ERG, TUNEL and autophagic-flux assays","pmids":["32678429","32744119"],"confidence":"High","gaps":["How UXT regulates MTOR activity mechanistically not resolved","Whether autophagy regulation is direct or transcriptional unclear"]},{"year":2020,"claim":"Identified SCF(Fbxo7) as the E3 ligase driving UXT-V2 ubiquitination and turnover, establishing degradative control that tunes UXT's NF-κB cofactor pool.","evidence":"In vitro and in vivo ubiquitination assays, chain-linkage analysis, CHX chase, domain mapping and reporter assays","pmids":["33010352"],"confidence":"High","gaps":["Signals triggering Fbxo7-mediated degradation not defined","Functional meaning of mixed K48/K63 chains unresolved"]},{"year":2021,"claim":"Recast UXT as a selective-autophagy adaptor that oligomerizes to bridge ubiquitinated aggregates to p62/SQSTM1, with protective effect in a motor-neuron degeneration model.","evidence":"Y2H, Co-IP, in vitro aggregate-binding, Xenopus SOD1(A4V) model with interaction-disrupting mutants","pmids":["33782410"],"confidence":"High","gaps":["Selectivity of aggregate recognition undefined","Relationship to its prefoldin-like chaperone identity not established"]},{"year":2022,"claim":"Showed UXT directs SQSTM1-dependent autophagic degradation of STING1, providing a brake on cGAS-STING innate immunity validated in viral-infection and lupus mouse models.","evidence":"Co-IP, autophagy inhibitors, conditional knockout mouse models and PBMC functional assays","pmids":["35543189"],"confidence":"High","gaps":["How UXT selects STING1 as cargo undefined","Interplay with UXT's NF-κB and antiviral roles not integrated"]},{"year":2025,"claim":"Provided structural mechanism for the autophagy-adaptor function, showing β-hairpin-mediated hexameric and higher-order oligomerization is required for aggregate clearance, and a new antiviral mode in which UXT-V2 recruits TRIM21 for K48-ubiquitination of HSV-2 glycoprotein B.","evidence":"Structural homology modeling with oligomerization mutants and in vitro/Xenopus clearance assays; Co-IP, K48 ubiquitination assays and viral replication assays","pmids":["40092611","40907749"],"confidence":"Medium","gaps":["Experimental structure of the oligomer not determined","Whether oligomerization governs non-autophagy functions unknown"]},{"year":null,"claim":"How a single small protein coordinates its many partner-specific roles — isoform partitioning, oligomeric state, and post-translational switching — into a unified molecular logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental atomic structure of UXT in any complex","Rules governing selection among AR, NF-κB, Notch, Foxp3, p62 and STING1 partners unknown","Mechanistic link between prefoldin-like chaperone identity and transcriptional cofactor function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,7,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,23,26]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[23,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,26,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[23,26,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[22,29]}],"complexes":["NF-κB enhanceosome","TNF receptor signaling complex","MAVS–TRAF3 mitochondrial signalosome","URI/UXT prefoldin-like complex"],"partners":["AR","TRAF2","TRAF3","SQSTM1","STING1","FBXO7","FOXP3","TRIM21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBK9","full_name":"Protein UXT","aliases":["Androgen receptor trapped clone 27 protein","ART-27","Ubiquitously expressed transcript protein"],"length_aa":157,"mass_kda":18.2,"function":"Involved in gene transcription regulation (PubMed:21730289, PubMed:28106301). Acts in concert with the corepressor URI1 to regulate androgen receptor AR-mediated transcription (PubMed:11854421, PubMed:21730289). Together with URI1, associates with chromatin to the NKX3-1 promoter region (PubMed:21730289). Negatively regulates the transcriptional activity of the estrogen receptor ESR1 by inducing its translocation into the cytoplasm (PubMed:28106301). May act as nuclear chaperone that facilitates the formation of the NF-kappa-B enhanceosome and thus positively regulates NF-kappa-B transcription activity (PubMed:17620405, PubMed:21307340). Potential component of mitochondrial-associated LRPPRC, a multidomain organizer that potentially integrates mitochondria and the microtubular cytoskeleton with chromosome remodeling (PubMed:17554592). Increasing concentrations of UXT contributes to progressive aggregation of mitochondria and cell death potentially through its association with LRPPRC (PubMed:17554592). Suppresses cell transformation and it might mediate this function by interaction and inhibition of the biological activity of cell proliferation and survival stimulatory factors like MECOM (PubMed:17635584) Plays a role in protecting cells against TNF-induced apoptosis by preventing the recruitment of FADD and caspase 8 to the apoptotic complex I, composed of TRADD, TRAF2 and RIPK1/RIP","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q9UBK9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UXT","classification":"Common Essential","n_dependent_lines":1143,"n_total_lines":1208,"dependency_fraction":0.9461920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR2A","stoichiometry":4.0},{"gene":"POLR2E","stoichiometry":4.0},{"gene":"POLR2H","stoichiometry":4.0},{"gene":"PFDN6","stoichiometry":0.2},{"gene":"POLR2B","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"POLR3B","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2},{"gene":"RPAP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UXT","total_profiled":1310},"omim":[{"mim_id":"607544","title":"LEUCINE-RICH PPR MOTIF-CONTAINING PROTEIN; LRPPRC","url":"https://www.omim.org/entry/607544"},{"mim_id":"300234","title":"UBIQUITOUSLY EXPRESSED TRANSCRIPT; UXT","url":"https://www.omim.org/entry/300234"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UXT"},"hgnc":{"alias_symbol":["ART-27","STAP1","SKP2"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBK9","domains":[{"cath_id":"1.10.287.370","chopping":"8-142","consensus_level":"high","plddt":92.7089,"start":8,"end":142}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBK9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBK9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBK9-F1-predicted_aligned_error_v6.png","plddt_mean":88.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UXT","jax_strain_url":"https://www.jax.org/strain/search?query=UXT"},"sequence":{"accession":"Q9UBK9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBK9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBK9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBK9"}},"corpus_meta":[{"pmid":"11854421","id":"PMC_11854421","title":"Identification and characterization of ART-27, a novel coactivator for the androgen receptor N terminus.","date":"2002","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/11854421","citation_count":74,"is_preprint":false},{"pmid":"17620405","id":"PMC_17620405","title":"UXT is a novel and essential cofactor in the NF-kappaB transcriptional enhanceosome.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17620405","citation_count":54,"is_preprint":false},{"pmid":"14711828","id":"PMC_14711828","title":"ART-27, an androgen receptor coactivator regulated in prostate development and cancer.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14711828","citation_count":49,"is_preprint":false},{"pmid":"35543189","id":"PMC_35543189","title":"UXT attenuates the CGAS-STING1 signaling by targeting STING1 for autophagic degradation.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35543189","citation_count":46,"is_preprint":false},{"pmid":"10087202","id":"PMC_10087202","title":"Cloning and characterization of UXT, a novel gene in human Xp11, which is widely and abundantly expressed in tumor tissue.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10087202","citation_count":46,"is_preprint":false},{"pmid":"22933289","id":"PMC_22933289","title":"Epstein-Barr virus BGLF4 kinase downregulates NF-κB transactivation through phosphorylation of coactivator UXT.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22933289","citation_count":45,"is_preprint":false},{"pmid":"16221885","id":"PMC_16221885","title":"UXT is a novel centrosomal protein essential for cell viability.","date":"2005","source":"Molecular biology of the 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General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/33010352","citation_count":11,"is_preprint":false},{"pmid":"21907703","id":"PMC_21907703","title":"Alfa-class prefoldin protein UXT is a novel interacting partner of Amyotrophic Lateral Sclerosis 2 (Als2) protein.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21907703","citation_count":10,"is_preprint":false},{"pmid":"24136450","id":"PMC_24136450","title":"UXT is a novel regulatory factor of regulatory T cells associated with Foxp3.","date":"2013","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24136450","citation_count":9,"is_preprint":false},{"pmid":"30774773","id":"PMC_30774773","title":"Prostate-specific loss of UXT promotes cancer progression.","date":"2019","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30774773","citation_count":7,"is_preprint":false},{"pmid":"34767964","id":"PMC_34767964","title":"HOXD9 transcriptionally induced UXT facilitate breast cancer progression via epigenetic modification of RND3.","date":"2021","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/34767964","citation_count":7,"is_preprint":false},{"pmid":"29649254","id":"PMC_29649254","title":"UXT is required for spermatogenesis in mice.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29649254","citation_count":7,"is_preprint":false},{"pmid":"32678429","id":"PMC_32678429","title":"UXT in Sertoli cells is required for blood-testis barrier integrity†.","date":"2020","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/32678429","citation_count":7,"is_preprint":false},{"pmid":"30484154","id":"PMC_30484154","title":"Role of the Unconventional Prefoldin Proteins URI and UXT in Transcription Regulation.","date":"2018","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/30484154","citation_count":6,"is_preprint":false},{"pmid":"37152054","id":"PMC_37152054","title":"UXT at the crossroads of cell death, immunity and neurodegenerative diseases.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37152054","citation_count":4,"is_preprint":false},{"pmid":"36000398","id":"PMC_36000398","title":"The role of UXT in tumors and prospects for its application in hepatocellular carcinoma.","date":"2022","source":"Future oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36000398","citation_count":4,"is_preprint":false},{"pmid":"37468105","id":"PMC_37468105","title":"MYB regulates the SUMO protease SENP1 and its novel interaction partner UXT, modulating MYB target genes and the SUMO landscape.","date":"2023","source":"The Journal of biological 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Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/40907749","citation_count":0,"is_preprint":false},{"pmid":"41931169","id":"PMC_41931169","title":"Ubiquitously expressed prefoldin-like chaperone (UXT) regulates putrescine metabolism and promotes colorectal cancer progression.","date":"2026","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/41931169","citation_count":0,"is_preprint":false},{"pmid":"40092611","id":"PMC_40092611","title":"UXT oligomerization is essential for its role as an autophagy adaptor.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40092611","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.22.644712","title":"A genome-wide in vivo CRISPR screen identifies neuroprotective strategies in the mouse and human 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predominantly with the AR N-terminal region containing AF-1a (AR residues 153-336), localizes to the nucleus, and increases AR transcriptional activity when overexpressed. ART-27 interacts with AR in nuclear extracts from LNCaP cells in a ligand-independent manner. Native ART-27 is part of a multiprotein complex as shown by velocity gradient sedimentation of HeLa nuclear extracts.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from nuclear extracts, overexpression in mammalian cells, LexA fusion transcriptional assays, velocity gradient sedimentation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods (Y2H, nuclear extract Co-IP, sedimentation, transcriptional assays), replicated by subsequent studies\",\n      \"pmids\": [\"11854421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ART-27 (UXT) expression in LNCaP prostate cancer cells inhibits androgen-mediated cellular proliferation while enhancing androgen-mediated transcription of the PSA gene, establishing a growth-suppressive and differentiation-promoting function for ART-27 as an AR cofactor.\",\n      \"method\": \"Regulated expression (inducible overexpression) in LNCaP cells with proliferation and PSA transcription readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gain-of-function in defined cell line with two orthogonal phenotypic readouts (proliferation and PSA transcription), single lab\",\n      \"pmids\": [\"14711828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Naturally occurring AR mutations from prostate cancer (AR P340L) and androgen insensitivity syndrome (AR E2K) show reduced transcriptional responses to ART-27 coactivation. AR E2K shows reduced ART-27 protein association by co-immunoprecipitation, while AR P340L shows increased ART-27 association despite reduced transcriptional activation, indicating that aberrant AR–ART-27 physical interaction interferes with normal coactivator function.\",\n      \"method\": \"Transcriptional reporter assays, co-immunoprecipitation, AR mutation analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP combined with functional transcriptional assays using specific point mutants, single lab\",\n      \"pmids\": [\"15919721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"UXT localizes to centrosomes and is associated with gamma-tubulin. Overexpression of UXT disrupts centrosome structure, and siRNA-mediated knockdown of UXT leads to cell death, establishing UXT as a centrosomal component essential for cell viability.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation with gamma-tubulin, siRNA knockdown, overexpression studies\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (knockdown lethality, overexpression centrosome disruption), single lab, two orthogonal methods\",\n      \"pmids\": [\"16221885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UXT (specifically the V2 isoform) is expressed predominantly in the nucleus and interacts specifically with NF-κB inside the nucleus. UXT is recruited to the NF-κB enhanceosome upon stimulation and forms a dynamic complex with NF-κB. RNAi knockdown of UXT impairs NF-κB transcriptional activity, attenuates NF-κB-dependent gene expression, and sensitizes cells to TNF-alpha-induced apoptosis.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, RNAi knockdown, reporter assays, chromatin immunoprecipitation-like enhanceosome recruitment assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, Co-IP, RNAi + gene expression, apoptosis assay), replicated in subsequent studies\",\n      \"pmids\": [\"17620405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UXT interacts with the EVI1 transcriptional repressor through EVI1's repressor domain (Rp). Enforced UXT expression suppresses EVI1-induced cell transformation in Rat1 fibroblasts. Evi1 mutants lacking the UXT-binding site (Evi1Δ706-707) produce larger transformation colonies, indicating that endogenous UXT inhibits EVI1 biological activity.\",\n      \"method\": \"Yeast two-hybrid, colony formation assay, Evi1 deletion mutants, Rat1 fibroblast transformation assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus functional transformation assay with deletion mutants demonstrating domain specificity, single lab\",\n      \"pmids\": [\"17635584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"When overexpressed, GFP-tagged UXT localizes progressively from extranuclear cytosol to punctate cytosolic dots to perinuclear aggregates, coinciding with aggregation of mitochondria and LRPPRC, leading to mitochondrial aggregation and cell death. UXT was identified as a component of mitochondria-associated LRPPRC complex.\",\n      \"method\": \"GFP-UXT overexpression, fluorescence microscopy, co-localization with mitochondria and LRPPRC\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression artifact possible, co-localization without biochemical confirmation of interaction\",\n      \"pmids\": [\"17554592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UXT-V1 isoform localizes in the cytoplasm (in contrast to nuclear V2) and is a component of the TNF receptor signaling complex. UXT-V1 binds TRAF2 and prevents TRADD from recruiting FADD, thereby blocking formation of the apoptotic complex II. UXT-V1 is a short-half-life protein whose degradation facilitates complex II formation in response to TNF treatment.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, siRNA knockdown, cycloheximide chase, apoptosis assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, Co-IP, knockdown, protein stability assay), clear mechanistic model with specific binding partner identification\",\n      \"pmids\": [\"21307340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UXT-V1 is a novel TRAF3-binding protein that facilitates the interaction between TRAF3 and MAVS on mitochondria. The N-terminal TRAF-binding motif of UXT-V1 binds the C-terminal TRAF domain of TRAF3. UXT-V1 knockdown impairs virus-induced activation of NF-κB and IRF3, attenuates IFN-β induction, and blocks TRAF3 and TRADD recruitment to mitochondria upon virus infection.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, reporter assays, mitochondrial fractionation, domain mapping\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-level binding mapped, multiple orthogonal methods (Co-IP, fractionation, knockdown with functional readouts), single lab\",\n      \"pmids\": [\"22131337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EBV BGLF4 kinase phosphorylates UXT at Thr3. This phosphorylation interferes with the interaction between UXT and NF-κB, reducing NF-κB enhanceosome activity and downregulating NF-κB-dependent gene expression. Knockdown of UXT in EBV-positive NA cells induced spontaneous lytic cycle, demonstrating UXT is required for maintenance of EBV latency. Wild-type but not phosphorylation-deficient UXT enhanced lytic protein expression.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (Thr3), co-immunoprecipitation, reporter assays, lentiviral shRNA knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay establishing phosphorylation site, mutagenesis of phosphosite with functional validation, multiple biological readouts\",\n      \"pmids\": [\"22933289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"VHL interacts with UXT as identified by yeast two-hybrid and confirmed by GST pull-down and co-immunoprecipitation. UXT recruits VHL to the nucleus. VHL associates with the DNA-binding domain and hinge domain of AR and induces AR ubiquitination. VHL interaction with AR activates AR transactivation upon DHT treatment; VHL knockdown inhibits AR ubiquitination and decreases AR transcriptional activation.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, ubiquitination assay, AR reporter assay, siRNA knockdown\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (Y2H, pull-down, Co-IP, ubiquitination, reporter), single lab\",\n      \"pmids\": [\"23961993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"UXT interacts with SARM via yeast two-hybrid analysis. The two UXT isoforms have opposing effects on SARM-induced apoptosis: UXT-V1 co-expressed with SARM reduces caspase 8 activity, while UXT-V2 strongly increases caspase 8 activity and enhances SARM-induced apoptosis by activating the extrinsic pathway and depolarizing mitochondria.\",\n      \"method\": \"Yeast two-hybrid, caspase 8 activity assay, mitochondrial membrane potential assay, overexpression of isoforms\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H plus functional isoform comparison with enzymatic readout, single lab, limited binding confirmation\",\n      \"pmids\": [\"24021647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"UXT associates with Foxp3 in the nucleus of human regulatory T cells, interacting with the proline-rich domain in the N-terminus of Foxp3. UXT knockdown in Treg cells results in a less-suppressive phenotype, affects nuclear localization stability of Foxp3, and downregulates Foxp3-related gene expression.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, suppression functional assays, immunofluorescence\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus functional knockdown phenotype, single lab\",\n      \"pmids\": [\"24136450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UXT attenuates Notch signaling by binding to promoters of Notch-responsive genes and specifically interacting with the transactivation domain of the Notch intracellular domain (NICD), thereby impairing the interaction between NICD and the transcription factor RBP-Jκ. UXT knockdown in zebrafish results in shorter intersegmental vessels, loss of tip cell behavior, and impaired endothelial cell migration and division; blockade of Notch signaling rescues these defects.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (promoter binding), siRNA/morpholino knockdown in zebrafish, reporter assays, rescue experiments\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, in vivo knockdown with rescue), mechanistic pathway placement via epistasis\",\n      \"pmids\": [\"25617435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UXT binds MDMX and suppresses basal p53 activity. UXT-mediated p53 inhibition results in NF-κB activation leading to induction of glycolysis. UXT acts as an oncogene promoting cell proliferation in vitro and tumor progression in vivo in sarcoma cells.\",\n      \"method\": \"Co-immunoprecipitation (UXT–MDMX interaction), pathway reporter screen, siRNA knockdown, overexpression, xenograft tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding partner, functional knockdown/OE with pathway readouts, single lab\",\n      \"pmids\": [\"25974965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EZH1 physically interacts with UXT, and also with SUZ12 but not EED. Knockdown of EZH1 or SUZ12 impairs NF-κB target gene transcriptional activation induced by TNFα, similar to UXT knockdown. EZH1 and SUZ12 regulate recruitment of p65 and RNA Pol II to NF-κB target genes without affecting H3K27 methylation or p65 nuclear translocation, acting synergistically with UXT.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, chromatin immunoprecipitation with next-generation sequencing, reporter assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP-seq plus functional knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27127229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UXT was identified as a LOX-PP interacting protein. UXT associates with estrogen receptor alpha (ER) and decreases ER transcriptional activity and target gene expression. LOX-PP interaction relocalizes UXT to the cytoplasm, promotes UXT ubiquitination, and decreases UXT stability via proteasomal degradation, releasing repression of ER transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation (UXT–ER, UXT–LOX-PP), proteasome inhibitor rescue, subcellular fractionation, ER reporter assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, proteasome inhibitor rescue, reporter assays), single lab\",\n      \"pmids\": [\"28106301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Constitutive deletion of Uxt in mice is embryonic lethal. Conditional knockout of Uxt in the male germline results in a Sertoli cell-only phenotype during the first wave of spermatogenesis, manifesting between 6 and 7 days post-partum before meiotic entry. Gene expression analysis revealed that Uxt deletion downregulates transcription of genes governing SSC self-renewal, differentiation, and meiosis.\",\n      \"method\": \"Conditional knockout mouse model, histology, gene expression analysis (RNA-seq), immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with defined phenotype, gene expression analysis revealing mechanism, consistent with known transcriptional cofactor role\",\n      \"pmids\": [\"29649254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In prostate cells, URI is tightly bound to UXT; together they form a multiprotein complex acting as transcriptional repressors. URI regulates KAP1 through PP2A phosphatase activity, and the URI/UXT complex interacts with AR, KAP1, and PP2A.\",\n      \"method\": \"Co-immunoprecipitation, protein complex characterization\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review chapter describing interactions without original experimental detail in abstract, single context\",\n      \"pmids\": [\"30484154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Prostate-specific conditional knockout of Uxt in mice led to a hyperplastic phenotype with prostate secretion fluid blockage and PIN by 4–6 months; doubly mutant Uxt/Pten mice developed more aggressive PIN. UXT depletion in prostate cancer cells increased retroelement expression (LINE-1, Alu) and retrotransposition activity, and accumulated DNA damage.\",\n      \"method\": \"Prostate-specific conditional knockout mouse, tissue microarray, retrotransposition assay, DNA damage markers\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with multiple phenotypic readouts, functional assays in cells, single lab\",\n      \"pmids\": [\"30774773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional knockout of Uxt in Sertoli cells results in smaller testes, loss of germ cells in a subset of seminiferous tubules, and reduced transcription of genes involved in tight junctions of the blood-testis barrier (BTB). Tracer experiments and electron microscopy confirmed that the BTB is permeable in Sertoli-specific UXT KO animals.\",\n      \"method\": \"Sertoli cell-specific conditional knockout, gene expression analysis, tracer permeability assay, electron microscopy\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with structural (EM) and functional (tracer) validation of BTB permeability, multiple orthogonal methods\",\n      \"pmids\": [\"32678429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional knockout of Uxt in mice leads to retinal degeneration resembling retinitis pigmentosa, including progressive reduction of photoreceptors, increased apoptotic cells, and impaired ERG responses. Mechanistically, UXT suppresses photoreceptor apoptotic cell death by inhibiting autophagy through regulation of MTOR activity; UXT KO leads to enhanced autophagic flux and apoptosis.\",\n      \"method\": \"Conditional knockout mouse, ERG, TUNEL assay, autophagic flux measurement, MTOR activity assay, RNA-seq\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with multiple orthogonal functional readouts (ERG, TUNEL, autophagic flux, MTOR activity), single lab\",\n      \"pmids\": [\"32744119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SCF(Fbxo7) E3 ubiquitin ligase mediates polyubiquitination of UXT-V2 (with both K48 and K63 linkages), promoting its proteasomal degradation. The Ubl domain of Fbxo7 contributes to interaction with UXT-V2. UXT-V1 also interacts with and is ubiquitinated by Fbxo7. FBXO7 knockdown causes UXT-V2 accumulation and enhanced NF-κB reporter activity; Fbxo7-ΔF-box overexpression protects UXT-V2 from degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, cycloheximide chase, ubiquitin chain restriction analysis, siRNA knockdown, reporter assay\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstitution plus in vivo validation, domain mapping, multiple orthogonal methods including chain linkage analysis\",\n      \"pmids\": [\"33010352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UXT was identified as an interacting protein of p62/SQSTM1 via yeast two-hybrid. UXT binds both protein aggregates and the LB domain of p62, and forms oligomers that increase p62 clustering, promoting efficient targeting to protein aggregates and clearance via autophagy (aggrephagy). Ectopic expression of human UXT delays SOD1(A4V)-induced motor neuron degeneration in Xenopus; disruption of the UXT–p62 interaction suppresses this protection.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro aggregate binding assay, Xenopus in vivo model, UXT–p62 interaction disruption mutants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Y2H plus Co-IP plus in vitro binding plus in vivo rescue with interaction-disrupting mutants, multiple orthogonal methods\",\n      \"pmids\": [\"33782410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UXT was identified as a novel TSG101 interaction partner associated with TSG101-containing cytoplasmic vesicles by co-immunoprecipitation. UXT depletion promoted TSG101 vesicle–lysosome association and elevated autophagic carrier flux, enhancing CEP55 degradation through the lysosome pathway upon TSG101 overexpression. UXT plays a role in late endosome/autophagosome–lysosome fusion.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, lysosome inhibitor experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus knockdown phenotype, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"33486193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UXT interacts with DNMT3b (confirmed by co-immunoprecipitation) and inhibits lncRNA MEG3 expression by recruiting DNMT3b to the MEG3 imprinting control region, promoting hypermethylation. This negatively regulates the MEG3/p53 axis to promote breast cancer cell proliferation and tumor growth in a DNMT3b-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, methylation-specific PCR, RNA immunoprecipitation, xenograft tumor model, siRNA knockdown\",\n      \"journal\": \"Molecular therapy oncolytics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS-PCR for methylation plus xenograft, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35229028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UXT interacts with STING1 upon DNA mimic or cGAMP stimulation and promotes STING1 degradation through selective macroautophagy. UXT facilitates the interaction between SQSTM1/p62 and STING1 to enhance autophagic degradation of STING1. In vivo, UXT deficiency leads to enhanced cGAS-STING1 signaling in a DNA-virus infection mouse model and a TMPD-induced murine lupus model.\",\n      \"method\": \"Co-immunoprecipitation, autophagy inhibitor experiments, conditional knockout mouse models (DNA-virus infection, TMPD-lupus), PBMC functional assays, RNA-seq\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, multiple in vivo mouse models, human PBMC validation, multiple orthogonal methods, single lab with comprehensive mechanistic characterization\",\n      \"pmids\": [\"35543189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UXT acts as a repressor of SENP1 expression. MYB upregulates SENP1 while inhibiting UXT expression. By repressing SENP1, UXT affects the global SUMO landscape; reduced UXT leads to increased SENP1 activity, decreased SUMOylation of MYB targets, and autoactivation of MYB. UXT was identified as a novel SENP1 interaction partner by mapping of SENP1 interaction partners.\",\n      \"method\": \"RNA-seq after MYB knockdown/rescue with SUMO mutants, interactome mapping of SENP1, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction partner identification without deep biochemical characterization of UXT–SENP1 mechanism in abstract, single lab\",\n      \"pmids\": [\"37468105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UXT forms hexameric and higher-order oligomeric structures (via β-hairpin-mediated assembly of hexamers) that are essential for its function as an autophagy adaptor. The high-order oligomer of UXT is required for efficient clearance of SOD1(A4V) aggregates both in vitro and in vivo. Disruption of high-order oligomerization abolishes UXT's ability to promote aggregate clearance.\",\n      \"method\": \"In silico structural homology modeling, in vitro aggregate clearance assays, in vivo Xenopus model with oligomerization-disrupting mutants\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural modeling plus in vitro and in vivo functional validation with mutants, single lab\",\n      \"pmids\": [\"40092611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UXT-V2 restricts HSV-2 replication by facilitating K48-linked ubiquitination of the viral glycoprotein B (gB), targeting it for proteasomal degradation. UXT-V2 interacts with gB and recruits the E3 ligase TRIM21 to ubiquitinate gB. This anti-viral function is independent of UXT-V2's role in NF-κB regulation.\",\n      \"method\": \"Knockout/overexpression of UXT-V2, co-immunoprecipitation (UXT-V2–gB, UXT-V2–TRIM21), ubiquitination assay (K48 linkage), proteasome inhibitor rescue, viral replication assay\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding partners, ubiquitination assay with linkage specificity, KO plus OE with viral replication readout, single lab\",\n      \"pmids\": [\"40907749\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UXT (ART-27) is a prefoldin-like chaperone/coactivator that functions in multiple cellular compartments: in the nucleus it acts as a transcriptional cofactor for AR (via AF-1a binding), NF-κB (as an essential enhanceosome component regulated by EBV BGLF4-mediated phosphorylation at Thr3 and by SCF(Fbxo7)-mediated proteasomal degradation), Foxp3 in Tregs, and the Notch repressor pathway (by directly binding NICD and blocking RBP-Jκ activation); in the cytoplasm, its V1 isoform joins the TNF receptor signaling complex by binding TRAF2 to prevent FADD recruitment and complex II formation, and its V1 isoform also facilitates MAVS–TRAF3 complex assembly on mitochondria for antiviral signaling; in the autophagy pathway, UXT forms high-order oligomers that act as an adaptor bridging ubiquitinated protein aggregates to p62/SQSTM1 for aggrephagy, and separately promotes autophagic degradation of STING1 via SQSTM1 to dampen innate immune signaling; additionally, UXT-V2 recruits TRIM21 to direct K48-ubiquitination and proteasomal degradation of HSV-2 glycoprotein B; and in vivo, UXT is essential for spermatogenesis, blood-testis barrier integrity, and retinal photoreceptor survival through regulation of MTOR-dependent autophagy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UXT (ART-27) is a small prefoldin-like protein that functions as a context-dependent transcriptional cofactor and chaperone-adaptor, partitioning between the nucleus and cytoplasm in two isoforms (nuclear V2, cytoplasmic V1) to regulate hormone signaling, innate immunity, and selective autophagy [#0, #4, #7]. In the nucleus it was first defined as an androgen receptor coactivator binding the AR N-terminal AF-1a region and enhancing AR-driven transcription while suppressing androgen-mediated proliferation [#0, #1], and it more broadly modulates transcription factor activity by interacting with NF-\\u03baB as an essential, recruitable enhanceosome component [#4], with Foxp3 to stabilize regulatory T cell suppressive function [#12], and with the Notch intracellular domain to block NICD\\u2013RBP-J\\u03ba activation [#13]. Its activity as an NF-\\u03baB cofactor is tuned by post-translational control: EBV BGLF4 kinase phosphorylates UXT at Thr3 to disrupt the UXT\\u2013NF-\\u03baB interaction and maintain viral latency [#9], and SCF(Fbxo7) ubiquitinates UXT-V2 to drive its proteasomal turnover [#22]. In the cytoplasm, UXT-V1 enters TNF receptor signaling by binding TRAF2 to prevent FADD recruitment and apoptotic complex II formation [#7], and bridges TRAF3 to MAVS on mitochondria to enable antiviral IFN-\\u03b2 induction [#8]. UXT also acts as a selective autophagy adaptor, forming \\u03b2-hairpin-mediated higher-order oligomers that cluster ubiquitinated aggregates with p62/SQSTM1 for aggrephagy [#23, #28] and directing SQSTM1-dependent autophagic degradation of STING1 to dampen cGAS-STING innate signaling [#26]. In vivo, conditional Uxt deletion is embryonic lethal and demonstrates essential roles in spermatogenesis and blood-testis-barrier integrity [#17, #20] and in photoreceptor survival via MTOR-dependent restraint of autophagy [#21].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established UXT as a nuclear androgen receptor coactivator, defining its founding identity as a transcriptional cofactor rather than an orphan protein.\",\n      \"evidence\": \"Y2H, nuclear-extract Co-IP, transcriptional reporter assays and velocity gradient sedimentation in LNCaP/HeLa cells\",\n      \"pmids\": [\"11854421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the multiprotein complex members unresolved\", \"Mechanism by which UXT enhances AR transactivation not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed UXT functionally rewires AR output, suppressing proliferation while enhancing differentiation gene transcription, implying a growth-suppressive coactivator role.\",\n      \"evidence\": \"Inducible overexpression in LNCaP cells with proliferation and PSA transcription readouts\",\n      \"pmids\": [\"14711828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"Endogenous-level confirmation lacking\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected disease-associated AR mutations to altered UXT physical binding, linking the AR\\u2013UXT interface to androgen-pathology phenotypes; concurrently placed UXT at centrosomes as essential for viability.\",\n      \"evidence\": \"AR point-mutant Co-IP and reporter assays; immunofluorescence, gamma-tubulin Co-IP and siRNA in mammalian cells\",\n      \"pmids\": [\"15919721\", \"16221885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether centrosomal and nuclear pools are the same functional protein unclear\", \"Cause of knockdown lethality not mechanistically defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the nuclear V2 isoform as a recruitable NF-\\u03baB enhanceosome component required for NF-\\u03baB transcription and survival, and extended cofactor reach to the EVI1 repressor.\",\n      \"evidence\": \"Y2H, Co-IP, RNAi with gene-expression and apoptosis readouts; transformation assays with Evi1 deletion mutants\",\n      \"pmids\": [\"17620405\", \"17635584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of enhanceosome recruitment unresolved\", \"How UXT discriminates among transcription factors unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved isoform-specific cytoplasmic functions, showing UXT-V1 binds TRAF2 to block apoptotic complex II and binds TRAF3 to assemble the MAVS antiviral signalosome on mitochondria.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP, domain mapping, siRNA knockdown and reporter assays\",\n      \"pmids\": [\"21307340\", \"22131337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of TRAF-binding motif engagement limited\", \"Coordination between V1 and V2 functions unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a phosphoswitch (BGLF4 at Thr3) controlling the UXT\\u2013NF-\\u03baB interaction, establishing post-translational regulation of UXT cofactor activity and its requirement for EBV latency.\",\n      \"evidence\": \"In vitro kinase assay, Thr3 mutagenesis with functional validation, shRNA knockdown in EBV-positive cells\",\n      \"pmids\": [\"22933289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Host kinases acting on Thr3 not identified\", \"Structural consequence of phosphorylation unmapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded the cofactor repertoire and assigned in vivo pathway roles: UXT stabilizes Foxp3 in Tregs, recruits VHL to modulate AR ubiquitination, and represses Notch signaling to control angiogenesis.\",\n      \"evidence\": \"Co-IP with domain mapping, ChIP, ubiquitination assays, zebrafish knockdown with Notch-blockade rescue, SARM caspase assays\",\n      \"pmids\": [\"24136450\", \"23961993\", \"25617435\", \"24021647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions are direct or complex-mediated varies by study\", \"Tissue-specific selectivity among partners unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated UXT as a tumor-context oncogene through MDMX binding and p53 suppression, contrasting with its growth-suppressive AR-cofactor role.\",\n      \"evidence\": \"Co-IP, pathway reporter screen, knockdown/overexpression and xenograft in sarcoma cells\",\n      \"pmids\": [\"25974965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with growth-suppressive AR role not addressed\", \"Directness of UXT\\u2013MDMX effect on p53 unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed UXT within a chromatin cofactor module with EZH1/SUZ12 that controls p65 and Pol II recruitment to NF-\\u03baB targets independent of H3K27 methylation.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, ChIP-seq and reporter assays\",\n      \"pmids\": [\"27127229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of the UXT\\u2013EZH1\\u2013SUZ12 complex undefined\", \"Whether complex assembles before or after NF-\\u03baB activation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated cytoplasmic relocalization and proteasomal turnover as a regulatory mode releasing UXT-mediated repression of ER, broadening UXT's nuclear receptor regulation beyond AR.\",\n      \"evidence\": \"Y2H, Co-IP, proteasome inhibitor rescue, fractionation and ER reporter assays\",\n      \"pmids\": [\"28106301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating LOX-PP-driven degradation not identified\", \"Physiological context of ER repression unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the first in vivo essentiality evidence: Uxt is embryonic lethal and required cell-autonomously in the germline for spermatogonial transcription programs.\",\n      \"evidence\": \"Constitutive and germline-conditional knockout mice with histology and RNA-seq\",\n      \"pmids\": [\"29649254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets driving the spermatogenesis phenotype not pinpointed\", \"Which UXT partner mediates the germline role unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked UXT loss to prostate neoplasia and genome instability via derepression of retroelements, connecting UXT to suppression of transposon activity.\",\n      \"evidence\": \"Prostate-specific conditional knockout mice, retrotransposition assays and DNA-damage markers\",\n      \"pmids\": [\"30774773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which UXT restrains LINE-1/Alu undefined\", \"Relationship to its transcriptional cofactor activity unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined tissue-level physiological roles: Sertoli-cell UXT maintains blood-testis-barrier integrity, and retinal UXT preserves photoreceptors by restraining autophagy through MTOR.\",\n      \"evidence\": \"Sertoli- and retina-conditional knockout mice with EM, tracer permeability, ERG, TUNEL and autophagic-flux assays\",\n      \"pmids\": [\"32678429\", \"32744119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How UXT regulates MTOR activity mechanistically not resolved\", \"Whether autophagy regulation is direct or transcriptional unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified SCF(Fbxo7) as the E3 ligase driving UXT-V2 ubiquitination and turnover, establishing degradative control that tunes UXT's NF-\\u03baB cofactor pool.\",\n      \"evidence\": \"In vitro and in vivo ubiquitination assays, chain-linkage analysis, CHX chase, domain mapping and reporter assays\",\n      \"pmids\": [\"33010352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering Fbxo7-mediated degradation not defined\", \"Functional meaning of mixed K48/K63 chains unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Recast UXT as a selective-autophagy adaptor that oligomerizes to bridge ubiquitinated aggregates to p62/SQSTM1, with protective effect in a motor-neuron degeneration model.\",\n      \"evidence\": \"Y2H, Co-IP, in vitro aggregate-binding, Xenopus SOD1(A4V) model with interaction-disrupting mutants\",\n      \"pmids\": [\"33782410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of aggregate recognition undefined\", \"Relationship to its prefoldin-like chaperone identity not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed UXT directs SQSTM1-dependent autophagic degradation of STING1, providing a brake on cGAS-STING innate immunity validated in viral-infection and lupus mouse models.\",\n      \"evidence\": \"Co-IP, autophagy inhibitors, conditional knockout mouse models and PBMC functional assays\",\n      \"pmids\": [\"35543189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How UXT selects STING1 as cargo undefined\", \"Interplay with UXT's NF-\\u03baB and antiviral roles not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided structural mechanism for the autophagy-adaptor function, showing \\u03b2-hairpin-mediated hexameric and higher-order oligomerization is required for aggregate clearance, and a new antiviral mode in which UXT-V2 recruits TRIM21 for K48-ubiquitination of HSV-2 glycoprotein B.\",\n      \"evidence\": \"Structural homology modeling with oligomerization mutants and in vitro/Xenopus clearance assays; Co-IP, K48 ubiquitination assays and viral replication assays\",\n      \"pmids\": [\"40092611\", \"40907749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Experimental structure of the oligomer not determined\", \"Whether oligomerization governs non-autophagy functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single small protein coordinates its many partner-specific roles \\u2014 isoform partitioning, oligomeric state, and post-translational switching \\u2014 into a unified molecular logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental atomic structure of UXT in any complex\", \"Rules governing selection among AR, NF-\\u03baB, Notch, Foxp3, p62 and STING1 partners unknown\", \"Mechanistic link between prefoldin-like chaperone identity and transcriptional cofactor function undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 7, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 23, 26]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [23, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 26, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [23, 26, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [22, 29]}\n    ],\n    \"complexes\": [\"NF-\\u03baB enhanceosome\", \"TNF receptor signaling complex\", \"MAVS\\u2013TRAF3 mitochondrial signalosome\", \"URI/UXT prefoldin-like complex\"],\n    \"partners\": [\"AR\", \"TRAF2\", \"TRAF3\", \"SQSTM1\", \"STING1\", \"FBXO7\", \"Foxp3\", \"TRIM21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}