Affinage

UBA1

Ubiquitin-like modifier-activating enzyme 1 · UniProt P22314

Length
1058 aa
Mass
117.8 kDa
Annotated
2026-06-10
92 papers in source corpus 31 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBA1 is the principal E1 ubiquitin-activating enzyme that initiates the ubiquitin conjugation cascade by adenylating ubiquitin, forming a high-energy thioester at its catalytic cysteine (Cys632), and charging ubiquitin onto downstream E2 conjugating enzymes (PMID:38360993, PMID:37873213, PMID:23022194). Its C-terminal ubiquitin-fold domain (UFD) is the determinant of E2 selection and transfer specificity: replacing the UFD with a nanobody redirects ubiquitin transfer exclusively to epitope-tagged E2s (PMID:41203132). Charging activity is tunable through multiple inputs — acetylation of distinct ubiquitin lysines alters E2~Ub turnover (PMID:33848125), covalent modification of the UFD at Cys1039 by auranofin enhances E2 engagement across more than twenty E2 enzymes (PMID:37558718), and E2 N-terminal phosphorylation acts as a negative regulator at the E1-E2 interface (PMID:28162934). UBA1 exists as nuclear and cytoplasmic isoforms; the cytoplasmic isoform (UBA1b) is translated from Met41, and its nuclear pool is required to maintain ubiquitin-dependent turnover of replication-licensing factors and orderly S-to-G2 progression (PMID:33108101, PMID:24805847). The enzyme acts at DNA double-strand breaks, where poly(ADP-ribose) recruits UBA1 to support ubiquitin-conjugate formation, 53BP1/BRCA1 focus assembly, and ATR-dependent phosphorylation of RPA and CHK1 (PMID:22456334, PMID:30456359). Beyond bulk conjugation, UBA1 controls specific substrate-degradation events, directly ubiquitinating ATG5 to suppress autophagy (PMID:41765888) and BMAL1 to dampen REV-ERBα activity and amplify inflammatory cytokine output (PMID:41205381), and it participates in a non-canonical autophagy pathway and APC/C-coupled cyclin degradation conserved across model organisms (PMID:23873149, PMID:18045837, PMID:18636104). Somatic Met41 mutations selectively abrogate UBA1b, reducing E2 charging and causing the inflammatory-hematologic VEXAS syndrome, whereas germline mutations cause spinal muscular atrophy by rendering the enzyme thermolabile; non-Met41 disease variants instead impair transthioesterification or catalytic activity through distinct mechanisms including aberrant oxyester formation (PMID:33108101, PMID:35793467, PMID:38360993, PMID:37873213, PMID:27699224). UBA1 inhibition or loss is being leveraged therapeutically, with TAK-243-mediated E1 blockade impairing homologous recombination and sensitizing cancers to PARP inhibition (PMID:39626673).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2007 High

    Established that E1 ubiquitin activation gates cell-cycle progression and tissue homeostasis, not merely bulk protein turnover, by linking Uba1 loss to failed cyclin degradation and aberrant Notch signaling.

    Evidence Drosophila mosaic clonal genetics with multiple alleles, cyclin immunostaining and Notch epistasis

    PMID:18045837

    Open questions at the time
    • Does not identify which E3/E2 routes the cyclin and Notch ubiquitination
    • Phenotypes are organismal, leaving the direct substrate set undefined
  2. 2008 High

    Showed the sole organismal E1 is required across meiosis, fertility, and development and operates upstream of the APC/C, defining the breadth of processes dependent on ubiquitin activation.

    Evidence C. elegans temperature-sensitive uba-1 genetics, ubiquitin-conjugate immunoblot, epistasis with APC/C mutants

    PMID:18636104

    Open questions at the time
    • Does not resolve substrate-level mechanisms for individual phenotypes
    • Genetic, not biochemical, link to APC/C
  3. 2012 High

    Identified UBA1 as the specific E1 that drives ubiquitin-conjugate formation at DNA double-strand breaks, placing ubiquitin activation downstream of damage sensing but upstream of repair-factor recruitment.

    Evidence siRNA knockdown and chemical inhibition with IRIF imaging and comet repair assay, UBA6 negative controls

    PMID:22456334

    Open questions at the time
    • Does not identify the recruiting signal or relevant E2/E3 at breaks
    • Does not define which repair-pathway substrates require UBA1
  4. 2012 Medium

    Refined the catalytic mechanism by showing Cys278 influences ubiquitin charging through conformational change rather than direct chemistry, distinguishing the canonical catalytic Cys632 from allosteric cysteines.

    Evidence Site-directed mutagenesis (C278S, C632S), thioester assays in HEK293T and CMT93 cells

    PMID:23022194

    Open questions at the time
    • Single lab, no structural confirmation of the proposed conformational change
    • Downstream transfer defect inferred from conjugate persistence rather than direct kinetics
  5. 2013 High

    Revealed a ubiquitin-activation requirement for a non-canonical autophagy pathway independent of the Atg7/Atg3 conjugation machinery, broadening UBA1's role in degradative cell biology.

    Evidence Drosophila loss-of-function with autophagy/cell-size assays and Atg7/Atg3/Atg8 epistasis

    PMID:23873149

    Open questions at the time
    • Does not define the ubiquitin substrates that drive this autophagy route
    • Mechanism of Atg-independence unresolved
  6. 2014 Medium

    Demonstrated that nuclear UBA1 localization is specifically required to maintain ubiquitin-dependent turnover of replication-licensing factors and prevent S/G2 arrest, separating nuclear from cytoplasmic enzyme function.

    Evidence Temperature-sensitive CHO mutant (Met256Ile) complementation, GFP-Uba1 imaging, geminin/Cdt1 immunoblot

    PMID:24805847

    Open questions at the time
    • Single lab, single mutant
    • Mechanism of UBA1 nuclear import not addressed
  7. 2016 High

    Connected UBA1 reduction causally to spinal muscular atrophy pathology by showing AAV9-delivered UBA1 restores survival, motor function, and ubiquitin homeostasis in vivo.

    Evidence AAV9 gene therapy in SMA mice, zebrafish rescue, iPSC motor neurons, ubiquitin-conjugate measurement

    PMID:27699224

    Open questions at the time
    • Does not identify the disease-relevant substrates downstream of UBA1 loss
    • Does not explain how SMN loss reduces UBA1
  8. 2017 High

    Provided structural and biochemical definition of the E1-E2 interface and showed E2 N-terminal phosphorylation negatively regulates charging, identifying a post-translational control layer on UBA1 output.

    Evidence X-ray crystallography of S. pombe Uba1-Ubc15, structure-function mutagenesis, biochemical and cell-based phosphorylation assays

    PMID:28162934

    Open questions at the time
    • Structure from fission yeast ortholog
    • Generality of phospho-regulation across human E2s not exhaustively mapped
  9. 2017 Medium

    Showed XL-SMA adenylation-domain variants mostly retain thioester and transthioesterification activity, indicating SMA pathogenicity is not simply a charging block and pointing toward subtler defects.

    Evidence In vitro adenylation, thioester, and transthioesterification assays on three variants

    PMID:29034082

    Open questions at the time
    • Single lab, three variants only
    • Does not establish the in vivo defect for the two variants with normal in vitro activity
  10. 2018 High

    Identified poly(ADP-ribose) as the recruitment signal that brings UBA1 to damaged DNA and showed this association is required for ATR-dependent RPA/CHK1 phosphorylation, defining a mechanism for UBA1 action at breaks.

    Evidence Human cell-free system, direct UBA1-PAR binding assay, ATR signaling readouts, conservation analysis

    PMID:30456359

    Open questions at the time
    • Does not identify ubiquitination substrates feeding ATR activation
    • PAR-binding patch mapped by conservation rather than structure
  11. 2018 High

    Linked UBA1 to neuronal connectivity and identified GARS as a downstream target regulated non-canonically and independent of ubiquitylation, expanding UBA1 function beyond conjugation chemistry.

    Evidence AAV9-UBA1 rescue in SMA mice, proteomics, sensory-motor electrophysiology, GARS epistasis

    PMID:30239612

    Open questions at the time
    • Molecular nature of the non-canonical UBA1-GARS regulation unresolved
    • Generality beyond sensory neurons unknown
  12. 2018 High

    Validated UBA1 as the cellular target of TAK-243 and mapped the adenylation domain as the inhibitor binding site through resistance mutations, enabling pharmacological dissection and therapeutic targeting.

    Evidence Activity-based protein profiling in intact AML cells, selection of drug-resistant missense mutations

    PMID:29884901

    Open questions at the time
    • Selectivity over UBA6 later shown to be concentration-dependent
    • Does not define the substrate-level consequences of inhibition
  13. 2020 High

    Defined the molecular basis of VEXAS by showing somatic Met41 mutations ablate cytoplasmic UBA1b, generate an impaired Met67-initiated isoform, reduce ubiquitylation, and trigger innate immune activation.

    Evidence Immunoblotting, flow cytometry, transcriptome/cytokine profiling, CRISPR zebrafish knockout

    PMID:33108101

    Open questions at the time
    • Does not establish which inflammatory substrates accumulate
    • Cell-type origin of disease not pinpointed
  14. 2021 High

    Quantified ubiquitin acetylation as a regulator of UBA1 catalytic efficiency, showing site-specific lysine acetylation tunes E2~Ub turnover and adds a substrate-side control on the cascade.

    Evidence Synthetic acetylated ubiquitin variants and FRET-based kinetic E2-charging assay

    PMID:33848125

    Open questions at the time
    • In vitro only; physiological acetylation stoichiometry unknown
    • Single lab
  15. 2021 Medium

    Localized VEXAS inflammation to the hematopoietic stem cell compartment, showing UBA1-mutant HSPCs are myeloid-biased and intrinsically activate interferon/TNF programs.

    Evidence Single-cell transcriptome sequencing of patient bone marrow and HSPCs

    PMID:37586319

    Open questions at the time
    • Transcriptomic correlation rather than direct mechanism
    • Does not identify the molecular trigger of lineage bias
  16. 2022 High

    Established that residual UBA1b translation level dictates VEXAS severity, with Met41 variants ranked by translational output and a cis Gly40Ala mutation able to rescue UBA1b.

    Evidence In vitro reporter translation assay, patient-derived cells, multivariate survival analysis

    PMID:35793467

    Open questions at the time
    • Does not connect translation level to specific downstream substrate defects
    • Reporter-based quantification of translation
  17. 2023 High

    Showed UBA1 inhibition impairs homologous recombination and elevates PARylation, providing a mechanistic rationale for combining E1 blockade with PARP inhibition in cancer.

    Evidence Genome-wide CRISPR screen, genetic/pharmacological UBA1 inhibition, HR and PARylation assays, patient-derived xenograft

    PMID:39626673

    Open questions at the time
    • HR substrates requiring UBA1 not individually identified
    • Relationship to the PAR-recruitment mechanism at breaks not directly tested
  18. 2023 High

    Mapped a regulatory small molecule (auranofin) to the UFD at Cys1039 and showed UFD modification enhances E2 engagement and downstream E3 and ERAD/OMMAD activity, reinforcing the UFD as the E2-handoff module.

    Evidence Biochemical binding, Cys1039 mapping, E2-charging and E3-activity assays, cellular ERAD assay

    PMID:37558718

    Open questions at the time
    • Physiological ligand of this UFD site unknown
    • Whether endogenous modification regulates UBA1 in cells untested
  19. 2024 High

    Resolved the distinct biochemical lesions across UBA1 disease variants, showing Met41 mutations alter isoform expression while non-Met41 mutations impair catalysis (including aberrant oxyester formation) and SMA mutations confer thermolability.

    Evidence In vitro thioester, transthioesterification, and oxyester assays with mutagenesis and patient cells

    PMID:37873213 PMID:38360993

    Open questions at the time
    • Does not link each biochemical defect to a clinical phenotype quantitatively
    • In vitro assays may not capture cellular compensation
  20. 2025 Medium

    Identified the UFD as the structural determinant of E2 selection by demonstrating that a UFD-to-nanobody swap redirects ubiquitin transfer to tagged E2 partners.

    Evidence Domain-swap protein engineering and in vitro ubiquitin-transfer and polyubiquitin reconstitution

    PMID:41203132

    Open questions at the time
    • Engineered system; native UFD-E2 contact map not solved here
    • Single lab/study
  21. 2025 High

    Pinpointed neutrophils as the pathogenic cell type in VEXAS-like disease, showing partial Uba1 depletion in neutrophils—but not HSCs, lymphocytes, or megakaryocytes—reproduces autoinflammation.

    Evidence Nine Cre/flox conditional knockout mouse models with cytokine, flow, and histology readouts

    PMID:40906528

    Open questions at the time
    • Reconciliation with HSC-intrinsic inflammation reports unresolved
    • Molecular trigger within neutrophils not defined
  22. 2025 Medium

    Defined cell-death and inflammatory consequences of UBA1 dysfunction, linking Met41 mutation to TNF-driven RIPK1/MLKL/caspase-8 death, defective NF-κB induction, and impaired macrophage efferocytosis.

    Evidence CRISPR THP-1 UBA1 M41V model and patient samples, RIPK1/MLKL/caspase-8 and NF-κB and efferocytosis assays (preprint)

    PMID:bio_10.1101_2025.10.06.680650

    Open questions at the time
    • Not yet peer reviewed
    • Direct substrate causing NF-κB defect not identified
  23. 2025 Medium

    Revealed an acquired UBA6 dependency in UBA1-mutant cells, showing the paralogous E1 compensates and is selectively targetable, refining the pharmacology of E1 inhibition.

    Evidence CRISPR THP-1 UBA1 M41V model, proteomics, shRNA, phytic acid (UBA6 inhibitor), competition colony assays

    PMID:40588566

    Open questions at the time
    • Single lab, engineered cell model
    • Mechanism of UBA6 compensation not detailed
  24. 2025 Medium

    Extended UBA1's substrate repertoire to specific degradation targets driving disease, showing direct ubiquitination and proteasomal degradation of ATG5 (suppressing protective autophagy in cardiac hypertrophy), BMAL1 (amplifying inflammation in sepsis), and RBM15 in cancer.

    Evidence Co-IP, ubiquitination assays, in vivo conditional knockdown/knockout with epistasis (ATG5/BMAL1/RBM15)

    PMID:37854295 PMID:41205381 PMID:41765888

    Open questions at the time
    • Each substrate shown in a single lab/context
    • The E2/E3 partners mediating these specific events not identified
  25. 2025 High

    Connected splicing-factor mutations to UBA1 vulnerability, showing SF3B1K700E mis-splices UBA1 and lowers its level, sensitizing mutant hematopoietic cells to TAK-243.

    Evidence Isogenic SF3B1 iPSC-derived hematopoietic cells, full-length RNA-seq, Western blot, TAK-243 colony assay on primary CD34+ MDS cells

    PMID:40858805

    Open questions at the time
    • Does not establish therapeutic window in patients
    • Mechanism of selective vulnerability beyond UBA1 reduction not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which specific E2/E3 routes and substrate sets mediate UBA1's distinct functions at DNA breaks, in autophagy/cell cycle, and in inflammatory signaling, and how reduced cytoplasmic charging is mechanistically converted into the cell-type-specific inflammatory program of VEXAS.
  • No unified mechanism linking UBA1b loss to neutrophil-intrinsic inflammation
  • Substrate-level changes upon partial E1 loss largely uncharacterized
  • Reconciliation of HSC-intrinsic versus neutrophil-specific disease models pending

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 3 GO:0140657 ATP-dependent activity 3 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2
Partners
ATG5AZGP1P2BMAL1GARSRBM15UBA6

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Somatic mutations at p.Met41 in UBA1 result in loss of the canonical cytoplasmic isoform of UBA1 (UBA1b) and expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. Immunoblotting, flow cytometry, transcriptome and cytokine profiling, CRISPR-Cas9 zebrafish knockout The New England journal of medicine High 33108101
2022 The p.Met41Val variant supports less UBA1b (cytoplasmic isoform) translation than p.Met41Leu or p.Met41Thr, as shown by in vitro reporter assays. Residual UBA1b translation level is fundamental to VEXAS pathogenesis and prognosis. A second mutation (p.Gly40Ala) in cis rescued UBA1b translation levels reduced by p.Met41Leu. In vitro reporter translation assay, patient-derived cell analysis, multivariate survival analysis Blood High 35793467
2024 p.Met41 VEXAS mutations alter cytoplasmic isoform expression, whereas non-p.Met41 VEXAS mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms including aberrant oxyester formation. Non-p.Met41 mutations most prominently impair transthioesterification (ubiquitin transfer to cytoplasmic E2 enzymes). SMA-causing UBA1 mutations instead render UBA1 thermolabile rather than blocking E2 charging. In vitro enzymatic assays (ubiquitin thioester formation, transthioesterification, oxyester detection), mutagenesis, patient-derived cell analysis The EMBO journal High 37873213 38360993
2012 UBA1 is required for ubiquitin conjugate formation at DNA double-strand break sites. siRNA knockdown of UBA1 (but not UBA6) impaired formation of ubiquitin conjugates at DNA damage sites and prevented IR-induced foci (IRIF) by 53BP1 and BRCA1. Chemical inhibition of UBA1 prevented IRIF formation and severely impaired DSB repair. Upstream steps (H2AX phosphorylation, MDC1 recruitment) were unaffected. siRNA knockdown, chemical inhibition, immunofluorescence for IRIF, comet assay for DSB repair Cell cycle (Georgetown, Tex.) High 22456334
2018 TAK-243 preferentially binds UBA1 over related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Missense mutations in the adenylation domain of UBA1 confer resistance to TAK-243, identifying the adenylation domain as the inhibitor binding site. Activity-based protein profiling in intact cells, selection of drug-resistant cell populations with missense mutation identification Leukemia High 29884901
2017 Crystal structure of S. pombe Uba1 in complex with Ubc15 reveals a distinct E2 binding mode that substantially alters the interaction network at the E1-E2 interface compared to previously solved E1-E2 structures. The intrinsically low E2 activity of Ubc15 results from an acidic residue at its N-terminal region. Phosphorylation of serine/threonine-rich N termini of other Ub E2s was demonstrated biochemically and in cells to serve as a negative regulatory mechanism of E2 activity. X-ray crystallography, structure-function mutagenesis, biochemical E2 charging assays, cell-based phosphorylation assays Molecular cell High 28162934
2023 Auranofin binds to UBA1's ubiquitin fold domain and conjugates to Cys1039, enhancing UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes and facilitating ubiquitin charging to E2. This increases activities of seven representative E3s in vitro and promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation and outer mitochondrial membrane-associated degradation. Biochemical binding assay, covalent modification mapping (Cys1039), in vitro E2 charging assay, E3 activity assay, cellular ERAD assay Nature communications High 37558718
2018 UBA1 is recruited to DNA by poly(ADP-ribose) (PAR), and this PAR-mediated association is necessary for ATR-dependent phosphorylation of RPA and CHK1 in response to DNA damage. UBA1 interacts directly with PAR via a solvent-accessible, positively charged patch conserved in Animalia but not Fungi. Human cell-free system, PAR interaction assay, direct UBA1-PAR binding assay, ATR signaling readout (RPA/CHK1 phosphorylation) Life science alliance High 30456359
2016 UBA1 levels are reduced in mouse and zebrafish SMA models and in patient iPSC-derived motor neurons. Systemic AAV9-mediated restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular pathology, reversing widespread ubiquitin homeostasis perturbations. AAV9 gene therapy in SMA mice, zebrafish rescue experiments, iPSC motor neuron derivation, ubiquitin conjugate measurement JCI insight High 27699224
2018 Restoration of UBA1 was sufficient to correct sensory-motor connectivity defects in SMA mice. Aminoacyl-tRNA synthetase GARS was identified as a downstream target of UBA1, regulated by a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS disrupted sensory neuron fate, phenocopying GARS-dependent Charcot-Marie-Tooth defects. AAV9-UBA1 rescue in SMA mice, proteomics (GARS identification as UBA1 target), sensory-motor connectivity electrophysiology, genetic epistasis Brain : a journal of neurology High 30239612
2013 Uba1 (the E1 ubiquitin-activating enzyme) is required for an Atg7- and Atg3-independent autophagy pathway in Drosophila intestinal cells during programmed cell size reduction. Loss of Uba1 function blocks autophagy and cell shrinkage, revealing a role for ubiquitin activation in autophagy distinct from canonical Atg8 conjugation. Genetic loss-of-function in Drosophila, autophagy and cell size assays, epistasis with Atg7/Atg3/Atg8 Nature cell biology High 23873149
2007 In Drosophila, weak Uba1 alleles protect cells from apoptosis while strong alleles cause apoptosis and cell cycle arrest with failure to degrade cyclins. Strong Uba1 mutant clones non-autonomously stimulate neighboring wild-type tissue to proliferate by failing to downregulate Notch signaling. Drosophila genetic mosaic analysis, clonal analysis, cyclin immunostaining, Notch pathway epistasis Development (Cambridge, England) High 18045837
2021 Acetylation of ubiquitin at K11, K27, K33, K48, or K63 alters the turnover number for E2~Ub conjugate formation by the E1 enzyme Uba1, as shown by FRET-based kinetic assays. Acetylation at specific Ub lysines modulates catalytic efficiency of the UBA1-mediated E2 charging step. In vitro synthesis of acetylated ubiquitin variants, FRET-based kinetic E2 charging assay (CyPet-Ub/YPet-E2) Biochemistry High 33848125
2023 A novel UBA1 variant p.Gly477Ala leads to both decreased E1 ubiquitin thioester formation and decreased E2 enzyme charging, demonstrated by in vitro enzymatic assays, expanding the catalog of catalytic loss-of-function mechanisms in VEXAS. In vitro ubiquitin thioester formation assay, E2 charging assay Arthritis & rheumatology (Hoboken, N.J.) Medium 36762418
2023 In vitro enzymatic assay of a novel UBA1 variant p.Ser621Cys demonstrated a catalytic defect, supporting pathogenicity in VEXAS syndrome. In vitro enzymatic assay JAMA Medium 36692560
2017 Of three known XL-SMA missense variants in the adenylation domain (Exon 15) of UBA1, only one impairs ubiquitin-adenylating (adenylation) activity in vitro, while all three retain normal ubiquitin thioester formation and transthioesterification rates equal to wild-type. In vitro Uba1 adenylation assay, thioester formation assay, transthioesterification assay F1000Research Medium 29034082
2014 A Met256Ile point mutation in Uba1 (tsTM3 cells) causes loss of nuclear UBA1 at non-permissive temperature, impairs ubiquitin system function in the nucleus, leads to accumulation of geminin and Cdt1 (DNA replication licensing factors), and causes S-to-G2 cell cycle arrest. Nuclear localization of UBA1 is required to rescue these defects. Temperature-sensitive CHO mutant complementation, GFP-Uba1 localization, fluorescent cell cycle indicator, Western blot for geminin/Cdt1 PloS one Medium 24805847
2012 Cys278 of UBA1 affects ubiquitin charging through conformational changes rather than direct participation at the UBA1-ubiquitin interface; UBA1(C278S) mutant forms a thioester on Cys632 (canonical catalytic cysteine) but ubiquitin conjugates persist longer compared to wild-type, indicating impaired downstream transfer. Site-directed mutagenesis (C278S, C632S), ubiquitin thioester assay, transfection of HEK293T and CMT93 cells Biochemical and biophysical research communications Medium 23022194
2011 UBA1 localizes to the acrosomal caps of spermatids and is enzymatically active in isolated sperm acrosomes (confirmed by thiol ester assay with biotinylated ubiquitin). Pharmacological inhibition of UBA1 with PYR-41 during sperm capacitation alters outer acrosomal membrane remodeling, impairs capacitation-induced protein modifications, and significantly reduces in vitro fertilization rates. Western blotting, immunofluorescence, thiol ester assay on isolated acrosomes, flow cytometry (FITC-PNA), in vitro fertilization with PYR-41 inhibitor International journal of andrology Medium 21950462
2008 Temperature-sensitive mutation in C. elegans uba-1 (the sole E1 enzyme) substantially reduces ubiquitin conjugate levels and causes meiotic progression delays in early embryos, synthetic lethality with anaphase-promoting complex (APC/C) alleles, and defects in sperm fertility, body size control, and sex-specific development. C. elegans temperature-sensitive genetics, ubiquitin conjugate immunoblot, genetic epistasis with APC/C mutants PLoS genetics High 18636104
2025 UBA1M41V-mutated monocytes exhibit TNF-α-induced cell death characterized by RIPK1 phosphorylation and MLKL/caspase-8-mediated death, associated with defective NF-κB transcriptional induction and reduced cFLIP(L). UBA1-mutated macrophages display an inflammatory transcriptional profile with increased chemokine secretion and defective efferocytosis due to lysosomal dysfunction. CRISPR-engineered THP-1 monocytic cell model (UBA1 M41V), ex vivo patient samples, RIPK1 phosphorylation assay, MLKL/caspase-8 activation assays, NF-κB reporter, efferocytosis assay bioRxivpreprint Medium bio_10.1101_2025.10.06.680650
2025 Neutrophil-specific Uba1 depletion (to ~30% residual Uba1) in mice induces VEXAS-like autoinflammatory symptoms including increased neutrophil counts, elevated proinflammatory cytokines (IL-1β, IL-6, TNFα), myeloid vacuoles, and dermatitis. Loss of Uba1 in HSCs, B cells, T cells, or megakaryocytes does not produce autoinflammatory disease, identifying neutrophils as a key pathogenic cell type. Nine Cre/flox conditional knockout mouse models, flow cytometry, cytokine measurement, histology The Journal of clinical investigation High 40906528
2025 UBA1M41V mutant cells exhibit acquired dependency on UBA6 (a paralogous E1 enzyme) that compensates for UBA1 dysfunction. TAK-243 preferentially inhibits UBA6 activity over UBA1 at relevant concentrations. Genetic or pharmacological inhibition of UBA6 selectively impairs growth and colony formation of UBA1M41V cells while sparing wild-type cells. CRISPR-engineered THP1 UBA1M41V model, proteomic analysis, shRNA knockdown, phytic acid (UBA6-specific inhibitor), competition colony formation assay Leukemia Medium 40588566
2025 UBA1 directly interacts with ATG5 and promotes its ubiquitination and proteasomal degradation, leading to autophagy suppression. Cardiomyocyte-specific UBA1 knockdown protects against TAC-induced hypertrophy by preserving ATG5-mediated autophagy; ATG5 deletion abrogates this protection. Co-immunoprecipitation, ubiquitination assay, rAAV9-mediated knockdown/overexpression in mice, TAC model, ATG5 epistasis by deletion Cell communication and signaling : CCS Medium 41765888
2025 UBA1 interacts with BMAL1 and increases its ubiquitination and proteasomal degradation in macrophages, reducing REV-ERBα transcriptional activity and increasing proinflammatory cytokine production, thereby exacerbating sepsis-associated liver dysfunction. Macrophage-specific UBA1 knockout mice, co-immunoprecipitation, ubiquitination assay, CLP sepsis model, liver function and cytokine measurements International immunopharmacology Medium 41205381
2021 In VEXAS, UBA1-mutated hematopoietic stem and progenitor cells (HSPCs) are biased toward myeloid (granulocytic) differentiation and away from lymphoid differentiation. Activation of interferon and TNF-α inflammatory pathways occurs in primitive hematopoietic cells and particularly in the myeloid lineage, with inflammation intrinsic to UBA1-mutated HSCs. Single-cell transcriptome sequencing of bone marrow mononuclear cells and HSPCs from VEXAS patients Cell reports. Medicine Medium 37586319
2023 AZGP1P2 binds to UBA1 and RBM15; UBA1 promotes ubiquitin-dependent degradation of RBM15 via ubiquitination. This was shown by RNA pull-down with mass spectrometry, co-immunoprecipitation, and RNA immunoprecipitation assays. RNA pull-down/mass spectrometry, co-immunoprecipitation, RNA immunoprecipitation, xenograft mouse model Research (Washington, D.C.) Medium 37854295
2023 UBA1 inhibition by TAK-243 impairs homologous recombination (HR) DNA repair and increases PARylation, sensitizing HR-proficient ovarian cancer cells to PARP inhibitors. A genome-wide CRISPR knockout screen identified UBA1 depletion as conferring sensitivity to PARPi. Genome-wide CRISPR KO screen, siRNA/pharmacological UBA1 inhibition, HR repair assay, PARylation assay, patient-derived xenograft in vivo combination study Cell reports. Medicine High 39626673
2025 A modular Uba1-nanobody (VHH05) fusion enzyme (Uba1-VHH05), in which the ubiquitin-fold domain (UFD) is replaced by a nanobody, selectively transfers ubiquitin to E2 enzymes fused to the cognate epitope tag, demonstrating that the UFD of Uba1 is the domain responsible for E2 selection and ubiquitin transfer specificity. Domain-swap protein engineering, in vitro ubiquitin transfer assay, Ub-Dha activity-based probe, polyubiquitin chain formation reconstitution The Journal of biological chemistry Medium 41203132
2025 SF3B1K700E mutation causes mis-splicing of UBA1 transcripts in hematopoietic cells, introducing protein instability and decreasing total UBA1 protein levels, thereby rendering SF3B1-mutated cells selectively vulnerable to UBA1 inhibitor TAK-243. Isogenic SF3B1K700E/WT iPSC lines differentiated into hematopoietic cells, full-length RNA sequencing, Western blot, TAK-243 colony-forming assay on primary CD34+ MDS cells Leukemia High 40858805

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. The New England journal of medicine 925 33108101
2021 Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1. Blood advances 197 34427584
2023 Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA 190 36692560
2021 Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS. Arthritis & rheumatology (Hoboken, N.J.) 171 33779074
2021 Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS. The Journal of allergy and clinical immunology 160 34048852
2013 Uba1 functions in Atg7- and Atg3-independent autophagy. Nature cell biology 156 23873149
2022 Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood 147 35793467
2015 UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration. Trends in molecular medicine 118 26432019
2021 Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis. Annals of the rheumatic diseases 109 33789873
2021 UBA1 Variations in Neutrophilic Dermatosis Skin Lesions of Patients With VEXAS Syndrome. JAMA dermatology 93 34495287
2012 Ubiquitin-activating enzyme UBA1 is required for cellular response to DNA damage. Cell cycle (Georgetown, Tex.) 89 22456334
2018 Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia. Leukemia 76 29884901
2016 Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI insight 73 27699224
2008 E1 ubiquitin-activating enzyme UBA-1 plays multiple roles throughout C. elegans development. PLoS genetics 65 18636104
2002 UBA1 and UBA2, two proteins that interact with UBP1, a multifunctional effector of pre-mRNA maturation in plants. Molecular and cellular biology 62 12024044
2023 Spanish cohort of VEXAS syndrome: clinical manifestations, outcome of treatments and novel evidences about UBA1 mosaicism. Annals of the rheumatic diseases 60 37666646
2007 The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously. Development (Cambridge, England) 58 18045837
2023 Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies. Leukemia 54 36823397
2023 Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS. Cell reports. Medicine 53 37586319
1996 Transcriptional analysis of the candidate spermatogenesis gene Ube1y and of the closely related Ube1x shows that they are coexpressed in spermatogonia and spermatids but are repressed in pachytene spermatocytes. Developmental biology 53 8948595
2021 Characteristic bone marrow findings in patients with UBA1 somatic mutations and VEXAS syndrome. Seminars in hematology 51 34802541
2023 Novel Somatic UBA1 Variant in a Patient With VEXAS Syndrome. Arthritis & rheumatology (Hoboken, N.J.) 48 36762418
2017 S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. Molecular cell 46 28162934
2024 Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes. Blood 44 38687605
2023 AZGP1P2/UBA1/RBM15 Cascade Mediates the Fate Determinations of Prostate Cancer Stem Cells and Promotes Therapeutic Effect of Docetaxel in Castration-Resistant Prostate Cancer via TPM1 m6A Modification. Research (Washington, D.C.) 44 37854295
2013 Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene. Neuromuscular disorders : NMD 44 23518311
2023 Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort. American journal of hematology 41 38108611
2022 Targeting the Ubiquitin-Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 41 35165102
2018 UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. Brain : a journal of neurology 37 30239612
2024 Shared and distinct mechanisms of UBA1 inactivation across different diseases. The EMBO journal 34 38360993
2024 Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome. Rheumatology (Oxford, England) 33 37606963
2011 Ubiquitin-activating enzyme (UBA1) is required for sperm capacitation, acrosomal exocytosis and sperm-egg coat penetration during porcine fertilization. International journal of andrology 33 21950462
2022 UBA1 and DNMT3A mutations in VEXAS syndrome. A case report and literature review. Modern rheumatology case reports 31 34480172
2020 The pivotal role of ubiquitin-activating enzyme E1 (UBA1) in neuronal health and neurodegeneration. The international journal of biochemistry & cell biology 30 32315770
2022 GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma. Cell death discovery 21 35347123
2023 Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes. Nature communications 20 37558718
2021 GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death. Cell death & disease 20 34301924
2022 Targeting the E1 ubiquitin-activating enzyme (UBA1) improves elexacaftor/tezacaftor/ivacaftor efficacy towards F508del and rare misfolded CFTR mutants. Cellular and molecular life sciences : CMLS 19 35292885
2021 Acetylated Ubiquitin Modulates the Catalytic Activity of the E1 Enzyme Uba1. Biochemistry 19 33848125
2017 Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy. F1000Research 19 29034082
2021 Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production. Journal of immunology (Baltimore, Md. : 1950) 16 34193603
2018 Administration of ubiquitin-activating enzyme UBA1 inhibitor PYR-41 attenuates angiotensin II-induced cardiac remodeling in mice. Biochemical and biophysical research communications 16 30249396
2023 Sensitivity to targeted UBA1 inhibition in a myeloid cell line model of VEXAS syndrome. Blood advances 15 38091008
2014 Characterization of ubiquitin-activating enzyme Uba1 in the nucleus by its mammalian temperature-sensitive mutant. PloS one 15 24805847
2024 UBA1 inhibition sensitizes cancer cells to PARP inhibitors. Cell reports. Medicine 14 39626673
2018 Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling. Life science alliance 14 30456359
2015 A catechin-enriched green tea extract prevents glucose-induced survival reduction in Caenorhabditis elegans through sir-2.1 and uba-1 dependent hormesis. Fitoterapia 14 25771124
2015 X-linked spinal muscular atrophy (SMAX2) caused by de novo c.1731C>T substitution in the UBA1 gene. Neuromuscular disorders : NMD 13 26028276
2024 UBA1 dysfunction in VEXAS and cancer. Oncotarget 12 39347709
2023 CircItgb5 promotes synthetic phenotype of pulmonary artery smooth muscle cells via interacting with miR-96-5p and Uba1 in monocrotaline-induced pulmonary arterial hypertension. Respiratory research 12 37344798
2022 Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report. BMC rheumatology 11 36038944
2020 Inhibition of the Ubiquitin-Activating Enzyme UBA1 Suppresses Diet-Induced Atherosclerosis in Apolipoprotein E-Knockout Mice. Journal of immunology research 11 32258175
2025 Hypomethylating agents for patients with VEXAS without myelodysplastic syndrome: Clinical outcome and longitudinal follow-up of vacuolization and UBA1 clonal dynamics. British journal of haematology 10 39806534
2024 Methodology and clinical utility of longitudinal UBA1 tracking in VEXAS syndrome. British journal of haematology 9 39533868
2024 Dynamic monitoring of UBA1 somatic mutations in patients with relapsing polychondritis. Orphanet journal of rare diseases 8 38167209
2022 ABCB1 limits the cytotoxic activity of TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1. Frontiers in bioscience (Landmark edition) 8 35090310
2020 A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2). Frontiers in pediatrics 6 32181232
2019 X-linked infantile spinal muscular atrophy (SMAX2) caused by novel c.1681G>A substitution in the UBA1 gene, expanding the phenotype. Neuromuscular disorders : NMD 6 31932168
2024 Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome. Rheumatology (Oxford, England) 5 38552317
2023 Novel Isoform DTX3c Associates with UBE2N-UBA1 and Cdc48/p97 as Part of the EphB4 Degradation Complex Regulated by the Autocrine IGF-II/IRA Signal in Malignant Mesothelioma. International journal of molecular sciences 5 37108544
2025 UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice. The Journal of clinical investigation 4 40906528
2022 X-Linked Spinal Muscular Atrophy 2 due to a Synonymous Variant in the UBA1 Gene in a Family with Novel Findings from Turkey. Molecular syndromology 4 35707597
2022 Uba1: A Potential Ubiquitin-like Activator Protein of Urm1 in Toxoplasma gondii. International journal of molecular sciences 4 36142209
2021 Mode of inhibitory binding of epigallocatechin gallate to the ubiquitin-activating enzyme Uba1 via accelerated molecular dynamics. RSC advances 4 35423322
2015 Nuclear localization of ubiquitin-activating enzyme Uba1 is characterized in its mammalian temperature-sensitive mutant. Genes to cells : devoted to molecular & cellular mechanisms 4 26059705
2025 SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms. Leukemia 3 40858805
2025 Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations. Leukemia 3 41068485
2023 High-Accuracy Prediction of Stabilizing Surface Mutations to the Three-Helix Bundle, UBA(1), with EmCAST. Journal of the American Chemical Society 3 37815921
2023 Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases. bioRxiv : the preprint server for biology 3 37873213
2022 Residual Structure in the Denatured State of the Fast-Folding UBA(1) Domain from the Human DNA Excision Repair Protein HHR23A. Biochemistry 3 35430812
2022 Identification of UBA1 as the causative gene of an X-linked non-Kennedy spinal-bulbar muscular atrophy. European journal of neurology 3 35996994
2012 The functional role of UBA1 cysteine-278 in ubiquitination. Biochemical and biophysical research communications 3 23022194
2025 Rapid Screening and Monitoring of UBA1 Mutations in VEXAS Syndrome. The Journal of molecular diagnostics : JMD 2 40239805
2023 UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair. Frontiers in pharmacology 2 36959858
2015 Analysis of a temperature-sensitive mutation in Uba1: Effects of the click reaction on subsequent immunolabeling of proteins involved in DNA replication. FEBS open bio 2 25834782
2025 A novel UBA1 gene mutation in a patient with infantile respiratory distress syndrome. Human genome variation 1 39762237
2025 Rapid clinical deployment of UBA1 testing in patients with VEXAS syndrome. American journal of clinical pathology 1 40418703
2025 Characterization of E1 enzyme dependencies in mutant-UBA1 human cells reveals UBA6 as a novel therapeutic target in VEXAS syndrome. Leukemia 1 40588566
2025 Clinical Manifestations of VEXAS Syndrome Across a Broad Spectrum of UBA1 Mutation Burden. Arthritis & rheumatology (Hoboken, N.J.) 1 40976851
2025 Macrophage-specific UBA1 knockout attenuates sepsis-induced liver dysfunction by regulating inflammatory responses via the BMAL1/CLOCK-REV-ERBα axis. International immunopharmacology 1 41205381
2024 A novel XNA-based Luminex assay to detect UBA1 somatic mutations associated with VEXAS syndrome. Practical laboratory medicine 1 38715663
2026 A Case of VEXAS Syndrome Initially Masked as Myelodysplastic Syndrome: Importance of Marrow Vacuolization and UBA1 Testing: A Case Report. The American journal of case reports 0 41482697
2026 UBA1 promotes cardiac hypertrophy by suppressing autophagy via targeting ATG5 for ubiquitination. Cell communication and signaling : CCS 0 41765888
2026 CDH4/UBA1/RBMX axis promotes polycystic ovary syndrome progression through YAP1 activation. Cellular & molecular biology letters 0 41882537
2026 Assessing the Frequency of VEXAS-Related Canonical UBA1 Mutations in Myelodysplastic Syndrome Patients. European journal of haematology 0 42107927
2026 UBA1-CDK16: A female-specific chimeric RNA emerging through evolution and involved in immune regulation. Science advances 0 42213831
2026 UBA1 drives cell cycle to promote malignancy and serves as a therapeutic target in Ewing Sarcoma. BMC cancer 0 42251322
2025 Vacuolated Marrow Cytopenias from Copper Deficiency to UBA1-Mutant VEXAS: Molecular Landscape, Systematic Review, and Cost-Efficient Diagnostic Algorithm. International journal of molecular sciences 0 40869363
2025 A modular Uba1-nanobody fusion enables selective ubiquitin transfer to tagged E2 enzymes. The Journal of biological chemistry 0 41203132
2025 Targeting the E1 ubiquitin-activating enzyme Uba1 impairs male fertility in Bactrocera dorsalis. Pest management science 0 41287186
2024 UBA1-CDK16 : A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism. bioRxiv : the preprint server for biology 0 38405903
2023 Involvement in Fertilization and Expression of Gamete Ubiquitin-Activating Enzymes UBA1 and UBA6 in the Ascidian Halocynthia roretzi. International journal of molecular sciences 0 37445840

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