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Results for “Ubiquitin-Activating Enzymes”

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PubMed2026

Inflammatory cell death and monocyte dysfunction in VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe adult-onset autoinflammatory disease caused by somatic mutations in the UBA1 gene, disrupting cytoplasmic ubiquitin-activating enzyme E1 function in hematopoietic progenitors. Its pathogenesis remains poorly understood, particularly the mechanisms by which UBA1 mutations disrupt myeloid cell function in the context of inflammatory stimuli. Here, we combine a genetically engineered THP-1 monocytic model with ex vivo analyses of blood and tissue samples from patients with VEXAS syndrome to investigate the consequences of the canonical UBA1M41V mutation. We show that UBA1-mutated monocytes exhibit tumor necrosis factor α (TNF-α)-induced cell death, characterized by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) phosphorylation, and mixed lineage kinase domain-like- and caspase-8-mediated cell death. Importantly, we extend these findings to patient-derived CD14+ sorted cells, confirming that these cells undergo aberrant apoptotic and necroptotic cell death. Mechanistically, activation of these cell death pathways appears to be promoted by defective NF-κB-dependent transcriptional responses and reduced cFLIP(L) expression following TNF-α stimulation. UBA1-mutated monocytes also display blunted cytokine responses to Toll-like receptor (TLR) agonists despite preserved TLR expression, linked to an impaired NF-κB response. UBA1M41V-derived macrophages exhibit a proinflammatory transcriptional profile with increased chemokine secretion that promotes monocyte recruitment. In addition, these UBA1-mutated macrophages display impaired efferocytosis due to lysosomal dysfunction. Together, these findings reveal a pathogenic axis in VEXAS syndrome linking UBA1 loss of function and defective ubiquitination to RIPK1-mediated inflammatory cell death, impaired antimicrobial signaling, and defective resolution mechanisms. Our study provides novel mechanistic insights into the myeloid dysfunction underlying inflammation and cytopenia in VEXAS syndrome and supports the therapeutic targeting of inflammatory cell death pathways.

Humans↗

PubMed2026

Quercetin, a flavonoid, suppresses viral proliferation by interfering with the ubiquitin transfer from E1 to E2 enzymes.

Quercetin is recognized for diverse pharmacological activities. However, the mechanism underlying its broad-antiviral effects has not been elucidated. Herein, we identified quercetin as a potent inhibitor of both double-stranded DNA virus Bombyx mori nucleopolyhedrovirus (BmNPV) and single-stranded RNA virus porcine reproductive and respiratory syndrome virus (PRRSV). Surface plasmon resonance (SPR) revealed that quercetin targets host ubiquitin-activating enzyme 1 (Uba1) homologs. Uba1 knockdown reduced viral proliferation and enhanced the antiviral effect of quercetin, whereas Uba1 overexpression functioned oppositely. Quercetin bound Uba1 homologs with high affinity. Notably, mutation of two binding residues, Q977 and G978, significantly disrupted the binding between BmUba1 and quercetin, and abolished quercetin's antiviral activity. Quercetin obstructed the transfer of ubiquitin from Uba1 to the E2 enzyme Ubc6, impairing the ubiquitination process. Similarly, quercetin inhibited PRRSV proliferation via targeting Uba1 in mammals. These findings elucidate the molecular mechanism underlying the pharmacological effects of quercetin, providing a theoretical basis for the development of novel antiviral agents against both DNA and RNA viruses.

Quercetin↗

PubMed2025

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: A comprehensive review of cases across different ethnicities.

OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) is an autoinflammatory disease associated with somatic mutations in the UBA1 gene. Although the disease has been described in many different countries, no studies have investigated the origin of patients to determine if the disease is universal across ancestries. The aim of this study is to investigate the distribution of VEXAS syndrome across continents and ethnicities. METHODS: A literature review of all reported cases of VEXAS syndrome was conducted between October 2020 and April 2025 using the term 'VEXAS' with the all-field filter in the Pubmed and Web of Science databases. Epidemiological and clinical data were collected for included patients. If the country of origin was not described, it was assumed to be the same as the country of clinical evaluation. A subgroup analysis was performed for patients whose country of origin or ethnicity was documented by the authors. RESULTS: 674 cases of VEXAS syndrome were collected, with patients described from four continents and 32 countries. Considering the subgroup of patients with documented country of origin, 451 patients were from four continents and 19 countries. Of these, ethnicity was recorded for 372 patients with the presence of Caucasian, Central or East Asian, South Asian, Middle Eastern, Central American and South American ethnicities. CONCLUSION: The results support a broad global distribution of the disease and highlight the importance of investigating the disease regardless of the patient's origin and ethnicity in cases of compatible symptoms.

Humans↗

PubMed2025

American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.

OBJECTIVE: Vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality. METHODS: Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts. RESULTS: Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management. CONCLUSION: This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.

Humans↗

PubMed2021

Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS.

OBJECTIVE: Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. METHODS: Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. RESULTS: Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×103 /μl differentiated VEXAS-RP from RP with 100% sensitivity and 96% specificity. CONCLUSION: Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.

Aged↗

PubMed2025

Diagnostic and Monitoring Strategies for VEXAS Syndrome: Evaluating Sanger Sequencing, NGS, and the SWIM-Score.

VEXAS syndrome is an adult-onset autoinflammatory disorder caused by somatic UBA1 variants, but there are no standardized criteria for genetic testing or diagnostics. This study compared Sanger sequencing and next-generation sequencing (NGS) for detecting UBA1 variants in patients with suspected VEXAS, assessed the ability of Sanger sequencing to estimate variant allele fractions (VAFs), and evaluated the Maeda et al. scoring system for selecting patients for genetic testing in a primary cohort and a validation cohort. In the primary cohort of 104 patients, Sanger sequencing identified VEXAS variants in 12%, with no additional cases detected by NGS. Sanger sequencing accurately quantified VAFs ranging from 0.1 to 0.9. In a small longitudinal subset (n = 3), VAFs in blood correlated with CRP levels, increased over time despite various treatments, but decreased in two patients after initiation of Azacitidine treatment. The novel parameters, VAF in myeloid cells and VEXAS cell concentration, showed promise as exploratory markers for patient monitoring. The Maeda-score, requiring a threshold score of 2 for 100% sensitivity, exhibited low specificity-29% in the primary cohort and 41% in the validation cohort (n = 62, with 2 carrying VEXAS variants). In contrast, the simplified SWIM-score-based on Skin involvement, Weight loss, Inflammation, and Macrocytic anemia-achieved 100% sensitivity in both cohorts, with higher specificities of 47% and 65%, respectively. In conclusion, Sanger sequencing reliably detected UBA1 variants and quantified VAFs. Monitoring VAF and VEXAS cell concentration may track disease progression, and the SWIM-score demonstrated potential for accurately selecting patients for UBA1 testing.

Humans↗

PubMed2025

HDAC6-dependent deacetylation of SAE2 enhances SUMO1 conjugation for mitotic integrity.

Mammalian cells express three conjugatable SUMO variants: SUMO1 and the closely related SUMO2 and SUMO3 (together referred to as SUMO2/3). While some substrates are modified by both, others show a clear preference, though the basis for this selectivity remains unclear. Here, we examine a modification of the catalytic component of the human SUMO activation enzyme, SAE2. We find that lysine 164 of SAE2 undergoes HDAC6-dependent deacetylation during mitosis. A non-deacetylatable acetyl-mimetic mutant, SAE2-K164Q, selectively enhances SUMO2 over SUMO1 activation and conjugation, and distinguishes between SUMO1 and SUMO2/3 based on differences in their C-terminal tails. Complementation of SAE2-deficient or inhibited cells with SAE2-K164Q suppresses mitotic SUMO1 conjugation and promotes multipolar spindle formation. We identify NuMA as a SUMO E1-dependent substrate and demonstrate that mitotic defects caused by SAE2-K164Q or HDAC6 inhibition are rescued by SUMO1 overexpression or expression of a GFP-SUMO1-NuMA-K1766R fusion. These results support a model in which SAE1:SAE2 deacetylation during early mitosis promotes SUMO1 conjugation to ensure mitotic fidelity, highlighting a regulatory role for the SUMO-activating enzyme in the selection of SUMO proteins.

Humans↗

PubMed2026

Assessing the Frequency of VEXAS-Related Canonical UBA1 Mutations in Myelodysplastic Syndrome Patients.

OBJECTIVES: Somatic mutations in the UBA1 gene cause VEXAS syndrome, which presents with inflammatory and hematological symptoms. Case studies show a strong overlap between VEXAS and myelodysplastic syndrome (MDS). Recognizing VEXAS is important for differential diagnosis in patients with both inflammation and MDS, as accurate identification guides treatment. The study focuses on determining how often canonical UBA1 mutations linked to VEXAS occur in MDS patients. METHODS: Patients diagnosed with MDS were enrolled in the study, and genomic DNA was isolated from bone marrow FFPE samples. Molecular analysis was performed using a specifically designed ARMS-PCR approach. Additionally, protein-protein interaction (PPI) studies combined with bioinformatic analyses were carried out to explore potential links between UBA1 and pyroptosis. RESULTS: Among the 149 MDS patients analyzed, none exhibited high-Variant Allele Frequency (VAF) the canonical UBA1 point mutations linked to VEXAS syndrome. PPI analysis revealed a possible association between UBA1 and the NLRP3 inflammasome component. CONCLUSIONS: Expanding the sample size and using targeted NGS or ddPCR would improve mutation detection sensitivity and could reveal UBA1 canonical and non-canonical variants and more accurately estimate the frequency of VEXAS-related mutations in the MDS population.

Humans↗

PubMed2026

Disruption of the ubiquitin-mediated proteolysis pathway: a study of seed aging in Saposhnikovia divaricata caused by UBC1 gene family suppression.

BACKGROUND: Saposhnikovia divaricata (Turcz.) Schischk. is a perennial herb whose seed aging during storage significantly reduces germination rates, limiting industrial-scale production. Reactive oxygen species (ROS)-induced oxidative damage is a key driver of seed aging, but the underlying mechanisms in Saposhnikovia divaricata remain unclear. RESULTS: Suppression of the UBC1 gene family reduces the activity of ubiquitin-conjugating enzymes, leading to dysfunction of the ubiquitin-mediated proteolysis pathway, which in turn decreases protein degradation efficiency and causes the accumulation of damaged proteins. Transcriptome analysis revealed predominant downregulation of genes crucial for seed physiological maintenance. By the fourth year of storage, germination dropped sharply to 30.67%, accompanied by embryo cavitation. Downregulation of ribosome pathway genes hindered ribosome assembly and protein synthesis, while suppression of endoplasmic reticulum protein processing genes led to unfolded/misfolded protein accumulation and intensified cellular stress, accelerating aging. Proteomic analysis showed increased total differential and antioxidant-related proteins. ROS content fluctuated with storage time: peroxyl radicals peaked in year two (5.68 RFU/mg), whereas hydroxyl radicals and hydrogen peroxide were highest in year four (0.0655 pg/mL and 0.0946 pg/mL, respectively), with significant differences across periods. Elevated membrane-related proteins, increased electrical conductivity, and malondialdehyde content (maximum 54.30 nmol/g at year four) confirmed oxidative membrane damage. ROS-induced stress promotes protein misfolding, and reduced UBC1 expression is associated with impaired clearance of misfolded proteins by the ubiquitin-mediated proteolysis pathway. CONCLUSIONS: This study provides the first integrated transcriptomic and proteomic insight into UBC1 deficiency-mediated seed aging in Saposhnikovia divaricata. The findings enhance molecular understanding of seed aging and offer new directions for improving seed storage and viability.

Ubiquitin-Conjugating Enzymes↗