Dysregulation of protein homeostasis by mutant UBA1 in VEXAS syndrome [WES]
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ABSTRACT:
PROVIDER: PRJNA1251042 | ENA |
REPOSITORIES: ENA
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Project description:VEXAS is a hematopoietic disorder characterized by hyperinflammation,high mortality, and mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. Here, we developed ahuman model of VEXAS by engineering the male THP1 cell line to express the UBA1-M41V mutation. We found that UBA1-M41V cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating features of VEXAS.Proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1-M41V cells, with alterations in inflammatory and stress-response pathways. UBA1-M41V cells were sensitive to genetic or pharmacological inhibition of E1 enzymes. Treatment with theE1 inhibitor TAK-243 preferentially suppressed colony formation of UBA1-M41V cells. Moreover,UBA1-M41V cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1 ,suggesting that UBA6 may compensate for UBA1 dysfunction. Targeting UBA6 using shRNA orthe UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 inUBA1-M41V cells. Phytic acid impaired UBA1-M41V cells while sparing WT cells. Together, these findings establish a novel human model of VEXAS, identify key roles for UBA1 and UBA6, and demonstrate that UBA6 inhibition represents a therapeutic strategy for selectively targeting UBA1 mutant clones.
2025-08-06 | GSE294656 | GEO
Project description:VEXAS is a hematopoietic disorder characterized by hyperinflammation,high mortality, and mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. Here, we developed ahuman model of VEXAS by engineering the male THP1 cell line to express the UBA1-M41V mutation. We found that UBA1-M41V cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating features of VEXAS.Proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1-M41V cells, with alterations in inflammatory and stress-response pathways. UBA1-M41V cells were sensitive to genetic or pharmacological inhibition of E1 enzymes. Treatment with theE1 inhibitor TAK-243 preferentially suppressed colony formation of UBA1-M41V cells. Moreover,UBA1-M41V cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1 ,suggesting that UBA6 may compensate for UBA1 dysfunction. Targeting UBA6 using shRNA orthe UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 inUBA1-M41V cells. Phytic acid impaired UBA1-M41V cells while sparing WT cells. Together, these findings establish a novel human model of VEXAS, identify key roles for UBA1 and UBA6, and demonstrate that UBA6 inhibition represents a therapeutic strategy for selectively targeting UBA1 mutant clones.
2025-08-06 | GSE294655 | GEO
Project description:VEXAS is a hematopoietic disorder characterized by hyperinflammation,high mortality, and mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. Here, we developed ahuman model of VEXAS by engineering the male THP1 cell line to express the UBA1-M41V mutation. We found that UBA1-M41V cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating features of VEXAS.Proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1-M41V cells, with alterations in inflammatory and stress-response pathways. UBA1-M41V cells were sensitive to genetic or pharmacological inhibition of E1 enzymes. Treatment with theE1 inhibitor TAK-243 preferentially suppressed colony formation of UBA1-M41V cells. Moreover,UBA1-M41V cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1 ,suggesting that UBA6 may compensate for UBA1 dysfunction. Targeting UBA6 using shRNA orthe UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 inUBA1-M41V cells. Phytic acid impaired UBA1-M41V cells while sparing WT cells. Together, these findings establish a novel human model of VEXAS, identify key roles for UBA1 and UBA6, and demonstrate that UBA6 inhibition represents a therapeutic strategy for selectively targeting UBA1 mutant clones.
2025-08-04 | PXD063068 | Pride
Project description:VEXAS is a hematopoietic disorder characterized by hyperinflammation,high mortality, and mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. Here, we developed ahuman model of VEXAS by engineering the male THP1 cell line to express the UBA1-M41V mutation. We found that UBA1-M41V cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating features of VEXAS.Proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1-M41V cells, with alterations in inflammatory and stress-response pathways. UBA1-M41V cells were sensitive to genetic or pharmacological inhibition of E1 enzymes. Treatment with theE1 inhibitor TAK-243 preferentially suppressed colony formation of UBA1-M41V cells. Moreover,UBA1-M41V cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1 ,suggesting that UBA6 may compensate for UBA1 dysfunction. Targeting UBA6 using shRNA orthe UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 inUBA1-M41V cells. Phytic acid impaired UBA1-M41V cells while sparing WT cells. Together, these findings establish a novel human model of VEXAS, identify key roles for UBA1 and UBA6, and demonstrate that UBA6 inhibition represents a therapeutic strategy for selectively targeting UBA1 mutant clones.
2025-08-04 | PXD063067 | Pride
Project description:Dysregulation of protein homeostasis by mutant UBA1 in VEXAS syndrome [RNA-seq]
| PRJNA1251039 | ENA
Project description:Acquired mutations in the UBA1 gene, occurring in myeloid cells and resulting in expression of a catalytically impaired isoform of the enzyme E1, were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). The precise physiological and clinical impact of these mutations remains poorly defined. Here, we studied a unique prospective cohort of individuals with severe autoinflammatory disease with (VEXAS) or without (VEXAS-like) UBA1 somatic mutations and compared with low-risk myelodysplastic syndromes (MDS) and aged gender-matched healthy controls. We performed an integrated immune analysis including multiparameter phenotyping of peripheral blood leukocytes, cytokines profiling, bulk and single-cell gene expression analyses and skin tissue imaging mass cytometry. Focusing on myeloid cells, we show that monocytes from UBA1-mutated individuals were quantitatively and qualitatively impaired and displayed features of exhaustion with aberrant expression of chemokine receptors. Within affected tissues, pathological skin biopsies from VEXAS patients showed an abundant enrichment of CD16 + CD163 + monocytes adjacent to blood vessels and M1 macrophages, possibly promoting local inflammation in part through STAT3 activation. In peripheral blood from VEXAS patients, we identified a significant increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirmed the role of circulating cells in the IL-1β and IL-18 dysregulation in VEXAS patients and revealed a significant enrichment of TNF-a and NFkB signaling pathways that could mediate cell death and inflammation. Single-cell analysis confirmed the inflammatory state of monocytes from VEXAS patients and allowed us to identify specific molecular pathways that could explain monocytopenia, especially the activation of PANoptosis and a deficiency in the TYROBP/DAP12 axis and β-catenin signaling pathway. Together, these findings on monocytes from patients with UBA1 mutations provide important insights into the molecular mechanisms involving the mature myeloid commitment in VEXAS syndrome and suggest that the control of the undescribed inflammasome activation and PANoptosis could be novel therapeutic targets in this condition.
2023-11-06 | GSE216548 | GEO
Project description:UBA1 is an E1 enzyme essential for initiating ubiquitylation. We have identified 25 patients with somatic mutations in UBA1 that alter protein isoform expression in myeloid cells. We studied the transcriptional profiles of whole blood, and sorted cell populations from VEXAS patients.
2020-10-29 | GSE160268 | GEO
Project description:Somatically acquired mutations in the E1 ubiquitin-activating enzyme UBA1 within hematopoietic stem and progenitor cells (HSPCs) were recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic)1. Most VEXAS-associated mutations occur at Met41 in UBA1 and lead to clonal expansion within the HSPC and myeloid, but not lymphoid, compartments. Despite its severity and prevalence, the mechanisms whereby UBA1 mutations cause multiorgan autoinflammation and hematologic disease are unknown. Here, we employ mRNA-based electroporation of adenine base editing enzymes to mutate endogenous Uba1, generating canonical VEXAS-associated Met41 mutations in murine or human HSPCs and macrophages. Expression of Met41-mutant UBA1 in macrophages aberrantly triggered apoptotic and necroptotic inflammatory cell death programs upon exposure to TNF or LPS, which could be fully reversed by combined deletion of Mlkl or Ripk3 plus Casp8, or partially by genetic or pharmacologic targeting of RIPK1 kinase activity. In mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation, which was mediated by RIPK1 kinase activity and RIPK3-Caspase-8, respectively. In contrast, Uba1-mutant HSPCs displayed an unfolded protein response signature and spontaneous myeloid skewing that were independent of RIPK3-Caspase-8, thereby propagating an inflammatory cycle driven by their mature myeloid progeny. Mechanistically, we traced the dysregulated cell death response of Uba1-mutant macrophages to a cascading, kinetic defect in Lys63/Met1 (i.e., linear) polyubiquitylation of inflammatory signaling complexes. Collectively, our results link the pathogenesis of VEXAS with that of rarer germline monogenic causes of autoinflammation; highlight specific ubiquitin-associated defects stemming from an apical mutation in the ubiquitylation cascade; and nominate the RIPK1-RIPK3-caspase-8 death axis as a therapeutic target in VEXAS.
2025-10-08 | GSE299813 | GEO
Project description:Background and methods: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has been recently recognized as an adult-onset autoinflammatory syndrome due to somatic mutations affecting Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) gene. Following-up studies have been mostly limited to case reports; transcriptome of especially hematopoiesis in VEXAS syndrome has not been well characterized. Results: We performed whole transcriptome sequencing of single bone marrow cells (BMMNCs) and enriched Lineage-CD34+ hematopoietic stem and progenitor cells (HSPCs) from nine patients included in the original VEXAS cohort. We profiled inflammation and hematopoietic differentiation in these patients, and found activation of inflammatory gene programs particularly in marrow myeloid cells; HSPCs showed a preferred myeloid dominance. Patients had profound abnormalities in gene expression involved in pathways of inflammation, cell cycling and activation, and protein synthesis. We defined single bone marrow cells with expressed UBA1 mutations, and characterized gene expression of mutant myeloid cells as compared to that of wild-type, and observed upregulation of inflammatory pathways and immune activation; increased cell cycling might contribute to clonal dominance of UBA1 mutant cells. We were also able to profile other somatic mutations (DNMT3A) in two patients who had concurrent DNMT3A mutations at a high frequency. With coupled single cell T/B-cell receptor (TCR/BCR) sequencing, we characterized TCR and BCR repertoire in four patients, two of whom had B cell lymphocytosis. Cell-cell interaction analysis revealed enhanced interactions of myeloid cells with HSPCs, and interferons interaction with their receptors were frequent. We also performed bulk RNA sequencing of several leukemic cell lines with UBA1 knockdown, and observed upregulation of inflammatory pathways in these UBA1 knockdown cell lines. Conclusion: Our study discloses transcriptome signatures of hematopoietic cells in VEXAS syndrome, providing a broad perspective into potential pathogenesis of this novel disease.
2023-07-18 | GSE196052 | GEO
Project description:Somatic loss-of-function mutations of the ubiquitin-activating enzyme E1 gene (UBA1) that occur in VEXAS syndrome (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) also occur in myelodysplastic syndrome (MDS). This suggests that impairment of UBA1 activity contributes to the pathogenesis of these diseases, which are both characterized by systemic inflammation. We sought to determine whether abnormal expression of UBA1 in MDS contributes to disease development. We analyzed RNA sequencing results obtained from CD34+ bone marrow hematopoietic stem and progenitor cells of patients with treatment-naive MDS or chronic myelomonocytic leukemia and from heathy donors, and we detected significant downregulation of UBA1 RNA expression in MDS. In patients with MDS without excess blasts, UBA1 downregulation was associated with altered innate immune and autophagy signaling and co-occurred with SF3B1 mutations. Moreover, in cultured human bone marrow hematopoietic stem and progenitor cells and in mice, pharmacologic inhibition of UBA1 led to impaired hematopoietic repopulating activity, particularly in the erythroid compartment. These results indicate that, in addition to somatic mutations, downregulation of UBA1 may play a role in MDS pathogenesis.
2024-10-02 | GSE238153 | GEO