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Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterificlation to E2 ubiquitin-conjugating enzymes

ABSTRACT: UBA1 is the primary E1 ubiquitin-activating enzyme, regulating stability and function of numerous proteins via initiating their ubiquitination. Decreased or insufficient ubiquitination can cause or drive aging and many deadly diseases. Therefore, a small-molecule UBA1 activity enhancer could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis is a potent UBA1 activity enhancer. Auranofin binds to the UBA1’s ubiquitin fold domain in vitro with a KD of 5.19 nM. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of five representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. This study discovered the first small-molecule UBA1 activity enhancer, providing a much-needed tool for UBA1 research and therapeutic exploration.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Dingyin Tao

LAB HEAD: Dingyin Tao

PROVIDER: PXD042558 | Pride | 2023-07-10

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	Human_Reviewed_2019.fasta	Fasta
	IP_1stLongGraUBA1andAF.mzid.gz	Mzid
	IP_2ndLongGraUBA1andAF.mzid.gz	Mzid
	SY_IPLongGra10012021.mzML	Mzml
	Shengyun_IP_2ndLongGraUBA1andAF.mzML	Mzml

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Covalent binding of enzymes in the ubiquitylation cascade as a response to oxidative stress

Project description:In contrast to the general ubiquitin activation and transfer cascade, we show that Uba1 binds to ubiquitin conjugating enzymes (Ubc) even in the absence of ubiquitin under mild oxidizing conditions. We show that this binding is ATP-dependent and leads to a disulfide-linkage between the catalytic cysteine residues as demonstrated with gel shift assays and visualized in a high-resolution structure of a covalent Uba1Ubc13 complex. The structure provides additional insights into the Uba1-Ubc binding mode and reveals unexpected structural changes in the N-terminus of Uba1, leading to a more open ATP-binding pocket. Immunoprecipitation experiments with yeast cells in combination with mass spectrometry revealed that several Uba~Ubc complexes are generated in vivo under oxidative stress conditions.

2017-04-11 | PXD005588 | Pride

Mass spectrometry analysis of in vitro Tau ubiquitination by the UBA1/Hsp70/CHIP machinery

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2024-06-18 | PXD034527 | Pride

CRL4(CRBN) ubiquitin ligase profiling

Project description:In the 1950s the drug thalidomide administered as a sedative to pregnant women led ot the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and ist IMiD derivatives recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase. Through an unbiased screen we identify the homeobox trranscription factor MEIS2 as an endogenous substrate of CRL4(CRBN). By definition, a specific target of CRL4(CRBN) is expected to have a very low intensity on negative control arrays (E1_E2), (E1_CRBN), (E1_E2_Cdt2), (E1_E2_Cdt2_revlimid), (E1_E2_Cdt2_CSN) or with CRL4(CRBN) in presence of inhibitor (E1_E2_CRBN_revlimid) and high intensity on arrays with CRL4(CRBN) (E1_E2_CRBN) or CRL4(CRBN) in presence of CSN (E1_E2_CRBN_CSN) Accordingly 16 protein microarrays were subjected to in vitro ubiquitylation using the following enzyme combinations: 3x Uba1+UbcH5a; 2x Uba1+UbcH5a+CRL4(DDB2); 3x Uba1+UbcH5a+CRL4(CRBN); 2x Uba1+UbcH5a+CRL4(CRBN)+lenalidomide; 2x Uba1+UbcH5a+CRL4(CRBN)+CSN; 2x Uba1+UbcH5a+CRL4(Cdt2); 1x Uba1+UbcH5a+CRL4(Cdt2)+CSN; 1x Uba1+UbcH5a+CRL4(Cdt2)+lenalidomide

2014-05-13 | E-GEOD-57554 | biostudies-arrayexpress

Orthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin enzymes

Project description:Protein ubiquitination is mediated sequentially by ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2, and ubiquitin ligase E3. Uba1 was thought to be the only E1 until the recent identification of Uba6 as an alternative. To differentiate the biological functions of Uba1 and Uba6, we applied a novel orthogonal ubiquitin transfer (OUT) technology to profile their ubiquitination targets in mammalian cells. By expressing pairs of an engineered ubiquitin and engineered Uba1 or Uba6 that were generated for exclusive interactions, we identified 697 Uba6 targets and 529 Uba1 targets with 258 overlaps. Bioinformatics revealed substantial differences in pathways involving Uba1- and Uba6-specific targets. We demonstrated that polyubiquitination and proteasomal degradation of ezrin and CUGBP1 require Uba6, but not Uba1, and Uba6 is involved in the control of ezrin localization and epithelial morphogenesis. These data reveal the distinctive substrate pools for Uba1 and Uba6 and manifest non-redundant biological roles for Uba6

2018-10-26 | PXD005500 | Pride

Downregulation of UBA1 Expression in Myelodysplastic Syndrome

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

Orthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin activating enzymes

2017-07-31 | PXD005513 | Pride

Shared and Distinct Mechanisms of UBA1 Inactivation Across Different Diseases

Project description:UBA1 initiates most cellular ubiquitin signaling by activating and transferring ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause a severe inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked autoinflammatory, somatic) syndrome. Despite extensive investigation into the clinical manifestations of this lethal disease, little is known about the underlying molecular mechanisms. Here, we systematically dissect VEXAS-causing mutations in UBA1 to better understand disease pathogenesis. We find that only UBA1 p.Met41 mutations alter cytoplasmic isoform expression, while the remaining mutations reduce catalytic function of both cytoplasmic and nuclear isoforms by diverse mechanisms, including defective ubiquitin adenylation, reduced thioesterification, and aberrant oxyester formation. Strikingly, most non-p.Met41 mutations prominently affect transthioesterification, revealing ubiquitin conjugation to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes.

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Project description:How cancer cells escape immune surveillance and resist immunotherapies remain to be elucidated. By screening candidate genes frequently amplified in cancer, we identified expression of ubiquitin-activating enzyme (UBA1) as being the most negatively correlated with signatures related to effector CD8+T cells. High expression of UBA1was strongly predictive of resistance to immune checkpoint blockade (ICB) and poor survival in ICB cohorts. In immunocompetent syngeneic models, but not in immunodeficient models, we found that overexpression ofUba1in cancer cells promoted tumor growth and reduced functional, intratumoral CD8+T cells. Conversely, depletion ofUba1impaired tumor progression, accompanied with increase of functional, intratumoral CD8+T cells. CD8+T cell depletion rescued tumor growth impairment mediated byUba1depletion. Additionally, a selective, small molecule inhibitor of UBA1, TAK-243, delayed tumor growth and augmented ICB in various syngeneic models, in a manner dependent on CD8+T cells. Intratumoral administration of TAK-243 and tumor rechallenge experiments revealed that TAK-243 treatment exhibited a remarkable abscopal effect and provided prolonged protection against cancer, accompanied with elevation of memory CD8+ T cells. Mechanistically, depletion or inactivation of UBA1 stabilized the short-lived interferon (IFN) pathway component, JAK1, upregulated both type-I and -II IFN signaling pathways, and resulted in elevation of key immune modulators, including CXCL9, CXCL10, and MHC-I. Taken together, our data supports that UBA1 mediates cancer immune escape via suppressing interferon signaling and suggests that targeting UBA1 may activate systemic cancer immunity.

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Ubiquitin-activating enzyme mediates immune escape via suppressing interferon signaling [bulk RNA-seq]

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