UBR5 mediates chemoresistance in colorectal cancer by attenuating ferroptosis via Lys11 ubiquitin-dependent stabilization of Smad3-SLC7A11 signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE236003 | GEO | 2024/01/22
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC6467774 | biostudies-literature
Project description:RIG-I like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses to numerous RNA viruses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we generated, screened 375 definite ubiquitin ligase knockout cell lines and identified UBR5 as a positive regulator of RLR transcription. UBR5 deficiency (UBR5-/-) reduced antiviral immune responses to RNA viruses, while increased viral replication in primary cells and mice. Ubr5-/- mice were more susceptible to lethal RNA virus infection than Ubr5+/+ littermates. Mechanistically, UBR5 mediated the Lysine 63-linked ubiquitination of TRIM28, an epigenetic repressor of RLRs. This modification prevented intramolecular SUMOylation of TRIM28, thus disengaged the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.
2023-12-13 | GSE245604 | GEO
Project description:RIG-I like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses to numerous RNA viruses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we generated, screened 375 definite ubiquitin ligase knockout cell lines and identified UBR5 as a positive regulator of RLR transcription. UBR5 deficiency (UBR5-/-) reduced antiviral immune responses to RNA viruses, while increased viral replication in primary cells and mice. Ubr5-/- mice were more susceptible to lethal RNA virus infection than Ubr5+/+ littermates. Mechanistically, UBR5 mediated the Lysine 63-linked ubiquitination of TRIM28, an epigenetic repressor of RLRs. This modification prevented intramolecular SUMOylation of TRIM28, thus disengaged the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.
2023-12-13 | GSE245603 | GEO
Project description:RIG-I like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses to numerous RNA viruses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we generated, screened 375 definite ubiquitin ligase knockout cell lines and identified UBR5 as a positive regulator of RLR transcription. UBR5 deficiency (UBR5-/-) reduced antiviral immune responses to RNA viruses, while increased viral replication in primary cells and mice. Ubr5-/- mice were more susceptible to lethal RNA virus infection than Ubr5+/+ littermates. Mechanistically, UBR5 mediated the Lysine 63-linked ubiquitination of TRIM28, an epigenetic repressor of RLRs. This modification prevented intramolecular SUMOylation of TRIM28, thus disengaged the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.
2023-12-13 | GSE245602 | GEO
Project description:Pluripotent stem cells undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome, a capacity that demands a highly induced proteostasis network. As such, induced pluripotent stem cells (iPSCs) suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington’s disease (HD). Here we show that proteasome activity determines HTT levels, preventing the accumulation of polyQ-expanded aggregates in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit intrinsic high levels of UBR5, an E3 ubiquitin ligase that we find required for proteasomal degradation of both normal and mutant HTT. When UBR5 fails to monitor HTT proteostasis, the concomitant up-regulation of HTT expression particularly results in polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens protein aggregation and neurotoxicity in polyQ-expanded invertebrate models. Notably, ectopic expression of UBR5 is sufficient to induce polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD cell models. However, UBR5 is dispensable for the proteostasis of other aggregation-prone proteins linked with Machado-Joseph disease or amyotrophic lateral sclerosis in iPSCs. Besides its role in HTT regulation, we find that intrinsic high levels of UBR5 also determine the global proteostatic ability of iPSCs preventing aggresome formation, suggesting a role in the control of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a central component of super-vigilant proteostasis of iPSCs with the potential to correct proteostatic deficiencies in HD.
2018-06-14 | PXD009803 | Pride
Project description:In order to understand the molecular mechanisms underlying the regulatory activities of UBR5 and CDC73 in dovitinib-induced apoptosis in 4T1 tumor cells that were Dox-silenced for the expression of Ubr5, Cdc73, or both and treated with dovitinib.
2023-01-27 | GSE222787 | GEO
Project description:Purpose: The goal of this study is to compare the transcriptome changes between Negative control, UBR5 depleted and MYC depleted HeLa cells Methods: Gene expression profiles of Negative control, UBR5 depleted and MYC depleted HeLa cells were generated by deep sequencing, in triplicate. Results:The data were analyzed, and we sucessfully detected global differences in the gene expression between the given groups. Conclusions: UBR5 depletion induces gene expression changes that are partly overlapping with gene expression changes induced by MYC depletion
2020-01-15 | GSE143517 | GEO
Project description:Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5 with the majority of mutations within the HECT domain of the protein which can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B cell maturation and activation we generated a conditional mutant disrupting UBR5’s C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and up-regulation of proteins associated with mRNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B cell maturation by regulating alternative splicing of key transcripts during B cell development and suggests UBR5 mutations may promote mantle cell lymphoma initiation.
2020-11-19 | PXD014307 | Pride
Project description:RNA-seq analysis of peritoneal macrophages derived from non-tumor bearing, WT ID8 tumor-bearing, and Ubr5 KO ID8 tumor bearing C57BL/6 mice.
2020-11-10 | GSE158911 | GEO
Project description:Almost half of the patients with advanced colorectal cancer (CRC) are resistant to oxaliplatin based therapy, the first line treatment for CRC. Therefore, predicting and understanding oxaliplatin resistance is important to improve CRC patient survival. Investigated here is the use of proteomic folding stability measurements to differentiate oxaliplatin resistant and sensitive CRCs using patient-derived CRC cell lines and patient-derived xenografts (PDXs). Three protein stability profiling techniques (including the Stability of Proteins from Rates of Oxidation (SPROX), the Thermal Protein Profiling (TPP), and Limited Proteolysis (LiP) approaches) were employed to identify differentially stabilized proteins in 6 patient-derived CRC cell lines with different oxaliplatin sensitivities and 8 CRC PDXs derived from 2 of the patient derived cell lines with different oxaliplatin sensitivity. A total of 23 proteins were found in at least 2 techniques to be differentially stabilized in both the cell line and PDX studies of oxaliplatin resistance. These 23 differentially stabilized proteins included 9 proteins that have been previously connected to cancer chemoresistance. Over-representation analysis (ORA) of all the differentially stabilized proteins identified here, revealed novel pathways related to oxaliplatin resistance. Compared to conventional protein expression level analyses, which were also performed on the cell lines and PDXs, the stability profiling techniques identified novel proteins and pathways and provided new insight on the molecular basis of oxaliplatin resistance. Our results suggest that protein stability profiling techniques are complementary to expression level analyses for identifying biomarkers and understanding molecular mechanisms associated with oxaliplatin chemoresistance in CRC and disease phenotypes in general.
2023-04-28 | PXD036298 | Pride