Saccharomyces cerevisiae
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA396954 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5891380.fastq.gz | Fastqsanger.gz | |||
| SRR5891375.fastq.gz | Fastqsanger.gz | |||
| SRR5891376.fastq.gz | Fastqsanger.gz | |||
| SRR5891377.fastq.gz | Fastqsanger.gz | |||
| SRR5891378.fastq.gz | Fastqsanger.gz |
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Project description:The conserved Ccr4-Not complex regulates all aspects of the RNA polymerase II (Pol II) gene expression pathway, while it also controls proteasome assembly and function. The Not4 RING domain ubiquitin ligase is a core subunit that also contains an RNA recognition motif (RRM) and C3H1 domain (collectively referred to as the RRM-C) whose function is unknown. Herein, we demonstrate that the Not4 RRM-C contributes to both Not4-dependent regulation of the proteasome and Pol II. Disruption of both Not4 ligase activity and the RRM-C domain simultaneously replicates the proteasome-dependent deubiquitylation and catalytic activity misregulation found in Not4-deficient cells. Transcriptome analysis reveals that the Not4 RRM-C affects a subset of Pol II-dependent genes involved in specific biological functions, including transcription elongation, cyclin-dependent kinase regulated nutrient responses, and ribosomal biogenesis. At these genes, the Not4 RRM-C negatively regulates Pol II binding. While Not4 RRM-C disruption modestly increases between Ccr4-Not and Pol II, a Not4 ligase mutant decreases Ccr4-Not association with Pol II, thus implicating Not4-dependent ubiquitylation in mediating Ccr4-Not interaction with Pol II. Collectively, our results suggests the cellular RNA environment may integrate control of global proteostasis and Pol II transcription through the Not4 ubiquitin ligase.
2017-08-03 | GSE102192 | GEO
Project description:The Ccr4-Not complex containing the Not4 ubiquitin ligase regulates gene transcription and mRNA decay, yet it also has poorly defined roles in translation, proteostasis, and endolysosomal-dependent nutrient signaling. To define how Ccr4-Not mediated ubiquitin signaling regulates these additional processes, we performed quantitative proteomics in the yeast Saccharomyces cerevisiae lacking the Not4 ubiquitin ligase and in cells overexpressing either wild-type or functionally inactive ligase. Herein, we provide evidence that both increased and decreased Ccr4-Not ubiquitin signaling disrupts ribosomal protein (RP) homeostasis independently of reduced RP mRNA changes or reductions in known Not4 ribosomal substrates. Surprisingly, we also find that Ccr4-Not inhibits 40S ribosomal autophagy through Not4-dependent ubiquitin signaling and the additional Ccr4 subunit. This 40S autophagy is independent of canonical Atg7-dependent macroautophagy, thus indicating microautophagy activation is responsible. Furthermore, the Not4 ligase genetically interacts with endolysosomal pathway effectors to control both RP expression and 40S autophagy efficiency. Overall, we demonstrate that balanced Ccr4-Not ligase activity maintains RP homeostasis, and that Ccr4-Not ubiquitin signaling interacts with the endolysosomal pathway to regulate RP expression and inhibit 40S ribosomal autophagy.
2024-10-17 | PXD044420 | Pride
Project description:Dosage compensation in Drosophila is an epigenetic phenomenon utilizing proteins and long non-coding RNAs (lncRNAs) for transcriptional up-regulation of the entire X-chromosome. Here, UV cross-linking followed by deep sequencing (iCLIP) show that two enzymes in the Male-Specific Lethal complex, MLE RNA helicase and MSL2 ubiquitin ligase, bind evolutionarily conserved domains containing tandem stem-loops in roX1 and roX2 RNAs in vivo.
2013-07-18 | E-MTAB-1669 | biostudies-arrayexpress
Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant. Efficacy of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia requires degradation of the oncogenic fusion between the Promyelocytic Leukemia Protein (PML) with the Retinoic Acid Receptor Alpha (RARA). Here we use CRISPR-based screens to identify the HECT E3 ubiquitin ligase UBR5 as a ligase for PML-RARA and RARA and observe an agonist-dependent association between RARA and UBR5, which occurs directly on chromatin to regulate transcription. We present the cryo-EM structure of full-length human UBR5 and identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. We demonstrate that UBR5 utilizes this conserved degron to additionally regulate hormone dependent protein stability for the glucocorticoid, progesterone, and vitamin D receptors. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
2023-07-20 | PXD041749 | Pride
Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant. Efficacy of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia requires degradation of the oncogenic fusion between the Promyelocytic Leukemia Protein (PML) with the Retinoic Acid Receptor Alpha (RARA). Here we use CRISPR-based screens to identify the HECT E3 ubiquitin ligase UBR5 as a ligase for PML-RARA and RARA and observe an agonist-dependent association between RARA and UBR5, which occurs directly on chromatin to regulate transcription. We present the cryo-EM structure of full-length human UBR5 and identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. We demonstrate that UBR5 utilizes this conserved degron to additionally regulate hormone dependent protein stability for the glucocorticoid, progesterone, and vitamin D receptors. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
2023-07-20 | PXD040953 | Pride
Project description:In fission yeast, meiosis-specific transcripts are selectively eliminated during vegetative growth by the combined action of the YTH-family RNA-binding protein Mmi1 and the nuclear exosome. Upon nutritional starvation, the master regulator of meiosis Mei2 inactivates Mmi1, thereby allowing expression of the meiotic program. Here, we show that the E3 ubiquitin ligase subunit Not4/Mot2 of the evolutionarily conserved Ccr4-Not complex, which associates with Mmi1, promotes suppression of meiotic transcripts expression in mitotic cells. Our analyses suggest that Mot2 directs ubiquitination of Mei2 to preserve the activity of Mmi1 during vegetative growth. Importantly, Mot2 is not involved in the constitutive pathway of Mei2 turnover, but rather plays a regulatory role to limit its accumulation or inhibit its function. We propose that Mmi1 recruits the Ccr4-Not complex to counteract its own inhibitor Mei2, thereby locking the system in a stable state that ensures the repression of the meiotic program by Mmi1.
2017-08-23 | GSE72327 | GEO
Project description:CD8+ tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to differentiation to T cell exhaustion. In healthy tissues, tissue-resident memory T cells (TRM) survey tissues and sustain protective capacity for years, and tumors that contain TIL with TRM-features are associated with better patient prognosis. We identified protein homeostasis (proteostasis) significant in distinguishing TRM and progenitor-exhausted TIL (TPEX) from terminally-exhausted TIL (TEX) by identifying multiple E3 ubiquitin ligases that maintain T cell differentiation potential. Sustained ligase-expression in TIL enhanced T cell accumulation, preserved stem-like TCF1+ populations, and improved anti-tumor function, whereas ligase loss-of-function impaired TIL and altered T cell differentiation in acute infection. TEX experience a loss of proteostasis, marked by unfolded protein accumulation despite functional proteasomes. Enforced ligase expression rescued this unfolded protein accumulation in TIL and improved immunotherapy responses, demonstrating the role of proteostasis in maintaining differentiation potential and identifying new avenues for advancing cancer immunotherapies.
2026-04-22 | GSE298128 | GEO
Project description:CD8+ tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to differentiation to T cell exhaustion. In healthy tissues, tissue-resident memory T cells (TRM) survey tissues and sustain protective capacity for years, and tumors that contain TIL with TRM-features are associated with better patient prognosis. We identified protein homeostasis (proteostasis) significant in distinguishing TRM and progenitor-exhausted TIL (TPEX) from terminally-exhausted TIL (TEX) by identifying multiple E3 ubiquitin ligases that maintain T cell differentiation potential. Sustained ligase-expression in TIL enhanced T cell accumulation, preserved stem-like TCF1+ populations, and improved anti-tumor function, whereas ligase loss-of-function impaired TIL and altered T cell differentiation in acute infection. TEX experience a loss of proteostasis, marked by unfolded protein accumulation despite functional proteasomes. Enforced ligase expression rescued this unfolded protein accumulation in TIL and improved immunotherapy responses, demonstrating the role of proteostasis in maintaining differentiation potential and identifying new avenues for advancing cancer immunotherapies.
2026-04-22 | GSE298127 | GEO
Project description:Some proteins have acquired both ubiquitin ligase activity and RNA-binding properties and are therefore known as RNA-binding Ubiquitin ligases (RBULs). These proteins provide a link between the RNA metabolism and the ubiquitin proteasome system (UPS). The UPS is a crucial protein surveillance system of eukaryotes primarily involved in the selective proteolysis of proteins which are covalently marked with ubiquitin through a series of steps involving ubiquitin E1 activating, E2 conjugating and E3 ligating enzymes. The UPS also regulates other key cellular processes such as cell cycle, proliferation, cell differentiation, transcription and signal transduction. While RBULs have been characterized in other organisms, little is known about their role in Plasmodium falciparum, the causative agent of the deadliest human malaria, malaria tropica. In this study, we characterized a previously identified putative P. falciparum RING finger E3 ligase PfRNF1. We show that the protein is highly expressed in sexual stage parasites and mainly present in immature gametocytes. Using proximity interaction studies with parasite lines expressing PfRNF1 tagged with the Biotin ligase BirA, we identified an interaction network of PfRNF1 in both the asexual blood stages and gametocytes composed mainly of ribosomal proteins, RNA-binding proteins including translational repressors such DOZI, CITH, PUF1 and members of the CCR4-NOT complex, as well as proteins of the UPS such as RPN11, RPT1 and RPT6. Our interaction network analysis reveals PfRNF1 as a potential RNA-binding E3 ligase which links RNA dependent processes with protein ubiquitination to regulate gene expression.
| PXD040384 | JPOST Repository