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UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding

ABSTRACT: UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding

PROVIDER: PRJNA882453 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21641600_1.fastq.gz	Fastqsanger.gz
	SRR21641600_2.fastq.gz	Fastqsanger.gz
	SRR21641601_1.fastq.gz	Fastqsanger.gz
	SRR21641601_2.fastq.gz	Fastqsanger.gz
	SRR21641602_1.fastq.gz	Fastqsanger.gz

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UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding [RNA-Seq]

Project description:UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding [RNA-Seq]

| PRJNA882456 | ENA

UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding [ChIP-Seq]

Project description:UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding [ChIP-Seq]

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UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding [ChIP-Seq]

Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are important therapeutic targets in malignancy. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant: the oncogenic PML-RARA fusion between PML and the retinoic acid receptor (RARA) drives acute promyelocytic leukemia and degradation of PML-RARA induced by all-trans-retinoic acid (ATRA) is required for anti-tumor activity. We 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. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.

2023-07-20 | GSE213742 | GEO

UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Stability

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

UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Stability

2023-07-20 | PXD040953 | Pride

UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding [RNA-Seq]

Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are important therapeutic targets in malignancy. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant: the oncogenic PML-RARA fusion between PML and the retinoic acid receptor (RARA) drives acute promyelocytic leukemia and degradation of PML-RARA induced by all-trans-retinoic acid (ATRA) is required for anti-tumor activity. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.

2023-07-20 | GSE213793 | GEO

UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-20 | GSE213795 | GEO

UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors

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.

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A specialized Hsp90 co-chaperone network regulates steroid hormone receptor response to ligand

Project description:Heat shock protein-90 chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function towards client activity in cells remains elusive. Here, we dissected the impact of newly identified co-chaperones in higher eukaryotes, FNIP1/2 (FNIPs) and Tsc1, towards Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1 and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. Here, we provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.

2023-05-30 | PXD030486 | Pride

UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors (RNA-Seq)

2023-12-13 | GSE245603 | GEO