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Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [CRISPR]

ABSTRACT: Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [CRISPR]

PROVIDER: PRJNA1061568 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27442453.fastq.gz	Fastqsanger.gz
	SRR27442454.fastq.gz	Fastqsanger.gz
	SRR27442455.fastq.gz	Fastqsanger.gz
	SRR27442456.fastq.gz	Fastqsanger.gz

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Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response

Project description:Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response

| PRJNA1061572 | ENA

Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [CRISPR]

Project description:The ubiquitination and proteasome-mediated degradation of Hypoxia Inducible Factors (HIFs) is central to metazoan oxygen-sensing, but the involvement of deubiquitinating enzymes (DUBs) in HIF signalling is less clear. Here, using a bespoke DUBs sgRNA library we conduct CRISPR/Cas9 mutagenesis screens to determine how DUBs are involved in HIF signalling. Alongside defining DUBs involved in HIF activation or suppression, we identify USP43 as a DUB required for efficient activation of a HIF response. USP43 is hypoxia regulated and selectively associates with the HIF-1 isoform, and while USP43 does not alter HIF-1 stability, it facilitates HIF-1 nuclear accumulation and binding to its target genes. Mechanistically, USP43 associates with 14-3-3 proteins in a hypoxia-dependent manner to increase the nuclear pool of HIF-1, independently of DUB activity. Together, our results unveil the DUB landscape in HIF signalling, and highlight the multifunctionality of DUBs, illustrating that they can provide important signalling roles outside of their catalytic activity.

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Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [RNA-seq]

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Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [RNA-seq]

Project description:Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [RNA-seq]

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Deubiquitinating enzyme mutagenesis screens identify a USP43-dependent HIF-1 transcriptional response

Project description:The ubiquitination and proteasome-mediated degradation of hypoxia-inducible factors (HIFs) is central to metazoan oxygen-sensing, but the involvement of deubiquitinating enzymes (DUBs) in HIF signalling is less clear. Here, we conduct CRISPR/Cas9 mutagenesis screens using a bespoke DUBs sgRNA library to determine how DUBs are involved in HIF signalling. Alongside defining DUBs involved in HIF activation or suppression, we identify USP43 as a DUB required for efficient activation of a HIF response. USP43 is hypoxia-regulated and selectively associates with the HIF-1alpha isoform. While USP43 does not alter HIF-1alpha stability, it facilitates HIF-1 nuclear accumulation and binding to its target genes. Mechanistically, USP43 associates with 14-3-3 proteins in a hypoxia- and phosphorylation-dependent manner to increase the nuclear pool of HIF-1. Together, our results highlight the multifunctionality of DUBs, illustrating that they can provide important signalling functions alongside their catalytic roles.

| S-SCDT-10_1038-S44318-024-00166-6 | biostudies-other

Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response

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

2024-05-17 | GSE252655 | GEO

Transcriptional studies on the deubiquitinating enzyme Ubp10

Project description:Transcriptional analises of ubp10 null mutant, wild type and related null mutants. Keywords = deubiquitinating enzymes Keywords = yeast Keywords: repeat sample

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Lack of activity of recombinant HIF prolyl hydroxylases (PHDs) on reported non-HIF substrates

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VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha.

Project description:Hypoxia-inducible factor (HIF)-1alpha is a short-lived protein and is ubiquitinated and degraded through the von Hippel-Lindau protein (pVHL)-E3 ubiquitin ligase pathway at normoxia. Deubiquitination, by reversing ubiquitination, has been recognized as an important regulatory step in ubiquitination-related processes. Here, we show that pVHL-interacting deubiquitinating enzyme 2, VDU2, but not VDU1, interacts with HIF-1alpha. VDU2 can specifically deubiquitinate and stabilize HIF-1alpha and, therefore, increase expression of HIF-1alpha targeted genes, such as vascular endothelial growth factor (VEGF). These findings suggest that ubiquitination of HIF-1alpha is a dynamic process and that ubiquitinated HIF-1alpha might be rescued from degradation by VDU2 through deubiquitination. Although pVHL functions as a master control for HIF-1alpha stabilization, as pVHL-E3 ligase mediates the ubiquitination of both HIF-1alpha and VDU2, the balance between the pVHL-mediated ubiquitination and VDU2-mediated deubiquitination of HIF-1alpha provides another level of control for HIF-1alpha stabilization.

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Prolyl hydroxylase domain enzyme PHD2 inhibits proliferation and metabolism in non–small cell lung cancer cells in HIF-dependent and HIF-independent manner

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