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

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

PROVIDER: PRJNA1061572 | ENA |

REPOSITORIES: ENA

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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.

2024-05-17 | GSE252651 | GEO

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

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

| PRJNA1061568 | ENA

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

2024-05-17 | GSE252654 | GEO

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]

| PRJNA1061575 | ENA

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

2004-02-01 | GSE804 | GEO

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

Project description:Hypoxia Inducible Factor (HIF) prolyl hydroxylase domain (PHD) enzymes catalyse the posttranslational hydroxylation of conserved prolyl residues in the alpha-subunit of the HIF transcription factor. These modifications, which promote the degradation of HIF-alpha subunits by the pVHL E3 ligase complex and impart oxygen-dependent regulation of the HIF transcriptional response, have been extensively characterised at the molecular, cellular and organismal level. Since the discovery of the PHDs, a range of less well-characterised non-HIF substrates have been reported with the potential to confer oxygen-sensitivity to a diverse range of cellular processes. We sought to systematically compare all of the reported non-HIF substrates for their ability to support PHD-catalysed hydroxylation. We performed a comprehensive series of in vitro hydroxylation assays reacting synthetic peptides and full-length protein substrates generated by in vitro transcription and translation with purified recombinant enzyme preparations. Prolyl hydroxylation was assayed directly by mass spectrometry and radiochemical assay for hydroxyproline. Both methods enabled quantitative appraisal of enzyme-catalysed hydroxylation, with liquid chromatography mass spectrometry methods employing NMR-quantified peptide standards to calibrate retention time signatures and determine ionisation efficiencies for each target peptide. Using these approaches we assayed hydroxylation on 23 different proteins. Surprisingly, we did not detect measurable hydroxylation on any of the reported non-HIF substrates using either method. In contrast, control assays with HIF1-alpha substrate supported high stoichiometry (typically >90%) hydroxylation. Our findings suggest that PHD substrates are more restricted than has been reported.

2019-08-30 | PXD013112 | Pride

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.

| S-EPMC1299287 | biostudies-literature

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

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

| PRJNA999187 | ENA

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