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Hypusine Biosynthesis in β Cells Links Polyamine Metabolism to Facultative Cellular Proliferation to Maintain Glucose Homeostasis

ABSTRACT: Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that allows for inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation, reduced production of the cell cycle molecule Cyclin D2, impaired β-cell proliferation, and overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE136581 | GEO | 2019/08/30

REPOSITORIES: GEO

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Hypusine Biosynthesis in β Cells Links Polyamine Metabolism to Facultative Cellular Proliferation to Maintain Glucose Homeostasis

Project description:Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that allows for inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation, reduced production of the cell cycle molecule Cyclin D2, impaired β-cell proliferation, and overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

2020-02-17 | PXD015424 | Pride

: Hypusine Biosynthesis in β Cells Links Polyamine Metabolism to Facultative Cellular Proliferation to Maintain Glucose Homeostasis

Project description:: Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that allows for inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation, reduced production of the cell cycle molecule Cyclin D2, impaired β-cell proliferation, and overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.

2021-09-08 | PXD015414 | Pride

Deoxyhypusine Synthase Promotes a Pro-Inflammatory Macrophage Phenotype

Project description:Obesity is characterized by adipose tissue expansion, macrophage infiltration, and the development of chronic low-grade meta-inflammation that drives insulin resistance and metabolic dysfunction. Eukaryotic translation initiation factor 5A (eIF5A) is the only protein known to be uniquely post-translationally modified and activated by deoxyhypusine synthase (DHPS) to generate a hypusine (Hyp) residue. Activated eIF5A controls the translation of a subset of mRNAs that play a role in inflammation, but a role for the DHPS/eIF5AHyp axis in obesity-associated adipose tissue inflammation has not been tested. We found DHPS/eIF5AHyp levels to be increased in the stromal vascular fraction of adipose tissue from mice fed a high fat diet and in murine macrophages activated to a proinflammatory M1 phenotype. DHPS deficiency in M1 macrophages decreased global mRNA translation and protein synthesis of key inflammatory mediators, IL-1β and MIP-1α. Transcriptomes of LPS+IFN-γ-stimulated DHPS-deficient macrophages revealed reduced characteristics of an M1 signature and a phenotypic switch consistent with characteristics of an anti-inflammatory M2 signature. In support of these observations, macrophage migration in a zebrafish tailfin injury model was reduced with chemical inhibition of DHPS, and DHPS deficiency in myeloid cells of HFD-fed mice inhibited M1 macrophage accumulation in adipose tissue and improved glucose tolerance. Together, these findings indicate that DHPS is required for the translation of a subset of mRNAs required for inflammation and chemotaxis in macrophages and may contribute to a proinflammatory M1-like phenotype.

2021-09-15 | GSE144614 | GEO

Hypusination Orchestrates the Antimicrobial Response of Macrophages

Project description:Innate responses of myeloid cells defend against pathogenic bacteria via inducible effectors. Deoxyhypusine synthase (DHPS) catalyzes the transfer of the N-moiety of spermidine to the lysine-50 residue of eukaryotic translation initiation factor 5A (EIF5A) to form the amino acid hypusine. Hypusinated EIF5A (EIF5AHyp) transports specific mRNAs to ribosomes for translation. We show that DHPS is induced in macrophages by two gastrointestinal pathogens, Helicobacter pylori and Citrobacter rodentium, resulting in enhanced hypusination of EIF5A. EIF5AHyp was also increased in gastric macrophages from patients with H. pylori gastritis. Furthermore, we identify the bacteria-induced immune effectors regulated by hypusination. This set of proteins includes essential constituents of antimicrobial response and autophagy. Mice with myeloid cell-specific deletion of Dhps exhibit reduced EIF5AHyp in macrophages and increased bacterial burden and inflammation. Thus, regulation of translation through hypusination is a critical hallmark of the defense of eukaryotic hosts against pathogenic bacteria.

2021-04-06 | MTBLS607 | MetaboLights

Deoxyhypusine synthase (DHPS) mutations alter the post-translational modification of eukaryotic initiation factor 5A (eIF5A) resulting in impaired human and mouse neural homeostasis

Project description:DHPS deficiency is a rare genetic disease caused by biallelic hypomorphic variants in the Deoxyhypusine synthase (DHPS) gene. The DHPS enzyme functions in mRNA translation by catalyzing the post-translational modification, and therefore activation, of the eukaryotic initiation factor 5A (eIF5A). The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures. Therefore, to increase our understanding of this rare disease, it is critical to determine the mechanisms by which mutations in DHPS alter neurodevelopment. In this study, we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function. Moreover, we observe a shift in the abundance of the post-translationally modified forms of eIF5A, specifically, an increase in the nuclear localized acetylated form (eIF5AAcK47) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5AHYP). Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5AHYP-dependent mRNA translation; this translation defect results in altered expression of proteins required for proper neuronal development and function. This study reveals new insight into the biological consequences and molecular impact of human DHPS deficiency and provides valuable information towards the goal of developing treatment strategies for this rare disease.

2023-06-06 | MSV000092112 | MassIVE

Essential role of translation factor eIF5a in cytokine and cell cycle regulation in primary mouse CD8 T lymphocyte

Project description:Translation of specific mRNAs is tightly regulated in primary T cells to ensure correct timing and precise delivery of protein syntheses in response to environmental cues. Translation factor eIF5a is known to be important for protein synthesis and is expected to regulate translation of certain difficult mRNA motifs such as consecutive prolines. Functional eIF5a is dynamically regulated upon T cell activation largely through addition of hypusine, a unique post-translational modification, to the mature protein and remarkably the eIF5a family are the only proteins to carry this modification. Here we show that knockout of eIF5a and its hypusination pathway affected both global and gene-specific protein synthesis, especially regulators of cytokine production and cell cycle progression. Furthermore, mRNA targets regulated by eIF5a in activated mouse primary CD8 T cells were systematically identified. AHA-labelled nascent proteins in GC7 (Dhps inhibitor)-treated and eIF5a knockout OT-1 cells (generated using CRSPR-Cas9) were measured using LC-MS. Authors: Thomas CJ Tan, Van Kelly, Xiaoyan Zhou, Tony Ly and Rose Zamoyska

2022-11-11 | PXD021063 | Pride

Oxygen level regulates protein N-terminal translation elongation through deoxyhypusine hydroxylation

Project description:Hypusine is a post-translational modification on eukaryotic translation initiation factor 5A (eIF5A). The last step in the biosynthesis of hypusine, deoxyhypusine hydroxylation, is an oxygen dependent reaction. Here we show that deletion of deoxyhypusine hydroxylase, Lia1, compromises yeast respiration through translation downregulation of proteins in respiration pathway. The translation suppression, due to the lack of deoxyhypusine hydroxylation, mainly affects the translation of the N-termini of the proteins, which is independent of the presence of proline residues, but likely dependent on the interaction between the N-terminal nascent peptide and the ribosomal peptidyl exiting tunnel. Proteomics and biochemical studies revealed that Lia1 deletion decreased the N-terminal translation of proteins involved in mitochondrial respiration, oxidative stress response, and heat shock response. Our work uncovers previously unknown functions of the hypusine modification by considering the substrate requirement of the post-translation modification, highlights the unique challenges of translating the N-termini of proteins and demonstrates a novel oxygen sensing mechanism in eukaryotic cells.

2022-08-12 | PXD032321 | Pride

Global analyses of mRNA expression in human sensory neurons reveals eIF5A as a conserved target for inflammatory pain

Project description:Nociceptors are a type of sensory neurons that is integral to most forms of pain. Targeted disruption of nociceptor sensitization affords unique opportunities to prevent pain. An emerging model for nociceptors are sensory neurons derived from human stem cells. Here, we subjected five groups to high-throughput sequencing: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC-derived sensory neurons, mature co-cultures containing hiPSC-derived astrocytes and sensory neurons, mouse DRG tissues, and mouse DRG cultures. Co-culture of nociceptors and astrocytes promotes expression of transcripts enriched in DRG tissues. Comparisons of the hiPSC models to tissue samples reveals that many key genes linked to pain are present. Marker genes indicative of a range of neuronal subtypes present in the DRG were detected in mature hiPSCs. Intriguingly, translation factors were maintained at consistently high expression levels across species and culture systems. As a proof of concept for the utility of this resource, we validated expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissues and hiPSC samples. eIF5A is subject to a unique post-translational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo. One of two hypusine inhibitors diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a proof of concept for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.

2022-06-24 | GSE192566 | GEO

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [Ribo-seq]

Project description:Hypusinated EiF5A likely impacts diverse cellular pathways through direct regulation of its translational targets or via secondary effects on other biological processes. We examined the global effects of knockdown of EiF5A and Dhps on the transcriptome and translational landscape of MYC-induced lymphoma.

2022-12-31 | GSE190670 | GEO

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [RNA-seq]

Project description:Hypusinated EiF5A likely impacts diverse cellular pathways, through direct regulation of its translational targets or via secondary effects on other biological processes. We examined the global effects of knockdown of EiF5A and Dhps on the transcriptome and translational landscape of MYC-induced lymphoma.

2022-12-31 | GSE190669 | GEO

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