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

Padgett, Leah R.; Shinkle, Mollie R.; Rosario, Spencer; Stewart, Tracy Murray; Foley, Jackson R.; Casero, Robert A.; Park, Myung Hee; Chung, Wendy K.; Mastracci, Teresa L.

doi:10.1016/j.xhgg.2023.100206

Cited by 4 publications

(2 citation statements)

References 43 publications

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“…In fact, the pathways affected in the mutant β-cells in both studies included metabolism, protein transport and mRNA processing/translation, which demonstrates that the loss of eIF5A HYP affects processes involved in β-cell response to stress. Furthermore, if one considers the studies investigating DHPS/eIF5A HYP in the exocrine pancreas ( 28 , 29 ), brain ( 46 , 47 ), and β-cell ( 30 ), and this study, we can see a common theme that suggests eIF5A HYP is a gatekeeper of specialized translation that permits professional secretory cells (exocrine, endocrine, neuron) to maintain their functional capacity during times of stress. In fact, perhaps all metabolically responsive secretory cells require a specialized translation factor to facilitate the integrity of specific protein production during times of induced/increased demand.…”

Section: Discussionmentioning

confidence: 97%

A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates β-Cell Identity and Function

Connors,

Villaca,

Anderson-Baucum

et al. 2023

Diabetes

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As professional secretory cells, beta cells require adaptable mRNA translation to facilitate a rapid synthesis of proteins, including insulin, in response to changing metabolic cues. Specialized mRNA translation programs are essential drivers of cellular development and differentiation. However, in the pancreatic beta cell, the majority of factors identified to promote growth and development function primarily at the level of transcription. Therefore, despite its importance, the regulatory role of mRNA translation in the formation and maintenance of functional beta cells is not well defined. In this study, we have identified a translational regulatory mechanism mediated by the specialized mRNA translation factor eukaryotic initiation factor 5A (eIF5A), which facilitates the maintenance of beta cell identity and function. The mRNA translation function of eIF5A is only active when it is post-translationally modified (“hypusinated”) by the enzyme deoxyhypusine synthase (DHPS). We have discovered that the absence of beta cell DHPS in mice reduces the synthesis of proteins critical to beta cell identity and function at the stage of beta cell maturation, leading to a rapid and reproducible onset of diabetes. Therefore, our work has revealed a gatekeeper of specialized mRNA translation that permits the beta cell, a metabolically responsive secretory cell, to maintain the integrity of protein synthesis necessary during times of induced or increased demand.

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Section: Discussionmentioning

confidence: 97%

A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates β-Cell Identity and Function

Connors,

Villaca,

Anderson-Baucum

et al. 2023

Diabetes

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“…Furthermore, both eIF5A and DHS are essential for cell viability in eukaryotes [11][12][13], including pathogens [14][15][16]. Hypusinated eIF5A plays a role in various pathologies and physiological processes, contributing to the regulation of cancer [17][18][19][20], immune-related diseases [21], diabetes [22,23], neurological disorders [24], aging [25], and the replication of certain viruses [26].…”

Section: Introductionmentioning

confidence: 99%

An experimental target-based platform in yeast for screeningPlasmodium vivaxdeoxyhypusine synthase inhibitors

Silva,

Klippel,

Sigurdardóttir

et al. 2023

Preprint

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The enzyme deoxyhypusine synthase (DHS) catalyzes the first step in the post-translational modification of the eukaryotic translation factor 5A (eIF5A). This is the only protein known to contain the amino acid hypusine, which results from this modification. Both eIF5A and DHS are essential for cell viability in eukaryotes, and inhibiting DHS can be a promising strategy for the development of new therapeutic alternatives. The human and parasitic orthologous proteins are different enough to render selective targeting against infectious diseases; however, no DHS inhibitor selective for the parasite ortholog has previously been reported. Here, we established a yeast surrogate genetics platform to identify inhibitors of DHS fromPlasmodium vivax,one of the major causative agents of malaria. We constructed genetically modifiedSaccharomyces cerevisiaestrains expressing DHS genes fromHomo sapiens(HsDHS) orP. vivax(PvDHS) in place of the endogenous DHS gene fromS. cerevisiae. This new strain background was ∼60-fold more sensitive to an inhibitor of human DHS than the one previously used. Initially, a virtual screen using datasets from the ChEMBL-NTD database was performed. Candidate ligands were tested in growth assays using the newly generated yeast strains expressing heterologous DHS genes. Among these, two showed promise by preferentially reducing the growth of the PvDHS-expressing strain. Further, in a robotized assay, we screened 400 compounds from the Pathogen Box library using the sameS. cerevisiaestrains, and one compound preferentially reduced the growth of the PvDHS-expressing yeast strain. Western blot revealed that these compounds significantly reduced eIF5A hypusination in yeast. Our study demonstrates that this yeast-based platform is suitable for identifying and verifying candidate small molecule DHS inhibitors, selective for the parasite over the human ortholog.

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Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons

Shojaeinia,

Mastracci,

Soliman

et al. 2024

Mol Brain

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DHPS deficiency syndrome is an ultra-rare neurodevelopmental disorder (NDD) which results from biallelic mutations in the gene encoding the enzyme deoxyhypusine synthase (DHPS). DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5 A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of Dhps at birth impairs eIF5AHYP-dependent mRNA translation. This alters expression of proteins required for neuronal development and function, and phenotypically models features of human DHPS deficiency. We studied the role of DHPS in early brain development using a zebrafish loss-of-function model generated by knockdown of dhps expression with an antisense morpholino oligomer (MO) targeting the exon 2/intron 2 (E2I2) splice site of the dhps pre-mRNA. dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons. Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome.

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

Cited by 4 publications

References 43 publications

A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates β-Cell Identity and Function

A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates β-Cell Identity and Function

An experimental target-based platform in yeast for screeningPlasmodium vivaxdeoxyhypusine synthase inhibitors

Deoxyhypusine synthase deficiency syndrome zebrafish model: aberrant morphology, epileptiform activity, and reduced arborization of inhibitory interneurons

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