EIF5A hypusinaion in hepatic cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Hepatocyte, Cell Culture
SUBMITTER: 
Jin Zhou
LAB HEAD: Jin Zhou
PROVIDER: PXD028714 | Pride | 2022-09-21
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| FA.raw | Raw | |||
| FASpersiD.raw | Raw | |||
| FA_sper.raw | Raw | |||
| HFX4_FPEP210000911-1A_PeptideGroups.txt | Txt | |||
| HFX4_FPEP210000911-1A_Proteins.txt | Txt |
Items per page: 5 1 - 5 of 9 |
Publications
Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
Zhou Jin J Pang Jeremy J Tripathi Madhulika M Ho Jia Pei JP Widjaja Anissa Anindya AA Shekeran Shamini Guna SG Cook Stuart Alexander SA Suzuki Ayako A Diehl Anna Mae AM Petretto Enrico E Singh Brijesh Kumar BK Yen Paul Michael PM
Nature communications 20220903 1
Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5A<sup>H</sup>). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and ce ...[more]
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Project description:The eukaryotic translation factor eIF5A plays an essential role in translation elongation, especially across stretches of prolines and charged amino acids, and in translation termination. Although eIF5A is subjected to hypusination, a post-translational modification unique to this protein, how hypusination contributes to the eIF5A function remains elusive. Here we investigated the cellular defects induced by hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane). Through proteome, translatome and transcriptome analysis, we found that GC7 decreased a subset of mitochondrial proteins and DNA (mtDNA). Furthermore, chemical genomic screening using barcoded shRNA libraries identified genes for particular proteins involved in polyamine metabolism and a mitochondrial protein MPV17L2 as those altering the cytotoxicity induced by GC7. Depletion of MPV17L2 led to hypersensitivity to GC7 as well as the decreases in mitochondrial proteins and mtDNA. Moreover, metabolome analysis revealed that MPV17L2 depletion and GC7 treatment additively decreased the amount of proline and asparagine. Our results indicate that MPV17L2 displays a synthetic lethal interaction with the eIF5A hypusination targeted by GC7. The eukaryotic translation factor eIF5A plays an essential role in translation elongation, especially across stretches of prolines and charged amino acids, and in translation termination. Although eIF5A is subjected to hypusination, a post-translational modification unique to this protein, how hypusination contributes to the eIF5A function remains elusive. Here we investigated the cellular defects induced by hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane). Through proteome, translatome and transcriptome analysis, we found that GC7 decreased a subset of mitochondrial proteins and DNA (mtDNA). Furthermore, chemical genomic screening using barcoded shRNA libraries identified genes for particular proteins involved in polyamine metabolism and a mitochondrial protein MPV17L2 as those altering the cytotoxicity induced by GC7. Depletion of MPV17L2 led to hypersensitivity to GC7 as well as the decreases in mitochondrial proteins and mtDNA. Moreover, metabolome analysis revealed that MPV17L2 depletion and GC7 treatment additively decreased the amount of proline and asparagine. Our results indicate that MPV17L2 displays a synthetic lethal interaction with the eIF5A hypusination targeted by GC7. numerous molecules serving as valuable therapeutics. The marine natural product girolline has been described as an inhibitor of protein synthesis. Here, we demonstrate that it is not a general translation inhibitor but represents a sequence-specific modulator of translation factor eIF5A. Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling, primarily on AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in ribosome-associated quality control (RQC) and is important in maintaining the efficiency of translational progress. Girolline, therefore, provides a potent tool compound for understanding the interplay between protein production and quality control in a physiological setting and offers a new and selective means of modulating gene expression. numerous molecules serving as valuable therapeutics. The marine natural product girolline has27 been described as an inhibitor of protein synthesis. Here, we demonstrate that it is not a general28 translation inhibitor but represents a sequence-specific modulator of translation factor eIF5A.29 Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling, primarily on30 AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in31 ribosome-associated quality control (RQC) and is important in maintaining the efficiency of32 translational progress. Girolline, therefore, provides a potent tool compound for understanding33 the interplay between protein production and quality control in a physiological setting and offers34 a new and selective means of modulating gene expression.
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Project description:Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.
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