Hypusination of Eif5a regulates cytoplasmic TDP-43 aggregation and accumulation in a stress-induced cellular model

Smeltzer, Shayna; Quadri, Zainuddin; Miller, Abraian; Zamudio, Frank; Hunter, Jordan; Stewart, Nicholas J.; Saji, Sheba; Lee, Daniel; Chaput, Dale; Selenica, Maj‐Linda B.

doi:10.1016/j.bbadis.2020.165939

Cited by 10 publications

(6 citation statements)

References 65 publications

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“…HSP70 is a well-known therapeutic target for SAH 14 . In addition, HSP70 was shown to inhibit the cytoplasmic accumulation of TDP-43, which is responsible for the formation of insoluble inclusion bodies and is a hallmark of neurodegenerative diseases 15 , 16 . Moreover, TDP-43 was identified as a prognostic biomarker for SAH 17 .…”

Section: Introductionmentioning

confidence: 99%

Suberoylanilide hydroxamic acid suppresses axonal damage and neurological dysfunction after subarachnoid hemorrhage via the HDAC1/HSP70/TDP-43 axis

et al. 2022

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Increased focus has been placed on the role of histone deacetylase inhibitors as crucial players in subarachnoid hemorrhage (SAH) progression. Therefore, this study was designed to expand the understanding of SAH by exploring the downstream mechanism of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in SAH. The expression of TDP-43 in patients with SAH and rat models of SAH was measured. Then, western blot analysis, immunofluorescence staining, and transmission electron microscope were used to investigate the in vitro effect of TDP-43 on a neuronal cell model of SAH established by oxyhemoglobin treatment. Immunofluorescence staining and coimmunoprecipitation assays were conducted to explore the relationship among histone deacetylase 1 (HDAC1), heat shock protein 70 (HSP70), and TDP-43. Furthermore, the in vivo effect of HDAC1 on SAH was investigated in rat models of SAH established by endovascular perforation. High expression of TDP-43 in the cerebrospinal fluid of patients with SAH and brain tissues of rat models of SAH was observed, and TDP-43 accumulation in the cytoplasm and the formation of inclusion bodies were responsible for axonal damage, abnormal nuclear membrane morphology, and apoptosis in neurons. TDP-43 degradation was promoted by the HDAC1 inhibitor SAHA via the acetylation of HSP70, alleviating SAH, and this effect was verified in vivo in rat models. In conclusion, SAHA relieved axonal damage and neurological dysfunction after SAH via the HSP70 acetylation-induced degradation of TDP-43, highlighting a novel therapeutic target for SAH.

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Section: Introductionmentioning

confidence: 99%

Suberoylanilide hydroxamic acid suppresses axonal damage and neurological dysfunction after subarachnoid hemorrhage via the HDAC1/HSP70/TDP-43 axis

et al. 2022

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“…Currently, the translation elongation factor eIF5A is the only SG protein known to be modified with the spermidine derivative hypusine. , Nonetheless, chemical inhibition of this modification results in significant reductions in the number, size, and density of SGs in stressed cells. , The inhibition of hypusination also reduces the arsenite-induced disassembly of polysomes, suggesting that hypusine-modified eIF5A may facilitate stress-induced translational repression . Indeed, arsenite stress-induced eIF5A hypusination promotes efficient SG assembly.…”

Section: Regulation Of Stress Granule Dynamicsmentioning

confidence: 99%

“…215 Hypusinated eIF5A also promotes the cytoplasmic retention and localization of TDP-43 to SGs, likely through their physical association. 216 4.1.10. Arginylation.…”

Section: Phosphorylationmentioning

confidence: 99%

A New Phase of Networking: The Molecular Composition and Regulatory Dynamics of Mammalian Stress Granules

et al. 2023

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Stress granules (SGs) are cytosolic biomolecular condensates that form in response to cellular stress. Weak, multivalent interactions between their protein and RNA constituents drive their rapid, dynamic assembly through phase separation coupled to percolation. Though a consensus model of SG function has yet to be determined, their perceived implication in cytoprotective processes ( e.g. , antiviral responses and inhibition of apoptosis) and possible role in the pathogenesis of various neurodegenerative diseases ( e.g. , amyotrophic lateral sclerosis and frontotemporal dementia) have drawn great interest. Consequently, new studies using numerous cell biological, genetic, and proteomic methods have been performed to unravel the mechanisms underlying SG formation, organization, and function and, with them, a more clearly defined SG proteome. Here, we provide a consensus SG proteome through literature curation and an update of the user-friendly database RNAgranuleDB to version 2.0 (). With this updated SG proteome, we use next-generation phase separation prediction tools to assess the predisposition of SG proteins for phase separation and aggregation. Next, we analyze the primary sequence features of intrinsically disordered regions (IDRs) within SG-resident proteins. Finally, we review the protein- and RNA-level determinants, including post-translational modifications (PTMs), that regulate SG composition and assembly/disassembly dynamics.

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“…Even if localization of eIF5A depends largely on its post-translational modifications, it can be supposed that it exerts complementary functions in the nucleus and cytoplasm. Indeed, recent advances demonstrated that hypusinated eIF5A is a RNA-binding protein associated to other cargo proteins such as exportins [ 41 , 42 , 48 ], which participate in the nuclear export of specific mRNAs including Nos2 [ 41 , 42 , 48 ], TAR DNA-binding protein 43 (TDP-43) [ 49 ] or CD83 [ 48 , 50 ]. Now, concerning acetylation of the hypusine residue of eIF5A Lee et al [ 40 ] found that acetylation of the hypusine residue by SSAT1 inactivates eIF5A and suggested a potential regulation of the eIF5A activity by reversible acetylation/deacetylation at this site.…”

Section: The Nature Of Eif5amentioning

confidence: 99%

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

et al. 2021

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Since the demonstration of its involvement in cell proliferation, the eukaryotic initiation factor 5A (eIF5A) has been studied principally in relation to the development and progression of cancers in which the isoform A2 is mainly expressed. However, an increasing number of studies report that the isoform A1, which is ubiquitously expressed in normal cells, exhibits novel molecular features that reveal its new relationships between cellular functions and organ homeostasis. At a first glance, eIF5A can be regarded, among other things, as a factor implicated in the initiation of translation. Nevertheless, at least three specificities: (1) its extreme conservation between species, including plants, throughout evolution, (2) its very special and unique post-translational modification through the activating-hypusination process, and finally (3) its close relationship with the polyamine pathway, suggest that the role of eIF5A in living beings remains to be uncovered. In fact, and beyond its involvement in facilitating the translation of proteins containing polyproline residues, eIF5A is implicated in various physiological processes including ischemic tolerance, metabolic adaptation, aging, development, and immune cell differentiation. These newly discovered physiological properties open up huge opportunities in the clinic for pathologies such as, for example, the ones in which the oxygen supply is disrupted. In this latter case, organ transplantation, myocardial infarction or stroke are concerned, and the current literature defines eIF5A as a new drug target with a high level of potential benefit for patients with these diseases or injuries. Moreover, the recent use of genomic and transcriptomic association along with metadata studies also revealed the implication of eIF5A in genetic diseases. Thus, this review provides an overview of eIF5A from its molecular mechanism of action to its physiological roles and the clinical possibilities that have been recently reported in the literature.

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Hypusination of Eif5a regulates cytoplasmic TDP-43 aggregation and accumulation in a stress-induced cellular model

Cited by 10 publications

References 65 publications

Suberoylanilide hydroxamic acid suppresses axonal damage and neurological dysfunction after subarachnoid hemorrhage via the HDAC1/HSP70/TDP-43 axis

Suberoylanilide hydroxamic acid suppresses axonal damage and neurological dysfunction after subarachnoid hemorrhage via the HDAC1/HSP70/TDP-43 axis

A New Phase of Networking: The Molecular Composition and Regulatory Dynamics of Mammalian Stress Granules

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

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