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Hypusination, a Metabolic Posttranslational Modification of Eif5a in Plants During Development and Environmental Stress Responses

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Hypusination, a Metabolic Posttranslational Modification of Eif5a in Plants During Development and Environmental Stress Responses plants Review Hypusination, a Metabolic Posttranslational Modification of eIF5A in Plants during Development and Environmental Stress Responses Péter Pálfi, László Bakacsy, Henrietta Kovács and Ágnes Szepesi * Department of Plant Biology, Institute of Biology, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52., H-6726 Szeged, Hungary; palfi[email protected] (P.P.); [email protected] (L.B.); [email protected] (H.K.) * Correspondence: [email protected] Abstract: Hypusination is a unique posttranslational modification of eIF5A, a eukaryotic translation factor. Hypusine is a rare amino acid synthesized in this process and is mediated by two enzymes, deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). Despite the essential par- ticipation of this conserved eIF5A protein in plant development and stress responses, our knowledge of its proper function is limited. In this review, we demonstrate the main findings regarding how eIF5A and hypusination could contribute to plant-specific responses in growth and stress-related processes. Our aim is to briefly discuss the plant-specific details of hypusination and decipher those signal pathways which can be effectively modified by this process. The diverse functions of eIF5A isoforms are also discussed in this review. Keywords: hypusination; polyamines; eIF5A; deoxyhypusine synthase; deoxyhypusine hydroxylase; metabolic PTM Citation: Pálfi, P.; Bakacsy, L.; Kovács, H.; Szepesi, Á. Hypusination, a Metabolic Posttranslational Modification of eIF5A in Plants 1. Introduction during Development and Protein synthesis and protein modifications are important processes that help plants Environmental Stress Responses. survive in harsh conditions. Different types of posttranslational modifications (PTMs) of Plants 2021, 10, 1261. https:// proteins exist in plants. However, hypusination is unique because it is limited to only doi.org/10.3390/plants10071261 one protein, the eukaryotic translation factor 5A known as eIF5A (reviewed in [1]). This modification is catalysed by two sequential enzymatic steps leading to the activation of Academic Editor: Adnane Boualem eIF5A by the conversion of one conserved lysine to the unusual amino acid hypusine [2]. The first step is dependent on a triamine polyamine, called spermidine (Spd), which Received: 29 April 2021 provides the 4-aminobutyl moiety group destined to the lysine of eIF5A, forming an Accepted: 21 June 2021 Published: 22 June 2021 intermediate deoxyhypusine (Dh-Hyp). Each of the enzymes in the hypusination is coded by only one gene, respectively. However, eIF5A is encoded by a small multi-gene family. The Spd-mediated hypusination is essential in eukaryotes, demonstrating one of the main Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in functions of polyamines (PAs) in plant responses from development to stress [3]. eIF5A published maps and institutional affil- plays an important role in regulating translation under stress conditions in eukaryotic iations. cells and may be critical in adapting plants to prevailing environmental conditions. The disruption of hypusination leads to growth arrest in proliferating eukaryotic cells and is fatal for the developing mammalian embryo. Plant eIF5A proteins are also highly conserved and are involved in multiple biological processes, including protein synthesis regulation, translation elongation, mRNA turnover and decay, cell proliferation, leaf and root growth, Copyright: © 2021 by the authors. seed yield, leaf, flower and fruit senescence, and programmed cell death [4–6]. eIF5A is Licensee MDPI, Basel, Switzerland. This article is an open access article necessary for mRNA translation and translocation from the nucleus to the cytoplasm [7]. distributed under the terms and eIF5A promotes the translation of polyproline [8] and other non-polyproline stalling conditions of the Creative Commons motifs ([9,10] which are poor substrates for protein synthesis, causing ribosome stalling. Attribution (CC BY) license (https:// The identification of mRNA targets depending on eIF5A in plants was started by [11]. creativecommons.org/licenses/by/ Mandal et al. (2014) [12] compared the numbers of PPP and PPG motifs in proteins 4.0/). using phylogenetic analysis and found that these motifs increased via the developmental Plants 2021, 10, 1261. https://doi.org/10.3390/plants10071261 https://www.mdpi.com/journal/plants Plants 2021, 10, x FOR PEER REVIEW 2 of 14 identification of mRNA targets depending on eIF5A in plants was started by [11]. Mandal et al. (2014) [12] compared the numbers of PPP and PPG motifs in proteins using phylo- Plants 2021, 10,genetic 1261 analysis and found that these motifs increased via the developmental level of the 2 of 13 organisms, indicating that the complexity of an organism contributes to more functions that need these motifs for regulation. In Arabidopsis, more than 3500 proteins contain at least three consecutive proline (Pro) in their structure. These proteins gained new special- level of the organisms, indicating that the complexity of an organism contributes to more ized functions asfunctions products that of needlate evolutionary these motifs for events, regulation. contributing In Arabidopsis, to the morebetter than adapta- 3500 proteins tion of plants to changincontain atg leastconditions three consecutive [2,12,13]. The proline newest (Pro) results in their show structure. that Spd, These through proteins gained its involvement newin hypusination, specialized functions can act as as products a molecular of late sentinel evolutionary to prevent events, translation contributing to the anomalies that maybetter lead adaptation to activation of plants of the to changing nonsense conditions-mediated [2 ,12decay,13]. (NMD) The newest machinery results show that and subsequent Spd,mRNA through degradation its involvement [14]. in hypusination, can act as a molecular sentinel to prevent In this review,translation we focus anomalies on representing that may lead the tohypusination activation of process the nonsense-mediated and plant-specific decay (NMD) isoforms of eIF5Amachinery associated and with subsequent growth, mRNA development, degradation and [14 stress]. responses. The recent In this review, we focus on representing the hypusination process and plant-specific findings on hypusination and the diverse role of eIF5A isoforms in plants and their animal isoforms of eIF5A associated with growth, development, and stress responses. The recent counterparts willfindings also be on discussed. hypusination and the diverse role of eIF5A isoforms in plants and their animal counterparts will also be discussed. 2. Polyamine-Dependent Hypusination of eIF5A in Plants Polyamines2. (PAs) Polyamine-Dependent are essential polycations Hypusination with crucial of eIF5A roles in Plants in the growth, develop- ment, and stress responsesPolyamines of all (PAs) living are organisms essential polycations [3]. The main with PAs crucial in plants roles in are the diamine growth, develop- putrescine (Put),ment, and andthe stresshigher responses PAs spermidine of all living (Spd) organisms and tetraamine [3]. The main spermine PAs in plants (Spm). are diamine putrescine (Put), and the higher PAs spermidine (Spd) and tetraamine spermine (Spm). Polyamine metabolism is a fundamental process in all living organisms which is connect- Polyamine metabolism is a fundamental process in all living organisms which is connect- ing with other importanting with other pathways important regulating pathways growth regulating and growthdevelopment and development and also stress and also stress responses [15–17].responses The triamine [15–17]. Spd The triamineis essential Spd in is essentialcell growth in cell and growth development, and development, as mu- as mutant tant plants with plantsdepleted with Spd depleted suffer Spd embryo suffer death embryo [18]. death Spd [18 is]. the Spd substrate is the substrate for DHS, for DHS, the the first first enzyme involvedenzyme in involved hypusination in hypusination (Figure 1). (Figure 1). Figure 1. A schematic overview of the Spd-mediated hypusination process of eIF5A in plants and related pathways. Spd is essential for the DHS reaction to produce deoxyhypusine (Dh-Hyp) on inactive forms of eIF5A via cofactor NAD+. Spd is Figure 1. A schematic overview of the Spd-mediated hypusination process of eIF5A in plants and derived from both the PA biosynthesis catalysed by Spd-synthase (SPDS) and catabolism by polyamine oxidases (PAOs). It related pathways. Spd is essential for the DHS reaction to produce deoxyhypusine (Dh-Hyp) on is worth mentioning that the metabolism of Spd is strongly connected to the biosynthesis of important signal molecules inactive forms of eIF5A via cofactor NAD+. Spd is derived from both the PA biosynthesis catalysed such as nitric oxide (NO), hydrogen peroxide (H O ), gamma-aminobutyric acid (GABA), and ethylene (ET) providing by Spd-synthase (SPDS) and catabolism2 2by polyamine oxidases (PAOs). It is worth mentioning that routes for the complex influence of Spd levels in plants. The second step of hypusination is catalysed by DOHH, which the metabolism of Spd is strongly connected to the biosynthesis of important signal molecules such needs oxygen and diiron for its function, in order to produce the hypusine of mature eIF5A. Abbreviations: Put—putrescine; as nitric oxide (NO), hydrogen peroxide (H2O2), gamma-aminobutyric acid (GABA), and ethylene Spm—spermine; L-Arg—L-arginine; L-Orn—L-ornithine; ADC—arginine
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