Protein nitration: A connecting bridge between nitric oxide (NO) and plant stress

Plant Stress 2 (2021) 100026 Available online 13 July 2021 2667-064X/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Review Protein nitration: A connecting bridge between nitric oxide (NO) and plant stress Francisco J. Corpas * , Salvador Gonz´ alez-Gordo, Jos´ e M Palma Group of Antioxidants, Free Radicals and Nitric Oxide in Biotechnology, Food and Agriculture. Department of Biochemistry, Cell and Molecular Biology of Plants, Estaci´ on Experimental del Zaidín (Spanish National Research Council, CSIC), C/ Profesor Albareda, 1, 18008 Granada, Spain ARTICLE INFO Keywords: Nitric oxide Nitro-oxidative stress Tyrosine Nitration Reactive nitrogen species ABSTRACT Nitric oxide ( • NO) is a free radical which exerts a myriad of functions in the physiology of higher plants either under physiological and environmental stress conditions. NO, and derived molecules designated as reactive nitrogen species (RNS), can mediate posttranslational modifications (PTMs) of proteins which can affect their functionality. Among these NO/RNS-derived PTMs, it can be highlighted S-nitrosation, metal nitrosylation and nitration. This last one involves the addition of a nitro group (-NO 2 ) to some specific amino acids such as tyrosine or tryptophan. An increase in the content of protein nitration has been recognized as a suitable marker of nitrooxidative stress which is frequently associated with oxidative stress under diverse environmental stress conditions. This mini-review aims to provide a comprehensive overview of protein nitration and its significance in higher plants. Introduction Higher plants are exposed to continuous environmental changes of both biotic and abiotic origins such as pathogens, extreme temperatures, drought, salinity, heavy metals, ozone or mechanical wounding, respectively. As consequence, plants trigger a battery of responses to counteract their possible negative aftermaths which usually affect basic biochemical processes such as photosynthesis, respiration or nutrient uptake. The provoked metabolic imbalances finally interfere with growth, development, and productivity that can even trigger cell and plant death (Gong et al., 2020; St¨ ockle and Kemanian, 2020; Hamann et al., 2021; Sychta et al., 2021). Many stresses are associated with a generation of reactive oxygen species (ROS) and their uncontrolled overproduction usually generates as oxidative stress (Qi et al., 2018; Ehonen et al., 2019; Kaya et al., 2020). This is recognized by an increase in the levels of oxidized biomolecules including proteins, fatty acids and nucleic acids being protein carbonylation, lipid peroxidation or 8-oxoguanine some of the recognized biomarkers of these oxidative damages, respectively. The oxidative stress is also a consequence of an imbalance of the enzymatic and non-enzymatic antioxidant systems which are not sufficient to overcome the ROS overproduction. Under stress, this imbalance of ROS generation/scavenging in plant cells has also associated an alteration of the metabolism of nitric oxide and derived molecules designated as reactive nitrogen species (RNS) (Corpas et al., 2011). Therefore, it must be considered that plant stress usually undergoes together with a nitro-oxidative stress since the metabolism of both ROS and RNS are closely related, so they should be collectively considered (Airaki et al., 2012; Leterrier et al., 2012; Corpas and Barroso, 2013, 2017; Signorelli et al., 2013, 2019; Rodríguez-Ruiz et al., 2019a, 2019b). Nitric oxide ( • NO) is a free radical and, among its derived RNS, it could be distinguished those which come from the reaction of • NO with other inorganic molecules such nitrate (NO 3 − ), nitrite (NO 2 − ), nitrogen dioxide ( • NO 2 ), peroxynitrite (ONOO − ), but also those RNS which are a consequence of the interaction of • NO with organic compounds including nitrotyrosine (NO 2 -Tyr), nitrosoglutathione (GSNO), nitrosothiols (SNOs), nitro-γ-tocopherol, nitro-fatty acids (NO 2 -FA) and nitro-nuclei acids (Airaki et al., 2011; Mata-P´ erez et al., 2016; Izbia´ nska et al., 2018; Corpas et al 2020). At present, all these RNS have been demonstrated to be directly or indirectly involved in almost all physiological processes of higher plants from seed germination to fruit ripening, but also in the mechanism of response against (a)biotic stresses (Cellini et al., 2011; Airaki et al., 2015; Signorelli and Considine, 2018; Kolbert et al., 2019; S´ anchez-Vicente et al., 2019; Gonz´ alez-Gordo et al., 2019, 2020; S´ anchez-McSweeney et al., 2021). The present mini-review focuses on protein nitration, one of the NO-based PTMs which affects * Corresponding author. E-mail address: [email protected] (F.J. Corpas). Contents lists available at ScienceDirect Plant Stress journal homepage: www.sciencedirect.com/journal/plant-stress https://doi.org/10.1016/j.stress.2021.100026 Received 20 April 2021; Received in revised form 15 June 2021; Accepted 12 July 2021 Plant Stress 2 (2021) 100026 2 protein function, as well as on how its uncontrolled increase could be considered a reliable biomarker of nitro-oxidative stress in animal and plant cells (Radi 2004; Corpas et al., 2007; Souza et al., 2008; Bartesaghi and Radi, 2018; Arasimowicz-Jelonek et al., 2019). Protein nitration in higher plants This NO-derived PTM results in the addition of a nitro group (-NO 2 ) to some susceptible amino acids such as tyrosine (Tyr) or tryptophan (Trp). However, the majority of the studies in animal and plant cells has been done considering tyrosine nitration (Souza et al., 2008; Nuriel et al., 2011; Kolbert et al., 2017). In general, nitration is considered an irreversible process and, usually, it affects negatively the function of the target protein, although there are some cases where nitration does not affect (Rodríguez-Ruiz et al., 2017) or even it could have a positive effect on the protein function. At the molecular level, tyrosine nitration is not a random process; in fact, it is considered very specific and it is influenced by several protein features including the quaternary structure and the surrounding conditions where the protein is located either soluble or membrane-bound. The mechanism of nitration is a complex process that implies the intermediations of radical molecules (see Ferrer-Sueta et al., 2018 for deeper information). Fig. 1 shows a simple model where it is displayed the two main mechanisms responsible for either tyrosine or tryptophan nitration involving either peroxynitrite (ONOO − ) and/or the free radical nitrogen dioxide ( • NO 2 ). Peroxynitrite is generated by the fast reaction between two radical molecules, • NO and superoxide (O 2 •− ) with a second-order rate constant (k) of approximately 4–6 ×10 9 M −1 s −1 (Goldstein and Czapski 1995; Squadrito and Pryor 1995; Alvarez and Radi, 2003). NO is characterized to be neutral and hydrophobic with the capacity to cross membranes. Therefore, the formation of peroxynitrite is usually close to the place of the superoxide generation. Furthermore, at a physiological pH, peroxynitrite has high reactivity and, consequently, it can exert its nitrating effects in biomolecules around its cellular production. The reaction with Tyr/Trp is not direct and involves the formation of two radicals (tyrosine/tryptophan radical and • NO 2 ). On the other hand, the nitration mediated by • NO 2 could be also a consequence of the reaction of hydrogen peroxide (H 2 O 2 ) and NO 2 − in the presence of hemoperoxidase (HPO) (Ferrer-Sueta et al., 2018). Table 1 shows a list of plant proteins that have been identified to undergo tyrosine nitration as well as the Tyr residues specifically modified and how they affect the protein function. Protein nitration in higher plants under stress conditions Although protein nitration occurs endogenously at a physiological level, as it has been described during plant development (Airaki et al., 2015) or fruit ripening (Chaki et al., 2015; Zucarelli et al., 2021), an increase in protein tyrosine nitration has also been associated when the cell metabolism is subjected to stress conditions. Accordingly, many types of stresses are linked to an overproduction of ROS which could have associated an imbalance in RNS generation and an increase of peroxynitrite content. Consequently, a rise of protein nitration occurs. Table 2 provides representative examples of diverse plant species under physiological and environmental stressful conditions where an increase of protein nitration in different organs has been reported. However, this close relationship between stress and the increase of protein nitration is not an aleatory process since nitration is very specific and this means that it could have a signalling function to block or to trigger specific processes. Therefore, it is very important to identify the potential connection between specific stress(es), the ROS and RNS overproduction, the protein(s) that can undergo nitration, and their function. Furthermore, it should be distinguished between the local or systemic responses of these families of reactive species under stress conditions. Thus, in the model plant Lotus japonicus exposed to water stress, the analysis of ROS and RNS indicated an increase in lipid peroxidation and protein tyrosine nitration which was accompanied by an imbalance of the antioxidant system. However, whereas ROS metabolism was more accentuated in leaves with a higher level of lipid peroxidation (oxidative stress), the RNS metabolism was most Fig. 1. Simple model of protein tyrosine and tryptophan nitration. Two main nitrating reactions have been proposed to mediate this process: (a) by peroxynitrite (ONOO − ) which is formed by the quick reaction between nitric oxide ( • NO) and superoxide (O •− 2 ) radicals; and (b) By • NO 2 produced through the reaction of hydrogen peroxide (H 2 O 2 ) and nitrite (NO −2 ) in the presence of hemoperoxidase (HPO) (Souza et al., 2008. F.J. Corpas et al. Plant Stress 2 (2021) 100026 3 prominent in roots, with higher NO content and protein nitration (nitrosative stress) and a lower GSNO reductase activity. Therefore, water stress triggered a differential and spatially distributed nitrooxidative stress in this plant species (Signorelli et al., 2013). Likewise, in another study, using Cakile maritima seedlings as a model, when the hypocotyl was subjected to mechanical damage, after 3 hours it was found a local response with a higher ROS production, an imbalance of the antioxidant system and, consequently, with symptoms of oxidative damage. However, long-distance signals were also found in unwounded tissues (root), where the metabolism of RNS was exacerbated with increases of the NO content and protein nitration. These differences between local and long-distance responses seemed to be coordinated allowing the injured seedlings to survive (Houmani et al., 2018). Fig. 2A illustrates the appearance of a 7-day-old C. maritima seedling after 3 h of undergoing a mechanical wounding. Conclusion and future perspectives Protein nitration in higher plants is a NO-based PTM which could be considered a bridge that connects stress conditions with the metabolism of ROS and RNS. Subsequently, under stress conditions, an uncontrolled overproduction of both types of reactive species can trigger an increase of peroxynitrite, an oxidant/nitrating molecule that mediates protein nitration of target proteins that usually cause negative effects on their functions. It is relevant that some of these affected proteins correspond to key antioxidant enzymes such as catalase, superoxide dismutase or components of the ascorbate-glutathione cycle (Table 1). With the available data, it could be proposed that an increase of protein nitration should be considered a reliable footprint of nitro-oxidative stress. Fig. 2B displays the cascade of events that takes place in plant cells from the perception of environmental stress to its final consequence as nitrooxidative stress. It is worth mentioning that at present several antioxidant proteins have been identified that are susceptible to being nitrated causing a decrease in their activity, as it has been reported for catalase (Chaki et al., 2015; Rodríguez-Ruiz et al., 2019a; Palma et al., 2020), ascorbate peroxidase (APX) (Begara-Morales et al., 2014), monodehydroascorbate reductase (MDAR) (Begara-Morales et al., 2015) or several superoxide dismutase (SOD) isozymes (Holzmeister et al., 2015) (see Table 1). This clearly establishes a correlation between an increase in tyrosine nitration and the metabolism of ROS. On the other hand, very recently it has been reported that nitrate reductase (NR) can also undergo Tyr-nitration that causes a decrease in its activity (Costa-Broseta et al., 2021) and, therefore, in the generation of NO, which should be considered a feed-back mechanism of regulation and protection. However, research in this area should continue since protein nitration could have regulatory or signaling function either under physiological or stressful conditions . Declaration of Competing Interest The authors declare that they have no conflicts of interest to report regarding the present study. Table 1 Identified tyrosine nitrated proteins in different plant species and the effect on their corresponding function. Protein Plant species Identified nitrated Tyr Effects Reference Catalase Nicotiana tabacum, Capsicum annuum UN Inhibition Clark et al., 2000; Chaki et al., 2015 Cytosolic ascorbate peroxidase (APX) Pisum sativum Tyr235 (2) Decreased activity Begara-Morales et al., 2013 Glutathione reductase (GR) Helianthus annuus, P. ativum Tyr23 (1) No effect Chaki et al., 2009a; Begara-Morales, 2014 Monodehydroascorbate reductase (MDAR) P. sativum Tyr345 (2) Inhibition Begara-Morales et al., 2015 Superoxide dismutase isozymes (MnSOD1, CuZn SOD3, FeSOD3) Arabidopsis thaliana Tyr63 (3) in MnSOD1 Inhibition Holzmeister et al., 2015 S-adenosyl homocysteine hydrolase (SAHH) H, annuus Tyr448 (1) Decreased activity Chaki et al., 2009a Carbonic anhydrase (β-CA) H, annuus Tyr205 (1) Decreased activity Chaki et al., 2011 Peroxisomal hydroxypyruvate reductase (HPR1) P. sativum, A. thaliana Tyr198 (2,3) Decreased activity Corpas et al., 2013a,b PSBA(D1) of Photosystem II complex A. thaliana Tyr262 (2) Disassembly of PSII dimers Galetskiy et al., 2011 Methionine synthase A. thaliana Tyr 287 (2) Decreased activity Lozano-Juste et al., 2011 Glyceraldehyde-3-phosphate dehydrogenase (NADPGAPDH) A. thaliana Tyr318 (2) Inhibition Lozano-Juste et al. (2011) O-acetylserine(thiol)lyase A1 A. thaliana Tyr302 (2) Decreased activity ´ Alvarez et al., 2011 NADP-isocitrate dehydrogenase P. sativum, A. thaliana C. annuum Tyr392 (2) Tyr450 (3) Decreased activity Begara-Morales et al. 2013; Mu˜ noz-Vargas et al., 2018 NADP-malic enzyme A. thaliana Tyr73 Inhibition Begara-Morales et al., 2019 PYR/PYL/RCAR ABA receptor A. thaliana Tyr23, Tyr58, and Tyr120 (2) Inhibition Castillo et al., 2015 Cyclin-dependent kinase A (CDKA) Zea mays L. Tyr15 and Tyr19 (2) Decreased activity M´ endez et al., 2020 Nitrate reductase (NR1 and NR2) A. thaliana Tyr714 (NR1) and Tyr733 (NR2) (2) Decreased activity Costa-Broseta et al., 2021 (1) In silico identification. (2) Mass spectrometric techniques (LC-MS/MS). (3) Site-Directed Mutagenesis UN, unidentified F.J. Corpas et al. Plant Stress 2 (2021) 100026 4 Table 2 Representative examples where an increase of protein nitration in the different organs has been associated with either physiological processes or environmental abiotic/biotic stresses. Process Plant species Organ Ref Environmental stress Abiotic High light intensity; high and low temperature; continuous light and dark; wounding Pisum sativum L. Leaf Corpas et al., 2008 Salinity (100 mM NaCl) Arabidopsis thaliana Root seedling Corpas et al., 2009a,b High temperature Helianthus annuus L. Hypocotyl Chaki et al., 2013 Low temperature Capsicum annuum L. Leaf Airaki et al., 2012 500 µM arsenate (AsV) Arabidopsis thaliana Root and leaf Leterrier et al., 2012 300 µM ZnSO 4 Brassica juncea B. napus Root Feigl et al., 2015 Cd, Cr, Cu, Hg, Ni, Pb, and Zn B. napus H. annuus L. Root Feigl et al., 2020a,b Water stress Lotus japonicus L. Root and leaf Signorelli et al., 2013 Mechanical wounding H. annuus L. Cakile maritima Hypocotyl Green cotyledon Chaki et al., 2011 Houmani et al., 2018 Biotic Downy mildew (Plasmopara halstedii), H. annuus L. Hypocotyl Chaki et al., 2009 Nematode infection A. thaliana Root Labudda et al., 2020 Physiological process Natural senescence P. sativum Root Begara-Morales et al. 2013 Seedling development C. annuum Radicles, hypocotyls and green cotyledons Airaki et al., 2015 Natural fruit ripening C. annuum Solanum lycopersicum Fruit Chaki et al., 2015 Zuccarelli et al., 2021 Fig. 2. (A) Appearance of a 7-day-old Cakile maritima seedling after mechanical wounding (red arrow) in the hypocotyl. The injured zones appear with a blue color indicating that plasma membrane integrity is affected. ROS (H 2 O 2 ) content increases after 3 h in the injured area (local response) causing oxidative stress. Simultaneously, it is triggered an increase of nitric oxide (NO) and protein nitration in the root, which is an undamaged organ (long-distance response). (B) Sequence of events that can occur in response to environmental stress that triggers nitro-oxidative stress considering an increase in nitrated proteins as a consequence of an increase in peroxynitrite (ONOO - ). Some of the identified proteins which undergo nitration are antioxidant enzymes such as catalase, ascorbate peroxidase (APX), monodehydroascorbate reductase (MDAR) or superoxide dismutase (SOD), but also nitrate reductase (NR) which is involved in the NO generation. In all cases, nitration exerts an inhibitory effect on the activity. F.J. Corpas et al. Plant Stress 2 (2021) 100026 5 Acknowledgments SG-G acknowledges a “Formaci´ on de Personal Investigador” contract (BES-2016-078368) from the Ministry of Economy and Competitiveness, Spain. 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