International Journal of

Molecular Sciences

Review
Plant Growth-Defense Trade-Offs: Molecular Processes
Leading to Physiological Changes
Juan Pablo Figueroa-Macías 1 , Yamilet Coll García 1, *, María Núñez 2 , Katy Díaz 2 , Andres F. Olea 3 and
Luis Espinoza 2, *

1 Center for Natural Products Research, Faculty of Chemistry, University of Havana, Habana 10400, Cuba;
[email protected]
2 Departamento de Química, Universidad Técnica Federico Santa María, Avenida España 1680, Valparaíso
2340000, Chile; [email protected] (M.N.); [email protected] (K.D.)
3 Instituto de Ciencias Químicas Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, El Llano
Subercaseaux 2801, Santiago 8900000, Chile; [email protected]
* Correspondence: [email protected] (Y.C.G.); [email protected] (L.E.); Tel.: +56-32-2654225 (L.E.)

Abstract: In order to survive in a hostile habitat, plants have to manage the available resources
to reach a delicate balance between development and defense processes, setting up what plant
scientists call a trade-off. Most of these processes are basically responses to stimuli sensed by plant
cell receptors and are influenced by the environmental features, which can incredibly modify such
responses and even cause changes upon both molecular and phenotypic level. Therefore, significant
differences can be detected between plants of the same species living in different environments.
The comprehension of plant growth-defense trade-offs from the molecular basis to the phenotypic
expression is one of the fundamentals for developing sustainable agriculture, so with this review we
intend to contribute to the increasing of knowledge on this topic, which have a great importance for



future development of agricultural crop production.



Citation: Figueroa-Macías, J.P.; Keywords: growth-defense trade-offs; phytohormones; cell receptors

García, Y.C.; Núñez, M.; Díaz, K.;
Olea, A.F.; Espinoza, L. Plant
Growth-Defense Trade-Offs:
Molecular Processes Leading to 1. Introduction
Physiological Changes. Int. J. Mol. Sci.
Plants, as sessile organisms, are often facing various abiotic and biotic stresses that
2021, 22, 693. https://doi.org/
induce physiological, biochemical, and molecular changes, which are finally reflected
10.3390/ijms22020693
in terms of lowest growth and productivity. Plant stress tolerance and susceptibility
are governed by a complex exchange of signals and responses occurring at cellular and
Received: 16 November 2020
molecular levels. So, plant resistance relies strongly on timely stress recognition and the
Accepted: 4 January 2021
Published: 12 January 2021
rapid and effective activation of defense mechanisms [1]. The response of plants is dynamic
and complex and varies with the nature of these stresses, i.e., defense mechanisms for
Publisher’s Note: MDPI stays neu- pathogen infection or drought stress conditions are different.
tral with regard to jurisdictional clai- Plant immune responses are also modulated by abiotic signals such as light and
ms in published maps and institutio- temperature as well as the circadian clock [2]. In the absence of perceived pathogens or
nal affiliations. environmental changes, young tissues must suppress immune or adaptation responses
to maximize growth, whereas mature organs can be more prepared for defense [3]. Thus,
the activation of defense mechanisms at the expense of growth suspension is known as
the “growth-defense trade-off” phenomenon (GDT) and is the result of a delicate balance
Copyright: © 2021 by the authors. Li-
between growth and defense or adaptation responses. Competition for limited amount
censee MDPI, Basel, Switzerland.
of available resources has been considered as the driving force for trade-offs [4–7], but
This article is an open access article
recently it has been proposed that instead this could be the result of opposite molecular
distributed under the terms and con-
pathways regulating growth and defense [8,9].
ditions of the Creative Commons At-
Due to climate change that is impacting negatively agricultural crops production
tribution (CC BY) license (https://
creativecommons.org/licenses/by/
worldwide, GDT have acquired increasing importance from the ecological, agricultural,
4.0/).
and economic point of view. For centuries, agricultural crops have been bred with the

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Int. J. Mol. Sci. 2021, 22, 693 2 of 18

main goal of maximizing growth and yields. As a consequence, plants have diminished
its genetic diversity for abiotic stresses defense [10]. The knowledge about the molecular
and regulatory aspects that manage the above-mentioned phenomenon is the very first
step in the development of new agricultural products that stimulate both growth and
defense responses. Thus, in this review, we intend to make an interesting approach to the
GDT aimed to suggest elements for the analysis and better understanding of key pieces of
knowledge involved in further development of agricultural applications.

2. Regulatory Aspects
Plants count on specialized mechanisms designed to detect and identify environmental
changes, and subsequently produce the optimal response. Effective defense responses
against both biotic and abiotic stresses are triggered by a series of signaling molecules,
where phytohormones are the most important. Phytohormones, such as auxins (AUX),
gibberellins (GAs), cytokinins (CKs), abscisic acid (ABA), ethylene (ET), brassinosteroids
(BRs), salicylic acid (SA) and jasmonic acid (JA), are endogenous low-molecular-weight
molecules, which in addition of their defense signaling function, are also regulators of
growth, development, and a variety of physiological processes. In general, phytohormones
act by modulating expression of a number of different genes whose products are so
diverse as proteinases, cell-protection proteins, hydrolytic enzymes, pathogenesis-related
proteins, reactive-oxygen species. Several of these responses to stress show synergistic
or antagonistic effects and therefore these phytohormones should coordinate themselves
through an efficient crosstalk to get the optimal response to the environmental changes
and maintaining at the same time growth and development [11,12]. Understanding of
mechanisms involved in GDT is important considering the urgent need of optimizing
yields in agricultural crop species.
The role of these phytohormones in signaling mechanisms and crosstalk in response
to biotic stresses have been recently reviewed [12]. However, changes in resources allo-
cation induced by external pressures are quite difficult to determine. Thus, a working
framework to study the costs of plant defense at the expenses of other plant’s functions
has been proposed [13]. A common approach to study GDT is to detect and quantify the
production of defensive chemicals induced by herbivory. Attack of plants by herbivores
induces signals associated to wounding, damage-associated molecular patterns (DAMPs),
and oral secretion, herbivory-associated molecular patterns (HAMPs) and fatty acid con-
jugates. These cues activate mitogen-activated protein kinases (MAPKs), which initiate
signal transduction pathways, i.e., wound-induced protein kinases (WIPKs) are positive
regulators of JA, and initiate cascades stimulating salicylic-acid-induced protein kinases
(SIPKs) that additionally are agonistic of ET production and suppress SA synthesis. Thus,
plants respond to attack of herbivores by triggering a signaling cascade to produce a variety
of chemical defenses, and at the same time a series of metabolic changes that affect growth
are observed. This change in resource allocation resulting in both increased defense and
lowest rate of growth [14] requires a crosstalk between different phytohormones that often
play opposite roles.
Nonetheless, signaling molecules are the “real regulators” behind hormones, since
they are the ones that are activated upon perceptions and then, trigger the production
or inhibition of hormones. Downstream of MAPKs, WIPKs, SIPKs, and transcription
factor WRKY in the signal transduction network, they act to further enforce the regulatory
crosstalk between growth and defense [13]. A case in point could be an experiment
where oral secretions of caterpillars were applied to WIPK-silenced N. attenuate, treated
plants displayed a less accumulation of JA—as WIPKs are agonistic regulators of JA—and
consequently, they experienced higher growth and seed production relative to control
plants. On the contrary, the opposite effect was observed in SIPK-silenced plants that
underwent the same experiment, because plants accumulated high levels of SA and did
not benefit from reduced JA sensitivity, presumably because of the higher costs associated
with SA-mediated defense [14]. Another example is the transcription factor WRKY70
Int. J. Mol. Sci. 2021, 22, 693 3 of 18

that is MAPK-activated as result of insect attack. It has been shown that WRKY70 acts
to upregulate the lipoxygenase (LOX) gene involved in JA synthesis and concurrently
inhibits the plant growth hormone gibberellin (GA) by suppressing the GA synthesis gene
gibberellin 20–oxidase 7 (GA20ox7), resulting in a stunted phenotype [15]. From all that we
could conclude that plants use most of growth and defense processes, which are regulated
by these chemical messengers, and therefore phytohormones are who really determine
whether the plant grow or defend itself.
Brassinosteroids, are an important class of phytohormones that can be found in
almost all parts of the plants and play important role in a variety of biological processes,
such as plant growth regulation [16,17] and cell division and differentiation in young
tissues of growing plants [18–20]. It has also been shown that BRs increase resistance to
various kinds of biotic and abiotic stress factors, i.e., low and high temperature, drought,
heat, salinity, heavy metal toxicity, and pesticide [21–26]. Several studies have shown
that BRs increase antioxidant enzymatic activity and reduce drought stress effects on
plants as measured by different biochemical and physiological parameters, i.e., chlorophyll
accumulation, activity of antioxidant enzymes, total protein contents, stomatal conductance,
photosynthesis, and membrane stability. In leaves of drought-stressed soybean plants BL
increases photosynthesis, content of soluble sugars and proline, and activities of antioxidant
enzymes [27]. Recently, BRs have raised as decisive regulators in GDT playing the role of
mediators between stress and growing processes [11]. Results have shown that BR inhibit
or modulate the efficiency of plant immune signaling and responses [28–30]. Thus, under
stress conditions, BRs can cross talk among defense signaling pathways with a broad range
of hormones. For example, in rice, they have been found to be the master regulators of GAs
metabolism [31,32]. Also, it has been found that exogenous treatment with BRs provoked
an inhibition of pattern-associated immunity (PTI) because of some issues involving the
pattern-recognition receptors (PRRs) that are going to be further explained below [33–35].
As summarized by Eichmann and Schäfer, 2015 [9], hormones play a crucial role in
the underlying conflict between the immune and growing signaling. Growing processes
are favored under non-stress conditions, hormones that stimulate cell proliferation, elon-
gation and differentiation are secreted. Otherwise, biotic stress conditions set up fitness
towards the preparation of a suitable immune response. Basically, growth hormones
(AUX, GA, BR, CK) affect immune signaling, while typical stress hormones (SA, JA, ET,
ABA) influence growth and development. Nevertheless, it is worth to mention that it is
not possible to see immune and developmental processes apart from each other, but a
hormone-regulated overall balance shifted to either growth or defense, as a response to
environmental changes [36–38].

3. Receptors-Like Kinases at the Regulation Basis of GDT

Receptors-like kinases (RLKs) are a large family of receptor proteins that share a com-
mon architecture consisting of an intracellular kinase domain, a single membrane-spanning
helix and an extracellular domain. These features allow sort of a structural diversification
which make possible the perception of a huge variety of ligands in a specific manner [39,40].
Classification of RLKs based on the comparison of their domain structures [41] shows that
leucine-rich repeat receptor-like kinases (LRR-RLKs) represent one of the largest groups,
with over 170 genes in the Arabidopsis genome [42]. Studies suggest LRR domains are
involved in protein-protein interactions and consist of repeating units of around 24 amino
acids rich in leucine [43]. LRR-RLKs are involved in a variety of plant processes including
defense and growth, moreover it is thought most of PRRs associate with other RLKs and
function as part of multi-protein complexes at the cell surface, and looking deeper into
their functions is the key for understanding GDT [44].
Plants have evolved two branches in their immune system to defend themselves
against pathogen infections. The primary innate immune response is triggered by the
detection of evolutionarily conserved microbial- or pathogen-associated molecular patterns
(MAMPs or PAMPs, respectively) and is known as PAMP-triggered immunity (PTI). The
Int. J. Mol. Sci. 2021, 22, 693 4 of 18

second plant innate immune response is triggered by the recognition of specific pathogen
effector proteins and is referred to as effector-triggered immunity (ETI) [45–47]. The
perception of MAMPs or PAMS is carried out by patterns recognition receptors (PRRs),
most of them are LRR-RLKs, and in these process hormones play a significant role.
Some receptors make up the first line of plant defense at molecular level and are the
place where all PTI and ETI signaling processes start. Xanthomonas oryzae resistance 21
(Xa21) is a kinase that contains non-arginine-aspartate (non-RD) motif and LRR in the
extracellular domain [48], which provides the ability to identify lipopolysaccharides (LPS)
from bacteria [48]. The complex formed by Chitin Elicitor Binding Protein (CEBiP) and
Chitin Elicitor Receptor Kinase (CERK) is on charge of detecting chitin from fungi cell wall.
Besides, an insect bite erupts a series of volatile and peptidic hormones signaling cascades,
those that tell the plant and some of its neighbors to prepare for a forthcoming attack [49].
On the other hand, there are receptors that participate in plant growth and develop-
mental processes through the perception of endogenous hormone or peptide signaling.
Phytosulfokine (PSK) receptor (PSKR) senses this sulfated pentapeptide that stimulate
growth and root elongation; Clavata1 (CLV1) perceives the signaling peptide Clavata 3
(CLV3) to control shoot apical meristem maintenance; Erecta and Erecta-Like 1 (ERL1)
recognize the peptides Epidermal Patterning Factor 1 (EPF1) and EPF2 to regulate stomatal
development and patterning; Root Growth Factor (RGF) Receptor 1 (RGFR1), through
RGFR5, perceives RGF peptides to mediate root meristem development. All these re-
ceptors belong to the LRR-RLK family and most of them use Somatic Embryogenesis
Receptor Kinases (SERKs) as their co-receptors to turn on their intracellular transduction
reactions [50–55].
Later, on this section we are going to focus on the interesting and intriguing relation
between defense and hormone receptors sharing the same co-receptor protein.
Flagellin Sensing 2 (FLS2) is a LRR-RLK that operates as PRR for flagellin (flg22), which
is a 22-amino acid peptide located at the N-terminus of the bacterial flagellum and a con-
served microbial protein that is perceived as PAMP in plants, and even in animals [56]. FLS2
triggers the production of reactive oxygen species (ROS), the defense-related hormones
ET and SA, deposition of secondary compounds such as callose and global transcriptional
reprogramming involving WRKY transcription factors. The knowledge about FLS2 activ-
ity is important to establish a molecular control of its responses, avoiding unnecessary
production of constitutive defenses that lead to excessive growing costs [57].
On the other hand, Brassinosteroid Insensitive 1 (BRI1) receptor, another member
of the LRR-RLK family, is responsible for recognizing BRs, the growth-promoting hor-
mones [19]. To recognize brassinolide (BL), its natural ligand, the receptor count on
hydrophobic groove formed between the inner surface of the helical BRI1-LRR and a ~70-
residue island domain [58,59]. A nonpolar cleft lined by nonpolar aromatic and aliphatic
residues made up the binding site of BRI1, whereas hydroxyl groups form the cleft ridge.
This is located on the surface of the receptor ectodomain. BL fits into the cleft via its
nonpolar side and displays its hydroxyl groups towards the solvent and protein part-
ners [60,61]. Therefore, it could be assumed that plants perceive steroid hormones at the
plasma membrane and eventually stimulate gene expression through a signal transduction
pathway. Binding of BRs to inactive BRI1 homodimers, induces auto-phosphorylation of
its cytoplasmic kinase domain and thereby stimulates the interaction of BRI1 with another
related LRR-RLK, SERK3, also called BRI-Associated Kinase 1 (BAK1) [62,63]. Two models
have been proposed for BRI1/BAK1 interactions. The first suggests that BR allows BRI1
and BAK1 to interact, thereby allowing transphosphorylation of BAK1, whereas in the
second model BRI1 and BAK1 form a complex that is stabilized and activated by BR [64].
Recently, in vitro analysis suggests that heteromeric associations between BRI1 and BAK1,
as well as phosphorylation, are dependent on BR [65].
Regarding the relationship between BR signaling and immunity response,
Albrecht et al. [28] showed a unidirectional inhibition of both the BAK1-dependent, FLS2-
mediated immune response as well as a BAK1-independent immune response by BR
Int. J. Mol. Sci. 2021, 22, 693 5 of 18

perception through a yet unknown mechanism, suggesting that BAK1 is not rate-limiting
in these pathways. In contrast, it has also been showed that over-expression of BRI1 in
Arabidopsis brings about a reduction of BAK1-dependent, but not BAK1-independent,
immune responses [29]. However, the synergistic interaction between BR signaling and
immune response requires BAK1, which indicates the existence of a complex interplay
between BR signaling and immunity responses involving BAK1.
In 2007, Heese et al. identified SERK3/BAK1 as a component of plant PTI [66]. In
Arabidopsis thaliana, AtSERK3/BAK1, along with FLS2, forms a ligand-dependent complex
that initiate the flg22-dependent responses. It is also required for full responses to unrelated
PAMPs and for restriction of bacterial and oomycete infections. Thus, SERK3/BAK1
plays a significative role on plant-pathogen interaction and it seems to be involved in
the initiation of PAMPs-associates downstream [66]. Formation of this complex suggests
proximity of FLS2 and BAK1 in the plasma membrane. In addition, structural studies have
demonstrated that the N-terminal of flg22 binds to the concave surface of FLS2 ectodomain,
and the C-terminal region of the FLS2-bound flg22 interacts with BAK1 ectodomain. This
interaction leads to the stabilization of FLS2-BAK1 dimerization, and thus FLS2-BAK1
heterodimerization is both ligand and receptor mediated. Hence, it is proven that flg22
binds first to FLS2 and then to BAK1; therefore, BAK1 acts as a co-receptor for flg22
signaling [67]. Current studies have demonstrated that FLS2 and BRI1 form protein clusters
at different nano-domains of the plasma membrane, as it’s done by the Epidermal Growth
Factor (EGF) in animals [68]. This spatial organization allows that immune and growth
signaling platforms generate signaling specificity upon ligand perception, in addition to
potential differential phosphorylation of common signaling components. Consequently,
common signaling components could be employed along different and even antagonistic
signal transduction routes [68].

4. Design and Synthesis of Molecules for the Exogenous Stimulation of Receptors

Supported on new organic synthesis methods, chemists have modified or synthesized
analogues of naturals ligands looking forward plants’ response by the stimulation of a
specific cell receptor. Besides, model mechanisms of action have been proposed to explain
the bioactivity of existing molecules. In this quest, our group has obtained, through a
many years’ work, a library of BRs analogs exhibiting activities similar to that observed for
natural BRs-like hormones [69]. Between these new synthetic compounds there are steroids,
steroidal-sapogenin and phytosterol derivatives, having several chemical functions such as
oximes, ketones, epoxides, alcohols, and bromides [69]. On the other hand, molecular dock-
ing simulations have been carried out for most of these synthetic compounds (spirostanic
derivatives 1–3, Figure 1) to predict the affinity and binding modes between such ligands
and the ectodomain of BRI1, as well as to identify the most active compounds [61]. This
analysis suggested that the studied compounds were able to activate BRI1 receptor, and
in the majority of cases with a lower binding energy than that corresponding to BL, the
natural ligand [61].

Figure 1. Spirostanic derivatives 1–3.

Int. J. Mol. Sci. 2021, 22, 693 6 of 18

More recently, the effect of short alkyl side chains and the configuration at C22 on
the growth-promoting activity of a series of new brassinosteroid 24-norcholan-type and
benzoylated analogs (BRs derivatives 4–7, Figure 2) have been evaluated by the rice leaf
inclination test using BL as positive control [70,71]. Molecular docking of compounds 4–7
indicated a possible interaction with BRI1 receptor and that ligand recognition could be
enhanced by hydrophobic interactions of ligands with the BRI1LRR receptor and hydrogen
bonding with BAK1 in the complex [71]. Anyhow, in all these cases it has been shown that
synthetic analogs exhibit similar hormonal activity as natural BL. Thus, they can be used
as precursors of promising biostimulant formulations to improve crops yields.

Figure 2. Brassinosteroid 24-norcholan-type and benzoylated analogs.

Additionally, BRs analogues obtained from deoxycholic and hyodeoxycholic acids

have turned out to show excellent bioactivity in the rice lamina inclination assay [72,73].
Using a 3D-QSAR it has been possible to establish a structure-activity relationship which
indicates that activity is favored by the following structural parameters: presence of
hydroxyl groups at C22 and voluminous group in the end of alkyl chain; the hydroxyl
group in C3 of ring A is indispensable [74]. The 3D contour maps showed that the growth
promoting activity of the compounds was influenced mainly by electrostatic properties
and the presence of hydrogen-bond acceptor groups [74].
External application of BRs analogues enhances plant growing, stress resistance,
and defense responses. Application of the spirostanic analogue DI-31 (3) (Figure 2) on
strawberry (Fragaria x ananassa) produced an increase on leaf greenness, number of leaves
and stolon, and foliar area as compared to control plants. The effect on the activation of a
defense response was also evaluated, and results revealed that it exerted a protective effect
against Botrytis cinerea, the causal agent of the gray mold disease [75]. An increase in the
calcium influx and an overexpression of defense-associated genes in response to treatment
with DI-31 was observed, demonstrating the role of calcium in the signaling pathways
induced by BRs in strawberry plants [76].
For plague protection, generally, farmers use pesticides that severely affect the envi-
ronment and the integrity of ecosystem. Also, in many cases, transgenic crops capable
Int. J. Mol. Sci. 2021, 22, 693 7 of 18

of overexpressing defense genes that protect the plant against specific pathogen have
been developed. However, in many cases such methods have led to the emergence of
resistant strains which have turned out to cause a severer damage. Thus, the synthesis
of compounds, mimicking the function of PAMPs, DAMPs, HAMPs, and plant defense
hormones, has become a promising research field in chemical agriculture. Most of these
compounds do not have a proven antimicrobial activity, but they activate plant innate
immunity in local tissue (infected part) leading to transportation of the mobile defense
signals to systemic (uninfected) tissue, resulting in a long-lasting resistance to a broad
spectrum of pathogens. This acquired immunity is known as systemic acquired resistance
(SAR) [77,78].
SA was one of the first endogenous compounds reported to cause SAR, and its
acetylated derivative (ASA), well known as Aspirin, showed similar activity in tomato,
accompanied by accumulation of Pathogenesis-Related (PR) proteins and resistance to
Tobacco Mosaic Virus (TMV) [79]. Similar induced activities against the same virus were
reported for chlorinated derivatives [80]. Structure-activity studies have shown that deriva-
tives with electron-withdrawing groups, at 3 and 5 positions, are considerably more active
as SA-like SAR stimulators [81]. More recently, a new class of SA-glycoconjugates con-
taining hydrazide and hydrazone moieties showed significant in vivo antifungal activity
in cucumber plants [82]. These conjugates induce expression of JA marker genes instead
of SA marker genes. This result suggests that SA hydrazine derivative may not be a SA
agonist and function through targeting of other immune signaling components [82].
Jasmonic acid and its related derivatives, including hydroxylated and JA conjugates,
are hormones found all over the plant kingdom acting in numerous processes related to
stress and development. The occurrence, biosynthesis and metabolism of these compounds
have been reviewed [83,84]. Methyl jasmonate (MeJA), 8-((1S,2S)-3-oxo-2-((Z)-pent-2-
en-1-yl) cyclopentyl) octanoic acid (OPC-8:0) (8)—a JA precursor—and N-jasmonoyl-L-
isoleucine (JA-Ile) are among the best characterized members of the JAs family (Figure 3).
Many synthetic derivatives have been obtained and their biological activity as regulators
of physiological processes have been assessed [85]. For example, it has been shown that
a fluorinated analog 7F-OPC-8:0 (9) behaves similarly to the endogenous oxylipin 8 in
A. thaliana plants, and it also may act as systemic signal between distal tissues [86,87]. On
the other hand, two diastereomeric macrolactones derived from JA-Ile were synthesized
(10 and 11, Figure 3), and it was proved that 10 and 11 induce nicotine accumulation in
Nicotiana attenuata leaves at similar extent as MeJA does [88]. Additionally, it was found
that (10 and 11) activate jasmonic responsive gene (JRG) expression similarly to JA-Ile in
A. thaliana [88]. This result indicates that the free carboxyl group of JA-Ile is not essential
for this molecule to induce JRG expression [85,86]. Similar outcomes were observed in
other studies, so systematic structural modifications of JA revealed the minimal structural
requisites required for its bioactivity allowing for the synthesis of JA-mimics [85,89,90].
AUXs could be called the “Master of Plant Growth” and are one of the most widely
studied plant hormones. There are four natural auxins that are synthesized by plants:
indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), 4-chloroindole-3-acetic acid (4-Cl-
IAA), and phenylacetic acid (PAA) [89,90] (Figure 4).
However, at high doses the synthetic auxins are phytotoxic, inducing widespread
over-reaction to auxin stimulation, which leads to injury and death [91]. Moreover, the
interest in developing AUX-like compounds has increased for plant growth and weed
control. Several in silico studies have noted that the transport inhibitor response 1 (TIR1)
receptor family is variously selective to different auxin chemical scaffolds. Thus there
exist a huge array of synthetic analogues of auxins, for instance halogenated derivatives,
pyridine derivatives, quinolones, aromatic acetates, benzoic acids, and phenoxyacetic
acids [92].
Int. J. Mol. Sci. 2021, 22, 693 8 of 18

Figure 3. Jasmonic acid (JA), natural derivatives methyl jasmonate (MeJA), N-jasmonoyl-L-isoleucine (JA-Ile), JA precursor
8-((1S,2S)-3-oxo-2-((Z)-pent-2-en-1-yl) cyclopentyl) octanoic acid OPC-8:0 (8), and synthetic analogs 7F-OPC-8:0 (9) and
JA-Ile macrolactones (10 and 11).

Therefore, exist a variety of synthetic molecules that stimulate both growth and de-
fense by binding to cell receptors and mimicking the functions of natural hormones, so
they might be able to trigger a response, harsher or milder, depending on what is in-
tended to. Synthetic polymers, chitosan and others carbohydrate derivatives, lipoproteins,
vitamin-like molecules, cyclopentanoic acids, even antimicrobial peptides, uracil and urea
derivatives, and still mineral salts have been used because of their bioactivities under
specific conditions [93]. Despite these advantages, it is worth to consider that the activity
of almost every reported molecule is restrained to in vitro conditions or to a small number
of plant species. Other potential concern related with synthetic molecules deal with the
indiscriminate use of chemicals, which is responsible for the majority of soil contamination
Int. J. Mol. Sci. 2021, 22, 693 9 of 18

problems, although molecules from natural sources and their derivatives have proven to
have a great bioactivity and be innocuous to the environment.

Figure 4. Chemical structures of natural auxins.

5. GDT Influence over Secondary Metabolism

Trade-offs take part in the secondary metabolism as well, and hence depending upon
the conditions and features of the environment where the plant is in, the nature and
concentration of secondary metabolites change. Secondary metabolites are necessary for a
ubiquitous amount of processes that involve transduction, cell adaptation and survival,
communication, and protection, but the role of secondary metabolism upon defense and
defense response has been comprehensively studied in the last decade [94]. Transcription
factors responsible for regulating the expression of secondary metabolites biosynthesis
genes, are the result at molecular level of a response that was first activated by an intra- or
extracellular signal perceived by the membrane receptors, in a similar way as explained
above in this review [95].
The concentration of secondary metabolites could serve as reference to know about
the development stages and conditions of the ecosystem that surrounds the plant organism:
instances of nutrients availability, stress condition, herbivore attack, and some others.
The accumulation and cell secretion of nicotine and caffeine in tobacco and coffee plants,
respectively, upon tissue wounding, that could be interpreted as herbivore attack, could
explain the insecticide activity of these compounds [96,97]. The high conjugation displayed
in anthocyanins’ structure allow them to interact with light and absorb some kinds of
radiations, thus its production is stimulated under high-light exposure. As they also are
really good antioxidants, conditions such as nutrients deficiency, and pathogen attack
and wounding, may induce an over production of anthocyanins [98,99]. In leaves and
stem of Tithonia diversifolia, the production of sesquiterpenes, lactones as tagitinin A and C
(tagitinin C with potent cytotoxic activity on human malignant cells [100]) and phenolics as
5-O-caffeoylquinic acid (Figure 5) is determined by the amount of rainfall and temperature
changes occurring with seasonal variation [101]. On the other hand, the production of
phenolics and subsequent incorporation in plant cell wall as suberin or lignin is increased
Int. J. Mol. Sci. 2021, 22, 693 10 of 18

by cold stress [94], while tree adaptation was associated with production of chlorogenic
acid at high levels [95].

Figure 5. Chemical structures of tagitinin A, C and 5-O-caffeoylquinic acid detected in T. diversifolia extracts.

Some secondary metabolites are volatile organic compounds (VOCs), so they can
spread along and establish a sort of interaction within the plant itself and with its similar
ones on the field-side. Moreover, it was recently proposed that these compounds may
work in synergy with other secondary metabolites and hormones which are all synthe-
sized to regulate senescence [102]. For instance, the synergism between the production of
isoprenoids and biosynthesis of cytokinins turns out in increased antioxidant activity at
the foliar level, which by preventing degradation processes prolongs life span of leaves
and flowers. Trade-offs between benefits and costs of VOC emission as stress relief com-
pounds are still not well understood as experiments with transgenic plants suggest that
the metabolic cost for emitting isoprene (the most abundant VOC released from leaves)
outweighs benefits [103,104].
Many ecological experiments have been designed with the aim of observing behavior
of plants in wildlife conditions and get a comprehensive approach to the trade-off hypothe-
sis. As an example, Stryphnodendron adstringens is a tree whose bark is used in Brazil as
a source of medicinal tannins, nevertheless after bark harvesting, the tree generally dies.
Tuller et al. in 2018 [105], in a manipulative field experiment, tested the hypothesis that
harvesting leaves, which might serve as an alternative source of tannin, would be less
detrimental for tree survival, growth, reproduction, and defense. Clipping the totality
of leaves induced a trade-off such that reproduction (number of fruits) decreased but
tannin concentration increased in plant tissues, as leaves were the highest defended tissue.
These results are consistent with the hypothesis that damage induces higher secondary
compound production to reduce the likelihood of subsequent herbivore damage [106].
In addition, investment in defensive compounds following herbivore attack instead of
reproduction may be more profitable for long-lived trees, like S. adstringens, because they
may have many future reproductive episodes [105].

6. Trade-Offs Lead to Physiological Changes upon Environmental Stimuli

Until now, we have dealt only with the basis of trade-offs at a molecular level, but
we cannot forget that all signaling, and responses start with an environmental stimulus.
The huge array of cell receptors has evolved to become the way as cells perceive their
surroundings and interact with it. Then, once the stimuli are sensed and the responses
given, what comes next? Well, for plants, as for other living organisms, is quite important
to know if the given response was effective, so feedback processes must be established.
Therefore, a changing environment is not healthy for plant development since it makes
plants more susceptible to biotic and abiotic stresses. Environmental factors are also
responsible of phenotype-shaping whose expression depends on the genes that have been
activated by the transduced signal.
Int. J. Mol. Sci. 2021, 22, 693 11 of 18

Temperature is one of the main factors intervening in tolerance responses to stress

conditions, because such factor is always fluctuating along with the day, and changes
abruptly with the seasons of the year. Furthermore, global climate change is showing
a tendency to increasing temperature, and the understanding of the impact of this phe-
nomenon on plants is a priority to mitigate the contemporaneous agriculture problems. In
plants, temperature sensing is associated with fluctuations in membrane fluidity, histone
modifications, activation of protein kinase cascades, and generation of ROS [107].
Rice plants infected with Xanthomonas oryzae, at elevated temperature, displayed up-
regulation of ABA biosynthesis and signaling genes, and downregulation of SA-responsive
genes. Although, under the same conditions, rice plant carrying the Xa7 gene exhibit
resistance to this pathogen, suggesting that SA-independent defense signaling occurs at
high temperature [108]. This fact shows that temperature is involved in the regulation of
resistance genes expression upon pathogen attack and hormone crosstalk, since tempera-
ture accelerates breakdown in some plant-pathogen systems, though in some other cases
it stimulates an enhanced response [2,109] Similar behavior was observed in Arabidopsis
exposed to P. syringae, where susceptibility was enhanced by increasing temperature. This
effect is due to inhibition of SA-biosynthetic and SA-responsive gene expression, and
upregulating genes involved in JA-mediated signaling and ABA biosynthesis, suggesting
that an important interplay between SA and ABA/JA signaling is operating [110].
Extremes conditions of temperature affect negatively both the growth and defense
processes as plants have to adequate transcriptional pathways and produce osmotic fac-
tors to avoid freezing. Cold stress stimulates membrane rigidification and cytoskeletal
rearrangement. The cold signal is perceived by the membrane and temperature sensor
(COLD1/RGA1) and other components, leading to an influx of Ca2+ , ROS production, ABA
accumulation, and MAPK cascade (OsMKK6-OsMPK3) reactions [111]. Several studies
lead us to believe that ROS are the key for understanding trade-offs under stress conditions,
since at low concentration they trigger defenses and developmental responses at early
stages, whereas at highest concentration they attack the cell membrane for destroying the
cell under breakdown of the defense barrier [112,113]. The redirection of functions upon
chilling stress is logically associated with the DNA damage that induces protective death
of columella stem cell daughters leading to restoration of the aux-in maximum in the quies-
cent center (QC) and maintenance of functional stem cell niche activity in Arabidopsis roots.
This breakthrough supports a new concept in which DNA damage and ROS production
coordinate cell fate during responses to chilling stress [111,114].
Soil salinity is nowadays one of the most extended problems that agriculture is facing
worldwide, it has been provoked by mankind irresponsible soil exploitation, and bad
practices applied to extensive agriculture. This issue provokes significant economic losses
because of its effects on plant metabolism, it causes a total disorder of growth regulators
and uncoupling major physiological and biochemical processes [115]. Under salt stress the
secretion of ET occurs, as it does under other types of stresses. Through ET burst, plants
alert to other parts of itself and to its similar ones that it is under a harmful damage, so it can
start up with stress responses. However, when the stress persists, it can trigger the initiation
of senescence, chlorosis, and abscission processes, and ultimately lead to plant death [116].
Moreover, a recent research showed that lettuce plants exogenously treated with BRs
and spirostanic synthetic analogs, reduced significantly the ET production in roots and
shoots [117]. Furthermore, it has been shown that rice’s seedlings growth under NaCl stress
is significantly enhanced by treatment with BRs and its synthetic analogs [118–121]. Also
pigment concentration increases and proline content decreases in leaves, as an evidence of
adaptability to such stress conditions [33,69]. As BRs are so environmentally friendly, this
result is an evidence of sustainable solutions to the salinity problems that affect almost the
whole world today.
Biotic stress causes numerous losses in crops yearly. Both above- and belowground
microbes may affect the growth-defense balance of plants. In ecology, the growth-defense
hypothesis states that the faster the plant grows the greater the damages due to pathogen
Int. J. Mol. Sci. 2021, 22, 693 12 of 18

attacks are, and vice versa. Fast-growing species invest most of the available resources in
plant growth rather than in defense mechanisms, whereas the opposite occurs in slower-
growing species [122]. The majority of the tests designed to prove this hypothesis have been
carried out with aboveground tissues and this behavior seems to be the norm [5,122–125].
Similar results have been reported for the existing relationship between belowground
growth rate and soil biota effects (microbial fungi and bacteria) [101]. However, the estab-
lished relationships suggests that belowground plants are involved on many interactions
via their roots with antagonistic and mutualistic organisms [101]. Consequently, slower-
growing species are benefitted from the soil mutualist at higher extent than faster-growing
species. These studies demonstrate that GDT could be a complex regulator phenomenon
which can be used as a predictor of plant community responses to pathogens.
An interesting fact, evidencing GDT-induced changes is that axial resin ducts, which
are costly defensive structures, remain imprinted in tree rings of conifers, so they might
become a valuable proxy to evaluate defensive investment. Vázquez-González et al. [126]
recently studied the responses to both spatial and temporal environmental variation in
resin duct production, and to explore growth-defense trade-offs. To that aim, they applied
dendrochronological procedures to quantify annual growth and resin duct production
during a 31-year-period in a Mediterranean pine species, including trees from nine popu-
lations planted in two common gardens. Interestingly they found that annual resin duct
production differed among populations of Pinus pinaster. Such variation in defensive
traits can be logically expected as a proof of the optimization of resources provided by the
ecosystem which is part of the processes for long-term evolutionary adaptation. Besides,
they found a strong evidence of a physiological growth-defense trade-off at the phenotypic
level, indicated by a negative correlation between annual basal area increment—feature
associated with growth—and annual resin duct density. Climate conditions are strongly
related with the above correlation since it is expected that growth-defense trade-offs are
more likely to emerge under limiting environmental conditions determining physiological
constrains. Populations that evolved under more favorable growth conditions showed
stronger physiological defensive constraints. This can be explained by the fact that such
populations were the most dissimilar in climate conditions to the sites where the trees were
planted.

7. Conclusions and Perspectives

As plants either grow or defend themselves, they have to stablish a still not completely
known balance to warrant their survival in the location where they are fixed. Everyday soil
exploitation and bad practices combined with lack of nutrients, salinity, drought, degrada-
tion, along with the climate change, which effect is nowadays increasingly evident, are the
main challenges that demands from us a deeper knowledge of what really occurs inside the
plant organism and how they express to simple view. With this review we have summa-
rized the growth-defense trade-offs in a comprehensive way, intended to trace a guiding
line starting with the processes at the molecular level leading to phenotypic changes that
plants can experience upon their interaction with the environment. The understanding of
these topics is of great importance for today’s plant scientists and agricultural producers,
since sustainable technologies aimed to satisfy and ensure the necessities the humankind
demands are required to be developed. Therefore, eco-friendly solutions to help plants to
get a better adaptation to stress conditions and achieve better production yields are a great
challenge and a must for plant science research.

Author Contributions: J.P.F.-M. participated in references revision, discussion, and writing of the
manuscript; Y.C.G. supervised the manuscript redaction and revision. M.N. participated in references
revision and figures preparation. K.D. participated in references revision and discussion. A.F.O.
collaborated in the discussion, manuscript redaction and corrections. L.E. project administration,
supervised the whole work, collaborated on figures construction and manuscript revision. All
authors have read and agreed to the published version of the manuscript.
Int. J. Mol. Sci. 2021, 22, 693 13 of 18

Funding: This research was funded by FONDECYT (Fondo Nacional de Desarrollo Científico y
Tecnológico) (Grant No. 1191330).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Acknowledgments: M.N. thanks the support of Dirección General de Investigación y Postgrado
(DGIP-USM). Universidad Técnica Federico Santa María.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

GDT Growth-Defense Trade-off

AUX Auxins
GAs Gibberellins
CKs Cytokinins
ABA Abscisic Acid
ET Ethylene
BRs Brassinosteroids
SA Salicylic Acid
JA Jasmonic Acid
DAMPs Damage-Associated Molecular Patterns
HAMPs Herbivory-Associated Molecular Patterns
MAPKs Mitogen-Activated Protein Kinases
WIPKs Wound-Induced Protein Kinases
SIPKs Salicylic-acid-Induced Protein Kinases
PTI Pattern-associated Immunity
PRRs Pattern-Recognition Receptors
RLKs Receptors-Like Kinases
LRR-RLKs Leucine-Rich Repeat Receptor-Like Kinases
MAMPs or PAMPs Microbial- or pathogen-Associated Molecular Patterns
ETI Effector-Triggered Immunity
Xa21 Xanthomonas oryzae resistance 21
LPS Lipopolysaccharides
CEBiP Chitin Elicitor Binding Protein
CERK Chitin Elicitor Receptor Kinase
PSK Phytosulfokine
PSKR Phytosulfokine Receptor
CLV1 Clavata1
CLV3 Clavata3
ERL1 Erecta-Like 1
EPF1 Epidermal Patterning Factor 1
SERKs Somatic Embryogenesis Receptor Kinases
FLS2 Flagellin Sensing 2
ROS Reactive Oxygen Species
BRI1 Brassinosteroid Insensitive 1
BRs Brassinosteroids
BAK1 BRI-Associated Kinase 1
EGF Epidermal Growth Factor
3D-QSAR Three-Dimensional Quantitative Structure-Activity Relationship
Int. J. Mol. Sci. 2021, 22, 693 14 of 18

SAR Systemic Acquired Resistance

ASA Acetylated derivative of Jasmonic Acid
PR Pathogenesis-Related Tobacco Mosaic Virus (TMV)
TMV Tobacco Mosaic Virus
MeJA Methyl jasmonate
JA-Ile N-jasmonoyl-L-isoleucine
JRG Jasmonic Responsive Gene
IBA Indole-3-Butyric Acid
4-Cl-IAA 4-Chloroindole-3-Acetic Acid
PAA Phenylacetic Acid
TIR1 Transport Inhibitor Response 1
DNA Deoxyribonucleic Acid
VOCs Volatile Organic Compounds

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