Received: 31 August 2018 Revised: 12 November 2018 Accepted: 20 November 2018

DOI: 10.1111/pce.13494

REVIEW

Cytokinin action in response to abiotic and biotic stresses in

plants
Anne Cortleven | Jan Erik Leuendorf | Manuel Frank | Daniela Pezzetta | Sylvia Bolt |

Thomas Schmülling

Institute of Biology/Applied Genetics, Dahlem

Centre of Plant Sciences, Freie Universität
Berlin, D‐14195 Berlin, Germany
Correspondence
Prof. Dr. T. Schmülling, Institute of
Biology/Applied Genetics, Dahlem Centre of
Plant Sciences (DCPS), Freie Universität
Berlin, Albrecht‐Thaer‐Weg 6, D‐14195
Berlin, Germany.
Email: tschmue@zedat.fu‐berlin.de
Funding information
Deutsche Forschungsgemeinschaft (DFG),
Grant/Award Numbers: CRC973, Schm
814/29‐1
Abstract
The phytohormone cytokinin was originally discovered as a regulator of cell division.
Later, it was described to be involved in regulating numerous processes in plant
growth and development including meristem activity, tissue patterning, and organ
size. More recently, diverse functions for cytokinin in the response to abiotic and
biotic stresses have been reported. Cytokinin is required for the defence against high
light stress and to protect plants from a novel type of abiotic stress caused by an
altered photoperiod. Additionally, cytokinin has a role in the response to temperature,
drought, osmotic, salt, and nutrient stress. Similarly, the full response to certain
plant pathogens and herbivores requires a functional cytokinin signalling pathway.
Conversely, different types of stress impact cytokinin homeostasis. The diverse
functions of cytokinin in responses to stress and crosstalk with other hormones are
described. Its emerging roles as a priming agent and as a regulator of growth‐
defence trade‐offs are discussed.

KEY W ORDS

abiotic stress, Arabidopsis thaliana, biotic stress, drought stress, growth‐defence trade‐off, light
stress, nutrient stress, priming, temperature stress

1 | I N T RO D U CT I O N caused an altered response to stress. Molecular details were not

Cytokinin (CK) was identified in the 1950s as a compound inducing
cell division (Miller, Skoog, von Saltza, & Strong, 1955). Since then,
numerous other activities of CK in plant growth and development
have been uncovered such as a function in the meristem activity of
shoots and roots, in shoot and root branching, in regulating organ size
and developmental transitions such as germination and flowering, in
controlling leaf senescence, and many more (reviewed by Kieber &
Schaller, 2018; Müller, 2011, Werner & Schmülling, 2009). Already
early reports noted functions of CK in stress defence, leading to the
general notion that CK enhances resistance to adverse environments
(Skoog & Armstrong, 1970). Sometime later, a broad survey summa-
rized the available evidences for potential roles for CK in a large vari-
ety of stress responses (Hare, Cress, & van Staden, 1997). These roles
were suggested mainly based on changes in endogenous CK concen-
tration during stressful events or because exogenous addition of CK
described as CK metabolism and signalling genes were unknown and
genetic approaches in CK research at that time largely unsuccessful.
Numerous putative functions of CK in response to stress that were
indicated are nowadays further investigated to uncover mechanisms
of CK action.
As a modern counterpart of such correlative data, exploration of
genome‐wide changes of gene expression in response to CK clearly
shows that numerous stress‐related genes are regulated by CK in
Arabidopsis as well as in rice (Bhargava et al., 2013; Brenner,
Ramireddy, Heyl, & Schmülling, 2012; Brenner & Schmülling, 2015;
Raines et al., 2016). However, these results are potentially of limited
value as gene regulation does not necessarily indicate a functional
relevance. Complementary data sets showed that CK‐related genes
are regulated by different environmental cues (Bielach, Hrtyan, &
Tognetti, 2017; Pavlů et al., 2018; Ramireddy, Chang, & Schmülling,
2014) suggesting that plants adapt their CK status in response to

998 © 2018 John Wiley & Sons Ltd wileyonlinelibrary.com/journal/pce Plant Cell Environ. 2019;42:998–1018.
CORTLEVEN ET AL. 999

changing environments, consistent with earlier reports showing
altered CK content in response to stress.
Since the CK metabolism and signalling system of Arabidopsis has
been uncovered and CK mutants have become generally available,
there has been a rapid increase in publications ascribing functions in
a variety of abiotic and biotic stress responses to this hormone. This
has been summarised in several general reviews (Argueso, Ferreira, &
Kieber, 2009; Ha, Vankova, Yamaguchi‐Shinozaki, Shinozaki, & Tran,
2012; Heyl, Riefler, Romanov, & Schmülling, 2012; Hwang, Sheen, &
Müller, 2012; Kieber & Schaller, 2014; Werner & Schmülling, 2009;
Zürcher & Müller, 2016). Other reviews focused on the response to
abiotic stress (Pavlů et al., 2018; Zwack & Rashotte, 2015) and biotic
stress (Choi, Choi, Lee, Ryu, & Hwang, 2011; Naseem, Wölfling, &
Dandekar, 2014) or addressed specific aspects such as the interaction
of CK with other hormones in the stress response (Bielach et al., 2017;
O'Brien & Benková, 2013; Verslues, 2016), the potential role of cis‐
zeatin (cZ)‐type CKs (Schäfer, Brütting, et al., 2015), and the role of
reactive oxygen species (ROS; Tognetti, Bielach, & Hrtyan, 2017) or
discussed growth‐defence trade‐off (Albrecht & Argueso, 2017; Giron
et al., 2013; Naseem, Kaltdorf, & Dandekar, 2015), and priming and
cross‐tolerance (Hossain et al., 2018). Readers may refer to these
publications as a rich source of information.
Here, we summarise recent literature revealing more details of an
emerging role of CK in the response to different stresses. We begin
with abiotic stresses such as light and temperature stress, cover
soil‐borne stresses caused by lack of water or nutrients, and end with
a chapter on different aspects of biotic stress. For each of these
stresses, we will highlight well‐studied cases and illustrate details of
signalling pathways. We also consider roles of CK in priming of stress
responses (Hilker et al., 2016), which is a topic of this Special Issue,
and in regulating growth‐defence trade‐offs. Understanding the
diverse roles of this important growth‐regulating hormone in stress
defence is also relevant for understanding the impact of a changing
environment on plant growth and for application in agriculture in
order to ensure the sustainability of food supply.
2 | C K M E T A B O L I S M A N D SI G N A L LI NG
The first decade of this century has witnessed the identification of
genes encoding CK metabolism and signalling proteins in Arabidopsis,
which are essentially present in similar form in other plant species
(Hellmann, Gruhn, & Heyl, 2010) and provide a framework for the
analysis of CK action (Figure 1). In brief, CK synthesis starts with the
formation of CK nucleotides, which is catalysed by isopentenyl trans-
ferases (IPTs; Figure 1). The CK nucleotides become active CK, that is,
the free bases isopentenyladenine (iP) and trans‐zeatin (tZ), by the
activity of the LONELY GUY (LOG) enzymes. The generally less active
cZ is synthesised via a different route involving tRNA‐IPTs catalysing
the isopentenylation of adenine on tRNA, the degradation of which

FIGURE 1 Scheme of cytokinin metabolism

and signalling. As a first step of CK synthesis,
iP nucleotides are formed by IPT enzymes.
Conversion to the respective tZ nucleotides is
catalysed by CYP735As. In addition, cZ‐type
CKs are formed by tRNA‐IPT enzymes.
iPRMP, tZRMP, and cZRMP can be directly
converted to biologically active free bases
(green box) by LOG enzymes. Inactivation of
all metabolites is catalysed by CKX enzymes.
More information about other branches of CK
metabolism can be found in Sakakibara
(2006). iP, tZ, and cZ bind to HK receptors
thereby initiating phosphorelay signalling via
HPTs to RRBs, which activate cytokinin
response genes. Among these, RRAs act as
negative feedback regulators. Some HPT
variants lacking the canonical histidine residue
act also as negative regulator of the signalling
pathway. tZ: trans‐zeatin; tZR: tZ riboside;
tZRMP: tZR monophosphate; cZ: cis‐zeatin;
cZR: cZ riboside; cZRMP: cZR
monophosphate; iP: isopentenyladenine; IPR:
iP riboside; iPRMP: iPR monophosphate; IPT:
ISOPENTENYLTRANSFERASE; CYP735A:
CYTOCHROME P450 MONOOXYGENASE;
LOG: LONELY GUY; CKX: CYTOKININ
OXIDASES/DEHYDROGENASE; HK:
HISTIDINE KINASE; HPT: HISTIDINE
PHOSPHOTRANSFER PROTEIN; RRB: type B
RESPONSE REGULATOR; RRA: type A
RESPONSE REGULATOR
1000
liberates cZ nucleotides (Figure 1). CK breakdown is catalysed by CK
oxidase/dehydrogenase (CKX) enzymes; their inactivation may also
be achieved by conjugation to sugars. Figure 1 shows a simplified
scheme of CK metabolism; more details can be found, for example,
in Sakakibara (2006). The CK signal is perceived by membrane‐located
sensor histidine kinases (HK), named ARABIDOPSIS HISTIDINE
KINASE2 (AHK2), AHK3, and CK RESPONSIVE1 (CRE1)/AHK4 in
Arabidopsis. Ligand binding causes receptor activation by autophos-
phorylation and initiates a phosphorelay through a two‐component sig-
nalling system from the receptor(s) via histidine phosphotransfer
proteins (HPTs; also called AHP in Arabidopsis) to nuclear‐localised type
B response regulators (RRB; also called type B ARR in Arabidopsis),
which are transcription factors regulating the expression of CK
response genes. The CK signalling pathway is regulated by a negative
feedback loop involving type A RRs (RRA; also called type A ARR in
Arabidopsis), the encoding genes being a target of RRBs, and by HPTs
lacking the canonical histidine residue to accept the transferred phos-
phoryl moiety (e.g., AHP6 in Arabidopsis; Figure 1). All mentioned genes
are present in Arabidopsis as small gene families with two (CYP735A),
three (AHK) or more members, seven in the case of CKX and LOG genes,
nine for IPT genes, and 11 and 12 for RRA and RRB genes.
Downstream of this core signalling pathway, transcriptional net-
works are activated of which the architecture is not yet completely
known (Brenner et al., 2012). Part of the network are CK RESPONSE
FACTORs (CRFs), which are members of the APETALA2/ETHYLENE
RESPONSE FACTOR (AP2/ERF) transcription factor family. Several
CRF genes are transcriptionally regulated by CK, and their products
act presumably downstream of the core CK signalling pathway
(Rashotte et al., 2006). The system offers plenty of opportunities for
fine‐tuning and crosstalk, including cross‐activation of effector genes
by other hormones, coaction of RRBs with other transcription factors,
and regulation of protein stability (Kurepa, Li, & Smalle, 2014; Marín‐
de la Rosa et al., 2015; Müller & Sheen, 2008).
3 | T HE R OLE OF C K I N TH E RE SP ON SE T O
ABIOTIC STRESS
3.1 | Light as a stress factor
Light delivers energy for photosynthesis; it carries information about
the season and time of the day and influences the growth direction of
plants. Too much light or too low light causes stress to plants, and
recent findings indicate that also an altered day–night rhythm may
cause stress. CK is involved at different levels in the response to these
stresses, which will be briefly summarised in the following sections.
Although photosynthesis depends on light, excessive light causes
damage to the photosynthetic apparatus and other cellular compart-
ments. Plants have developed several protective mechanisms to avoid
stress by too much light (high light stress) such as the dissipation of
excess light energy as heat, cyclic electron transport, and light avoid-
ance movements of leaves and chloroplasts (Takahashi & Badger,
2011). Despite these protective mechanisms, high light may cause an
overreduction of the photosynthetic electron transport chain and
photoinhibition takes place lowering the efficiency of photosynthesis
CORTLEVEN ET AL.
(Yamamoto, 2016). Protein D1, which is part of the reaction centre
of photosystem II (PSII), is one of the major targets of photodamage
(Edelman & Mattoo, 2008). Plants with a reduced CK status showed
a decreased photoprotection and increased photoinhibition due to a
strong reduction of the D1 level (Cortleven et al., 2014). Further,
CK‐deficient plants exhibited a lower capacity to recover from
photoinhibition after high light stress due to insufficient D1 repair.
Lack of CK reduced also the antioxidant capacity of plants. Thus,
several photoprotective mechanisms were disturbed in CK‐deficient
plants revealing that the hormone is an essential factor to protect
plants against high light stress. CK activity was mediated by AHK3
and to a lesser extent by AHK2, and the type B RRs, ARR1, and
ARR12 (Cortleven et al., 2014; Figure 2a).
Other work is supportive for a protective role of CK for the pho-
tosynthetic apparatus under high light (Cortleven & Schmülling, 2015).
For instance, CK promotes the antioxidant‐based protection in chloro-
plasts resulting in an extension of their life span (Procházková, Haisel,
& Wilhelmová, 2008). Transgenic tobacco plants that produce more
CK under drought stress because of the induction of a PSARK:IPT gene
(see below) showed an increased catalase activity and increased CO2
respiration (Rivero, Shulaev, & Blumwald, 2009) suggesting protection
of photosynthetic processes. In contrast, another study reported that
reducing CK signalling in Arabidopsis by mutating the AHK2 and
AHK3 receptor genes resulted in stronger photo‐oxidative stress
tolerance under conditions of water deficit (Danilova et al., 2014).
Also, lack of light may cause considerable stress for plants
that have developed distinct response mechanisms. CK acts as an
important xylem‐carried signal for photosynthetic acclimation to
canopy light gradients in Arabidopsis and tobacco (Boonman, Prinsen,
Voesenek, & Pons, 2009). Low light induces the shade avoidance
response, which consists of the induction of elongation growth towards
light and the arrest of leaf growth. The CKX6 gene has been identified
as being essential for the shade‐dependent auxin‐induced degradation
of CK in developing leaf primordia. Enhanced CK degradation resulted
in a rapid arrest of leaf primordia growth, saving resources for extension
growth of the hypocotyl (Carabelli et al., 2007).
Characteristic features of light is to deliver information about day-
time and regulate the circadian clock. Recently, it has been discovered
that an extended light period causes stress symptoms in Arabidopsis
plants during the following night, a phenomenon named photoperiod
stress (Nitschke et al., 2016; Nitschke, Cortleven, & Schmülling,
2017). The stress phenotype was first discovered in CK‐deficient
plants and was characterised by a typical course of events: An
extended light period led several hours after the beginning of the night
to the induction of stress marker genes such as ZAT12 and BAP1 and a
strong increase in jasmonic acid (JA) concentration; the next day, a sig-
nificant reduction of PSII maximum quantum efficiency (Fv/Fm) and
lesion formation in the leaves became visible. Wild‐type plants
showed a much weaker stress response compared with CK‐deficient
plants indicating that CK has a protective function. Mutant analyses
revealed that CK acts mainly through AHK3 and the RRBs ARR2,
ARR10, and ARR12 (Figure 2b). Also, certain clock mutants (e.g.,
cca1 lhy) showed a strong stress response after photoperiodic stress.
Common to stress‐sensitive clock mutants and CK‐deficient plants
was a lowered expression or impaired functioning of CCA1 and LHY,
CORTLEVEN ET AL. 1001

FIGURE 2 Models for the protective function of cytokinin during high light and photoperiod stress. (a) High light (HL) causes the inhibition of
active PSII and the production of ROS, which can also inhibit D1 repair (dotted black lines). Plants have evolved several mechanisms such as
ROS scavenging and the D1 repair cycle to counteract the destructive effect of too much light (light grey boxes and solid black lines). Cytokinin
(CK) has protective functions in the light stress response by promoting both ROS scavenging and D1 repair (grey lines), which is mediated by the
AHK2 and AHK3 receptors and the RRBs ARR1 and ARR12. Adapted from Cortleven et al. (2014). (b) In plants with a reduced CK status or CCA1/
LHY expression or function, alteration of the photoperiod leads to a perturbation of the circadian clock, which results in a stress syndrome
characterised by the accumulation of ROS and jasmonic acid (JA) and the formation of lesions. CK acts via the AHK2 and AHK3 receptors and the
RRBs ARR2, ARR10, and ARR12 to maintain CCA1/LHY expression levels required for a functional circadian clock. Adapted from Nitschke et al.
(2016, 2017). CCA1: CIRCADIAN CLOCK ASSOCIATED 1; LHY: LATE ELONGATED HYPOCOTYL

two key regulators of the circadian clock, which indicates that a func-
tional clock is essential to cope with photoperiod stress. Although this
new kind of abiotic stress does not occur under natural conditions, it is
informative about links between CK and stress pathways, which have
so far gone unnoticed. It remains to be seen what the natural roles of
these mechanistic links are.
3.2 | Temperature stress
A second relevant environmental information for plants is the ambient
temperature, which may encompass enormous diurnal differences of
30°C or more, even in temperate climates. Temperature has a signifi-
cant impact on plants. Major temperature variations may cause cold
stress (chilling or freezing stress) or heat stress. As will be outlined
below, there is partly contradictory information about the role of CK
in the immediate cold stress response. Comparatively few is known
about a possible role of CK in the response to heat stress.
3.2.1 | The role of CK in the response to cold stress
Cold stress results among others in a loss of membrane integrity,
increased ion efflux, and an impaired water and nutrient balance.
The response to cold stress involves transcriptional and posttranscrip-
tional regulatory mechanisms that can be ABA dependent or ABA
independent. In Arabidopsis, the best studied response to cold stress
is the CBF/DREB signalling cascade, which is also called CBF regulon
and comprises the CBF1 to CBF3 genes as central regulatory elements
(Pareek, Khurana, Sharma, & Kumar, 2017).
The role of CK in the response to cold temperatures is not entirely
clear. Typically, cold temperatures lower the CK content and CK
signalling (e.g., Maruyama et al., 2014), which makes sense as a growth
reduction is caused by cold stress. However, exogenous addition of
CK to Arabidopsis seedlings may increase their freezing tolerance (Jeon
et al., 2010). On the other hand, Arabidopsis CK receptor mutants
(ahk2 ahk3 and ahk3 cre1) displayed an enhanced freezing tolerance
suggesting that the receptors act as negative regulators of the
response to cold stress. Surprisingly, cold stress activated CK
1002
receptors independent of CK (Jeon et al., 2010), and signal transfer
used proteins of the two‐component signalling system, in particular
several HPTs (AHP2, AHP3, and AHP5) and the RRB ARR1 (Jeon &
Kim, 2013). The cold‐regulated genes were distinct from those of
the CBF regulon (Jeon & Kim, 2013) and included a subset of RRA
genes, namely, ARR5, ARR6, ARR7, ARR15, and ARR22. arr5, arr6, and
arr7 mutants showed increased freezing tolerance, with or without
cold acclimation (Jeon et al., 2010). In contrast, other studies found
that overexpression of the same RRA genes (ARR5, ARR7, ARR15) as
well as of ARR22 increased freezing tolerance in Arabidopsis (Kang,
Cho, & Kim, 2013; Shi et al., 2012). Along these lines, our own analysis
of the cold stress response of Arabidopsis CK signalling and metabo-
lism mutants has in most cases not revealed any difference compared
with wild type (J.E.L., M. F., & T.S., unpublished result). Together, this
suggests that the activity of two‐component signalling genes in the
response to cold might be context dependent.
Besides these key components of the canonical CK signalling
pathway, several CRF genes have been linked to the cold stress
response in Arabidopsis. The CRF2 and CRF3 genes have been shown
to promote lateral root initiation and formation under cold stress
(Jeon, Cho, Lee, Van Binh, & Kim, 2016). CRF2 expression was directly
regulated by ARR1 (Jeon et al., 2016). Also, CRF4 was described to be
induced by cold and to be a positive regulator of freezing tolerance
impacting the expression of the CBF regulon (Zwack, Compton,
Adams, & Rashotte, 2016).
Together, these reports show that the response to cold may use
(part of) the CK signalling pathway or CK‐related transcription factors.
A true function for the hormone itself has not been demonstrated
unequivocally. Compared with other stresses, CK genes are—besides
those genes mentioned above—not particularly responsive to low
temperatures, which is consistent with a relatively minor role of the
hormone in the response to cold stress (Ramireddy et al., 2014).
3.2.2 | The role of CK in the response to heat stress
Heat stress damages cellular components by the generation of ROS
and the denaturation of proteins and negatively influences the photo-
synthetic capacity resulting in a metabolic imbalance. Upon heat
stress, plants activate various defence mechanisms including the
formation of heat shock proteins acting as molecular chaperones
preventing protein denaturation and aggregations (Mittler, Finka, &
Goloubinoff, 2011).
Heat stress decreases the CK content (Hare et al., 1997), and CK
treatment typically enhances heat stress resistance. For example,
exogenous application of CK and enhanced endogenous CK concen-
trations resulted in a decrease of the inhibitory effect of heat stress
on photosynthesis and chloroplast development (Caers, Rudelsheim,
& Van Onckelen, 1985; X. Liu & Huang, 2002) and caused a higher
activity of the antioxidant system and up‐regulation of heat shock pro-
teins in tobacco and creeping bentgrass (Harding & Smigocki, 1994;
Veerasamy, He, & Yuang, 2007; Xu, Tian, Gianfagna, & Huang, 2009;
Xu, Gianfagna, & Huang, 2010). Noteworthy, CK treatment increased
thermotolerance of reproductive tissue in maize, rice, and passion fruit
(Cheikh & Jones, 1994; Sobol et al., 2014; Wu et al., 2016, 2017)
suggesting priming of heat stress defence by CK (see below).
CORTLEVEN ET AL.
Transcriptomic and proteomic studies revealed more connections
between CK and the heat response. A substantial overlap of CK‐ and
heat‐responsive transcriptomic changes was identified in Arabidopsis
(Černý, Jedelský, Novák, Schlosser, & Brzobohatý, 2014). A high pro-
portion of the heat‐responsive proteome and several phosphoproteins
appeared to be coregulated by CK as the proteome response to CK
treatment at standard temperature partly mimicked the effects of heat
shocks on the proteome. Following high temperature treatment, a new
set of early CK response proteins was identified (Černý, Dyčka,
Bobál'ová, & Brzobohatý, 2011; Skalák et al., 2016). Taken together,
the prevailing evidence suggests that CK is involved in adaptive mech-
anisms to heat stress but the exact nature of its activity has as yet to
be clarified.
3.3 | Drought stress
Strategies to cope with periods of water restriction are vital for plant
growth and development. The restriction of water availability is com-
mon in drought, osmotic, salt, and freezing stress, resulting in an over-
lap in physiological responses. To optimise the use of water, several
mechanisms have evolved in plants including redirection of root
growth (Feng, Lindner, Robbins, & Dinneny, 2016), regulation of tran-
spiration through stomata, and alteration of cell membrane properties
(Zhu, 2016). The response to drought is tightly linked to the action of
ABA, which accumulates upon drought stress and binds to its cognate
receptor family PYRABACTIN RESISTANCE1 (PYR1)/PYR1‐LIKE
(PYL)/REGULATORY COMPONENTS OF ABA RECEPTORS (RCAR;
Figure 3). The ABA‐PYR/PYL complex binds to and thus inhibits PRO-
TEIN PHOSPHATASES 2C (PP2Cs), which, in the absence of ABA,
dephosphorylate and in this way keep subclass III SUCROSE NON‐
FERMENTING‐1 (SNF1)‐RELATED PROTEIN KINASES2 (SnRK2s)
inactive. Activated SnRK2s phosphorylate transcription factors named
ABSCISIC ACID‐RESPONSIVE ELEMENT (ABRE) BINDING PRO-
TEINs (AREBs)/ABRE BINDING FACTOR (ABFs), which regulate the
expression of target genes to increase plant resistance to drought
stress (Joshi et al., 2016; Miyakawa, Fujita, Yamaguchi‐Shinozaki, &
Tanokura, 2013). Another signalling pathway activated by drought
and osmotic stress is ABA independent and involves GROWTH‐
REGULATING FACTOR7 (GRF7; Kim et al., 2012; Q. Liu et al., 1998).
Drought generally causes a reduction of the CK content (e.g.,
Ghanem et al., 2008; Nishiyama et al., 2011; Todaka et al., 2017),
which is achieved in Arabidopsis and soybean by repression of IPT
genes and the up‐regulation of CKX genes (Y. Guo & Gan, 2011; Le
et al., 2012; Nishiyama et al., 2011; Ramireddy et al., 2014). In addi-
tion, the expression of CK signalling genes was lowered in response
to drought (Nguyen et al., 2016; Nishiyama et al., 2013). Consistently,
genetic studies in Arabidopsis have shown that CK acts as a negative
regulator of drought stress resistance (Nguyen et al., 2016; Nishiyama
et al., 2011; Nishiyama et al., 2013; Tran et al., 2007). Lowered CK
content and signalling had at least two main consequences, namely,
an increased sensitivity to ABA—establishing CK as an antagonist of
ABA (Tran et al., 2007)—and a reduction of shoot growth (Riefler,
Novak, Strnad, & Schmülling, 2006; Werner et al., 2003), which is an
adaptive response to survive drought.
CORTLEVEN ET AL.
FIGURE 3 Cytokinin‐ABA crosstalk during the response to drought
and osmotic stress. Upon drought and osmotic stress, ABA
accumulates and activates the PYR/PYL/RCAR receptor family (right
part), resulting in PP2C inhibition and thus in SnRK2 activation, which
leads to AREB/ABF activation and transcription of ABRE genes
mediating the stress response. ABA reduces via MYB2‐dependent
repression of IPT genes (left part) the CK concentration. In turn, this
lowers the output of the AHK/AHP/ARR signalling cascade
contributing to drought/osmotic stress adaptation. During the
absence of drought/osmotic stress, CK suppresses SnRK2 function via
RRBs thus shutting off the stress response. Upon stress, activated
SnRK2 phosphorylates ARR5, thereby reducing CK signalling. MYB2:
MYOSIN BINDING2; PYR/PYL/RCAR: PYRABACTIN RESISTANCE1/
PYR1‐LIKE/REGULATORY COMPONENTS OF ABA RECEPTORS;
PP2C: PROTEIN PHOSPHATASE 2C; SnRK2: SUCROSE NON‐
FERMENTING‐1 (SNF1)‐RELATED PROTEIN KINASE2; ABRE:
ABSCISIC ACID RESPONSIVE ELEMENT; AREB/ABF: ABRE
BINDING PROTEIN/ABRE BINDING FACTOR
Functionally relevant components of the CK signalling chain in the
response to drought stress have been identified (Li, Herrera‐Estrella, &
Tran, 2016). Plants with mutated CK receptor genes (AHK2 and
AHK3), HPT (AHP2, AHP3, and AHP5), or RRB (ARR1, ARR10, and
ARR12) genes showed an increased drought stress resistance (Nguyen
et al., 2016; Nishiyama et al., 2011). Drought resistance was associ-
ated with a number of physiological changes such as a reduced stoma-
tal aperture, increased cell membrane integrity, and increased
1003
sensitivity to ABA (Nguyen et al., 2016). Transcriptomic analysis sug-
gested that CK controls a great number of dehydration/drought‐
and/or ABA‐responsive genes contributing to drought adaptation
(Nguyen et al., 2016). The RRA genes ARR5, ARR6, ARR7, ARR15, and
ARR22, which respond to cold in a CK‐independent fashion (Jeon
et al., 2010; Jeon & Kim, 2013), were also up‐regulated under drought
and salt stress conditions (Kang, Cho, Kim, & Kim, 2012) indicating a
partial overlap of the response pathways. Plants that overexpress
ARR22 are more resistant to drought (Kang et al., 2013).
How is the drought stress response of the CK system linked to
the ABA‐dependent response pathway? One link in Arabidopsis
involves induction of MYB2 by ABA (Abe et al., 1997), which
represses IPT genes thus lowering the CK concentration (Y. Guo &
Gan, 2011). In turn, this lowers the output of the AHK/AHP/ARR sig-
nalling cascade contributing to drought/osmotic stress adaptation
(Figure 3). Another link is based on the interaction between SnRK2s
and RRAs and RRBs. Under non‐stress conditions, the RRBs ARR1,
ARR11, and ARR12 physically interact with SnRK2s and thus repress
their kinase activity, which shuts down the drought response
pathway. Conversely, in drought‐stressed plants, SnRK2s phosphory-
late the RRA ARR5 thus inhibiting CK signalling and suppressing
growth (Huang et al., 2018; Figure 3). This crosstalk illustrates
nicely how CK operates to regulate growth‐defence trade‐offs (see
further below).
The protective role of CK during drought stress has also been
used in biotechnological approaches. Expression of an IPT gene under
control of the maturation‐ and senescence‐induced SARK promoter
delayed drought‐induced leaf senescence in tobacco plants and main-
tained photosynthesis by increasing photorespiration during periods
of drought leading to a reduced yield loss compared to control plants
(Rivero et al., 2007, 2009). Similar observations were also made for
other crops expressing PSARK:IPT such as cassava (Zhang et al., 2010),
rice (Peleg, Reguera, Tumimbang, Walia, & Blumwald, 2011; Reguera
et al., 2013), peanut (Qin et al., 2011), creeping bentgrass (Merewitz
et al., 2012; Merewitz, Xu, & Huang, 2016), cotton (Kuppu et al.,
2013), and maize (Décima Oneto et al., 2016). Interestingly, in cotton,
this approach was effective in enhancing plant performance only
when drought stress occurred during the vegetative phase, while
drought stress during or after flowering did not cause a yield advan-
tage (Zhu, Li, Zhang, & Guo, 2018). Similar beneficial effects on plant
growth and yield by conditionally or locally enhanced CK synthesis
have been reported from canola and bentgrass using different
promoter‐IPT gene combinations (Kant et al., 2015; Xu, Burgess,
Zhang, & Huang, 2016). Notably, IPT transgenic canola showed a yield
increase under both stressed and nonstressed scenarios in the field
(Kant et al., 2015).
Another engineering approach to improve drought resistance in
plants has built on the knowledge that CK is a negative regulator of
elongation growth of the primary root and of root branching (Werner
et al., 2003; Werner, Motyka, Strnad, & Schmülling, 2001). Lowering
the CK content in the root of Arabidopsis, tobacco and barley plants
by root‐specific expression of CKX genes caused the formation of a
larger root system with mostly unaffected shoot growth and yield
(Macková et al., 2013; Ramireddy et al., 2018; Werner et al., 2010).
A higher survival rate of CKX‐transgenic tobacco plants under drought
1004
stress in an intermixed planting suggested that these plants competed
more successfully than wild‐type plants for limited water resources
(Werner et al., 2010). Transgenic barley with enhanced CK breakdown
in their roots showed dampened stress responses to long‐term
drought conditions, including a higher stomatal conductance and a
higher CO2 assimilation rate, a lower induction of key ABA metabolism
genes, and reduced accumulation of ABA (Ramireddy et al., 2018).
These beneficial effects have been partly attributed to the larger soil
volume explored by the CKX‐transgenic plants, but evidently,
additional mechanisms such as crosstalk between the CK and ABA
signalling pathways might contribute to the altered drought stress
response (Ramireddy et al., 2018; Vojta et al., 2016).
Taken together, different strategies have been employed success-
fully to increase drought resistance of plants by genetically engineer-
ing the plant CK system. However, it should be kept in mind that
there are numerous different drought scenarios affecting plants at
different times of their lives and each and every drought scenario
might need (partially) different solutions to combat its consequences
(Tardieu, 2012).
3.4 | Salt stress
During salinity stress, the high osmotic potential of the saline soil leads
to water loss from plant tissue, to a decrease of the water absorption
capacity of the plant root system and to the formation of harmful ROS
(Mahajan & Tuteja, 2005; Munns, 2002). To cope with salinity stress,
plants have developed different adaptation strategies, which are par-
tially overlapping with the responses to drought stress, and include
the reduction of water loss by regulation of stomata closure, reduced
growth and the protection from ion stress (Munns & Tester, 2008).
Responses to salt stress are regulated by different phytohor-
mones, most prominently by ABA, which has a protective role (Zhu,
2002). In contrast, CK is generally a negative regulator of the response
to salt stress. Regulation of IPT genes in salinity‐stressed Arabidopsis
wild‐type plants led to a reduction of the CK concentration (Nishiyama
et al., 2011). CK‐deficient plants were more tolerant to salinity stress
than wild type (Nishiyama et al., 2011; Tran et al., 2007). These salt‐
tolerant plants showed altered expression of numerous stress‐ and
ABA‐responsive genes (Nishiyama et al., 2012). Among the genes reg-
ulated by CK in Arabidopsis is HKT1;1, which encodes a sodium trans-
porter preventing hyperaccumulation of sodium ions. Mutants with
lower CK showed enhanced HKT1;1 expression and an enhanced salt
resistance, suggesting a functional relevance of this regulation (Mason
et al., 2010; Nishiyama et al., 2011). Overproduction of CK by induc-
ible expression of the IPT8 gene in Arabidopsis resulted in reduced
salinity stress adaptation, which was correlated with an enhanced
ROS production and with a decrease in ROS scavenging enzyme
expression (Wang, Shen, Chan, & Wu, 2015).
In contrast to the negative role of CK in salt stress resistance
shown by these genetic studies, other work described a positive effect
of CK under salinity stress. In tomato plants under salinity stress,
the application of INCYDE, an inhibitor of CKX enzymes, protected
the photosynthetic apparatus and increased the production of flowers
(Aremu et al., 2014). A protective effect of CK was also noted in a salt‐
CORTLEVEN ET AL.
sensitive rice cultivar. A knockdown of OsCKX2, which
caused increased CK levels and enhanced seed yield (Ashikari et al.,
2005), showed a reduced yield penalty under salinity stress (Joshi
et al., 2018).
3.5 | Nutrient stress
Lack of nutrients in the soil causes stress and induces a variety of
responses in which CK is involved at different levels (Pavlů et al.,
2018). The availability of nutrients modifies root system architecture
(RSA), and CK is one of the factors regulating RSA in response to nutri-
tional cues (Kroevoets, Venema, Elzenga, & Testerink, 2016). Both CK
metabolism and signalling genes are involved in regulating RSA
(Bielach et al., 2012; Chang, Ramireddy, & Schmülling, 2013; Chang,
Ramireddy, & Schmülling, 2015), and nutritional cues impact their
transcript levels (Bielach et al., 2017; Pavlů et al., 2018; Ramireddy
et al., 2014). CK regulates expression of numerous transporter genes
(Brenner, Romanov, Köllmer, Bürkle, & Schmülling, 2005; Werner
et al., 2010) and the production of passage cells (Andersen et al.,
2018), which impacts the ability to uptake nutrients by the plant. Thus,
CK regulates morphological and physiological adaptive responses to
cope with nutrient stress.
The first work that revealed a specific role of CK signalling in
nutrient sensing was a study on the phosphate starvation response
in Arabidopsis mutants and revealed that CK signalling is required for
a strong response to low phosphate availability (Franco‐Zorrilla et al.,
2002; Franco‐Zorrilla, Martín, Leyva, & Paz‐Ares, 2005). CK is a
negative regulator of sulfur acquisition suppressing the expression of
sulfate transporter genes (Maruyama‐Nakashita, Nakamura, Yamaya,
& Takahashi, 2004). Similarly, CK suppresses genes for iron uptake
and iron homeostasis (Séguéla, Briat, Vert, & Curie, 2008). As men-
tioned above, CK regulates sodium accumulation through the sodium
transporter gene HKT1;1 (Mason et al., 2010). CK deficiency induced
by low potassium levels or due to an experimentally lowered CK status
caused up‐regulation of the high‐affinity K+ transporter gene HAK5,
enhanced ROS accumulation, and increased root hair growth, suggest-
ing that CK has a role in the response to low potassium availability
(Nam et al., 2012). For yet another micronutrient, boron, it was found
in Brassica napus seedlings that increasing boron concentration in the
medium correlated with increased CK content, which was argued to
be a prerequisite for an adjusted growth response (Eggert & von
Wirén, 2017).
CK is an important regulatory factor in plant adaptation to arsenic
(As) stress (Mohan et al., 2016). Arabidopsis plants with a reduced CK
status were shown to be more tolerant than wild type to arsenate, the
most abundant form of As. CK deficiency increased expression of
As(V)/phosphate transporter genes and As tolerance mechanisms
causing accumulation of complexing agents (Mohan et al., 2016). In
contrast, in case of another soil contaminant, selenium (Se), higher
CK levels caused tolerance (Lehotai et al., 2012). These data suggest
that CK is a factor in regulating adaptation to As and Se stress.
How a growth regulatory function of CK in response to nutrient
stress could be exerted was elegantly shown by recent work address-
ing the role of CK in communicating the availability of nitrogen from
CORTLEVEN ET AL. 1005

roots to the shoot (Landrein et al., 2018; Poitout et al., 2018; Figure 4).
Quantitative microscopy was used to record the expression of a GFP
reporter gene under control of the WUS promoter, which regulates
the expression of a central regulator of shoot apical meristem (SAM)
activity (Landrein et al., 2018). Analysis of reporter gene activation in
the background of CK metabolism mutants revealed that the response
to altered nitrogen availability in the soil required de novo CK synthesis
by IPTs. Consistently, an increase of the soil nitrogen content
increased the concentration of tZR, which is the major transport form
of CK (Figure 4). The pWUS:GFP reporter gene response to altered
nitrogen availability occurred rapidly in the SAM within a day. Impor-
tantly, grafting experiments between wild type and CK mutants
showed that synthesis of precursors of active CKs may occur in the
root (or elsewhere in the plant) but that the reporter gene response
was strictly dependent on the ability to form active CKs in the shoot,
presumably by LOG enzymes in the SAM (Chickarmane, Gordon, Tarr,
Heisler, & Meyerowitz, 2012). Consistent with CK acting through
modulating the activity of WUS, several reports identified WUS as a
direct target gene of RRBs (Dai et al., 2017; T. Q. Zhang et al., 2017;
Zubo et al., 2017) suggesting a short signalling path in the responding
meristem (Figure 4). Poitout et al. (2018) ascribed an important role to
the ABCG14 transporter to export nitrate‐induced CK from roots as
its mutation disrupted systemic N‐signalling. Further, they identified
a major transcriptional reprogramming in shoots caused by root‐
derived CK, suggesting additional roles of the hormone beyond regu-
lation of SAM activity (Poitout et al., 2018). The increase of CK con-
centration in the root in response to altered nitrate availability
involves NLP transcription factors, which act as positive regulators
of IPT and CYP735A gene expression, whereas NIGT1 transcription
factors—also positively regulated by NLPs—act as negative regulators
of IPT and CYP735A gene expression (Maeda et al., 2018; Figure 4).
Taken together, it has been demonstrated that synthesis of CK in
the root and its translocation to the shoot carries relevant information
about soil conditions, notably nitrogen availability, to regulate shoot
activity. Results suggesting a role for CK as systemic nitrogen signal
were obtained also in the perennial grass Lolium perenne (Q. Guo
et al., 2017), suggesting that the function is evolutionary conserved.
4 | TH E R OL E O F C K I N TH E R E SP O NS E TO
B I O TI C S T R E S S
CKs are adenine derivatives, and numerous organisms other than
plants use adenine derivatives as signalling molecules. Therefore,
CKs are ideal molecules for interkingdom communication between
plants and phytopathogens.

FIGURE 4 Cytokinin functions as a long distance signal regulating shoot growth dependent on nitrate availability in the soil. (a) CK is involved in
responding to the availability of numerous nutrients in the soil (shown in grey; for details, see text). The role in the response to nitrate availability is
highlighted. (b) Upon nitrate sensing, biosynthesis of CK in the root is induced by NLPs, which are positive regulators of IPT and CYP735A gene
expression. NLPs induce also the expression of NIGT1 transcription factor genes encoding negative regulators of IPT and CYP735A gene
expression. tZR and tZ are transported via ABCG14 through the xylem to the shoot (dotted black lines). (c) In the leaves, CK signalling induces
transcriptional reprogramming leading to physiological changes. (d) In the SAM, CK enhances WUS expression and thus SAM size and organ
formation. SAM: shoot apical meristem; WUS: WUSCHEL
1006
Plants have evolved elaborate strategies to respond to attacks by
other living organisms, which rely often on the action of different
defence hormones, in particular salicylic acid (SA) to defend against
biotrophic and hemibiotrophic pathogens, and JA and ethylene (ET)
to defend against necrotrophic pathogens and herbivores (Conrath,
Beckers, Langenbach, & Jaskiewicz, 2015; Erb, Glauser, & Robert,
2012; Gao, Zhu, Kachroo, & Kachroo, 2015). In order to reduce costly
constitutive defence, plants have evolved several inducible defence
mechanisms such as Induced Systemic Resistance (ISR) and Systemic
Acquired Resistance (SAR; Fu & Dong, 2013; Pieterse et al., 2014).
For SAR, SA and SA conjugates, like the volatile and phloem mobile
methyl salicylate (MeSA), are key regulators and tightly connected to
the expression of pathogenesis‐related genes (e.g., PR1) in distal tis-
sues (Gao et al., 2015). CK action has to be linked to these established
defence pathways in order to shape defence responses. The emerging
picture of how this is realised will be outlined below, after an overview
of recent studies on the roles of CK in the interactions between plants
and pathogens.
4.1 Diverse functions for CK in interkingdom
| levels enhanced Arabidopsis resistance against the fungus.
communication
The role of CK in plant–pathogen interaction was initially highlighted
by its involvement in inducing neoplastic growth in host plants. The
best known example is Agrobacterium tumefaciens, which integrates a
piece of DNA, carrying, amongst others, a CK synthesis gene, to take
control of the growth of the infected host cell (Jameson, 2000;
Sakakibara et al., 2005). Neoplastic growth can also be caused by
the interaction of leaf‐mining and gall‐forming insects with plants
and has been proposed to be associated with altered CK (Giron
et al., 2013). Another classical example is the role of CK in green
island formation on leaves following infection with biotrophic or
hemibiotrophic fungi causing enhanced nutrient assimilation and allo-
cation and retardation of senescence (Walters & McRoberts, 2006).
Over the last years, a number of detailed studies covering a broad
range of other pathogens ranging from viruses and bacteria to fungi,
nematodes, herbivores, and even parasitic plants have documented
how ubiquitously CK is used in interkingdom communication (Albrecht
& Argueso, 2017). In the following section, we will highlight represen-
tative examples.
Pathogenicity proteins of some gemini viruses inhibit an adeno-
sine kinase, which phosphorylates CK nucleosides (Baliji, Lacatus, &
Sunter, 2010). As a consequence, upon viral infection, expression of
primary CK responsive genes was enhanced suggesting that the host
CK pathway is a target to boost viral infection. The gemini viruses
might benefit from the increased CK levels, which cause the promo-
tion of cell division, delay of senescence, and/or the increased avail-
ability of local resources.
The biotrophic actinomycete Rhodococcus fascians, causative
agent of the leafy gall syndrome, produces and releases a spectrum
of CK metabolites into its surroundings to induce tissue proliferation
of the host acting through AHK3 and AHK4. Interestingly, methylated
derivatives of CKs were among the CKs produced by the pathogen,
which turned out to be more stable against the plants' CKX enzyme
CORTLEVEN ET AL.
activity and thus may cause more persistent host tissue stimulation
(Pertry et al., 2009, 2010; Radhika et al., 2015).
An important role of CK for the successful establishment of plant–
fungus interaction was also shown in the biotrophic ergot Claviceps
purpurea. It synthesises a spectrum of CKs including cZ‐type CKs,
the predominant CK form in rye, the main host of C. purpurea (Hinsch,
Galuszka, & Tudzynski, 2016). C. purpurea strains with mutated CK
synthesis genes, in particular those with abolished synthesis of cZ‐
type CKs, and strains expressing a CKX gene showed reduced
virulence (Hinsch et al., 2016; Kind et al., 2018).
The clubroot disease of the Brassicaceae is caused by the obligate
biotrophic protist Plasmodiophora brassicae that produces CK and
induces an array of transcriptional CK responses upon infection. CKX
gene overexpressing lines developed reduced disease symptoms,
clearly indicating the importance of CK for pathogenesis of clubroot
(Siemens et al., 2006).
As a result of infection with the hemibiotrophic fungus Verticillium
longisporum, a vascular pathogen in Brassicaceae, tZ levels in
Arabidopsis decreased (Reusche et al., 2013). This seems to be part
of the infection strategy of the pathogen, because stabilisation of CK
The hemiparasitic plant Phtheirospermum japonicum induces hyper-
trophy on the roots of Arabidopsis thus reducing the biomass of the
host and increasing the haustoria density of the pathogen. This process
required the CK receptors AHK3 and AHK4 but did not rely on CK
synthesis by the host plant. Instead, expression of a CK‐degrading
enzyme in P. japonicum prevented host hypertrophy suggesting that
the parasitic plant was the source of CK (Spallek et al., 2017).
Parasitic nematodes manipulate production and signalling of CK
to activate cell division. Siddique et al. (2015) identified an IPT gene
in the nematode Heterodera schachtii and showed that silencing of this
gene led to a significant decrease in virulence. CK‐deficient plants
showed decreased susceptibility indicating that the host plants CK
system is required for virulence. This and additional work of Shanks
et al. (2015) underlined the functional relevance of CK for the parasitic
interaction and in particular for the induction of the nematode's
feeding site. Further, altered expression of plant CK genes at the
developing feeding sites showed that cyst and root‐knot nematodes
manipulated the host's own CK system (Dowd et al., 2017; Siddique
et al., 2015).
CK was also repeatedly shown to be involved in interactions
between plants and herbivores. Leaf wounding as well as oral secre-
tions of the herbivore Manduca sexta increased the levels of CK in
Arabidopsis and Nicotiana attenuata (Schäfer, Brütting, et al., 2015).
CK induced various defence responses in N. attenuata including the
accumulation of JA through two CK receptors (NaCHK2 and
NaCHK3). However, the formation of the bioactive JA‐Ile was not
promoted (Schäfer, Brütting, et al., 2015), and the JA pathway was
not required to increase the CK levels; in fact, it rather suppressed
the CK responses (Schäfer, Meza‐Canales, et al., 2015). Another herbi-
vore, the mirid Tupiocoris notatus, living also on N. attenuata, was
shown to transfer CK, in particular iP‐type CK, to the plant via its oral
secretions to increase sink strength and thus the food quality of the
leaves it feeds on (Brütting et al., 2018). Together, this clearly showed
that CK has an important role in plant–herbivore interactions and its
CORTLEVEN ET AL. 1007

formation and signalling may be induced in the plant by the herbivore
or produced by the herbivore itself, possibly involving endosymbionts
(Giron et al., 2013).
4.2 | Interaction between CK and SA‐dependent and
SA‐independent pathways
Probably the best studied activities of CK in defence are those against
biotrophic and hemibiotrophic pathogens such as the bacterium Pseu-
domonas syringae pv. tomato DC3000 (Pst) causing bacterial speck in
Arabidopsis (Choi et al., 2010) or the oomycete Hyaloperonospora
arabidopsidis (Hpa) Noco2 (Albrecht & Argueso, 2017). The defence
responses involving CK may be dependent or independent of the SA
pathway. The different modes of interaction will be described in the
following sections and are summarised in Figure 5.
A clear indication that the CK and SA pathways are linked came
from the analysis of the uni‐1D mutation in Arabidopsis. This mutation
caused constitutive activation of the UNI disease resistance protein,
which in turn caused activation of CK and, subsequently, of the SA
pathway, but not of the JA/ET defence pathway (Igari et al., 2008).
Enhanced expression of the resistance protein PR1 in the uni‐1D
mutant was abolished by abbreviating SA synthesis or by reducing
the CK content. Also, the activation of two other resistance proteins,
RPS2 and RPM1, induced the CK pathway supporting its relevance
for pathogen defence (Igari et al., 2008).

FIGURE 5 Model for cytokinin action in plant immunity. Many plant–pathogen interactions cause an increase in CK concentration. CK exerts its
protective functions against biotic stressors in both SA‐dependent or SA‐independent fashions. For example, the induction of phytoalexin
accumulation in tobacco, which confers resistance against Pseudomonas syringae, does not depend on SA. In the SA‐dependent defence, the CK
(dark grey boxes) and SA pathways (white boxes) are linked on various levels. CK potentiates SA‐dependent defence responses whereas RRAs
negatively regulate CK and SA pathways. Both CK and SA pathways are required to induce post‐invasive defence via the interaction of the
transcription factors ARR2, TGA3, and NPR1. Overexpression of CRF5 resulted in enhanced expression of defence‐related marker genes. The
action of CK to establish pre‐invasive defence responses involves ARR2, which induces H2O2 production via activation of apoplastic plant
peroxidases. Manipulation of the host CK pool by pathogen effectors may also cause suppression of defence mechanisms in the host cell. SA:
salicylic acid; NPR1: NONEXPRESSER OF PR GENES 1; TGA: TGA transcription factor; PRX: PEROXIDASE; CRF: CYTOKININ RESPONSE
FACTOR
1008
The molecular mechanism underlying the CK and SA pathway
interaction was revealed by Choi et al. (2010). They found that CK act-
ing through AHK2/AHK3 was required for resistance of Arabidopsis to
Pst. This defence was ineffective in a mutant defective in the SA
response factor gene TGA3, encoding a bZIP transcription factor. The
RRB ARR2 was shown to bind to TGA3 and activate SA‐related
defence genes including PR1 and ICS1/SID2, coding for isochorismate
synthase, which is involved in SA biosynthesis. This gene activation
was abolished in the tga3 mutant, in the SA signalling mutant npr1
and nahG‐overexpressing plants lacking SA. ARR2 was not able to bind
the PR1 promoter by itself; rather, the ARR2‐TGA3 interaction was
essential for binding and the induction of PR1 expression (Figure 5).
Further, SA‐enhanced ARR2‐TGA3 binding to the PR1 promoter was
dependent on NPR1, which functions as a transcriptional coactivator
(Choi et al., 2010). Besides this central regulatory module, part of
the CK response may also be mediated by CRF5. Arabidopsis thaliana
plants overexpressing the CRF5 gene showed enhanced expression
of PR1 and enhanced resistance to Pst (Liang et al., 2010). Notably,
bioinformatic analyses confirmed the CK‐SA synergism (Naseem
et al., 2012).
The relevance of the CK‐SA coaction was confirmed in a study of
Hpa infection in Arabidopsis (Argueso et al., 2012). The action of CK
was dose‐dependent as pre‐treatment with low CK concentrations
(48 hr prior to infection) caused higher susceptibility whereas higher
CK concentrations led to increased defence responses through
AHK2 and AHK3. Such dose‐dependent activities of CK are not
uncommon in plant–pathogen interactions (Babosha, 2009) or in the
regulation of developmental processes and have been explained by
bell‐shaped dose–response curves (Ferreira & Kieber, 2005). The effi-
cacy of pre‐treatment with CK was strongly dependent on SA, as the
eds16 mutant, which is defective in SA synthesis, did not show
enhanced defence following CK treatment. Mutation of RRA genes
led to higher CK sensitivity resulting in increased PR1 and ICS1 gene
expression and decreased susceptibility, indicating that RRAs nega-
tively regulate disease resistance. The authors presented a model in
which CK up‐regulates plant immunity via increased SA‐dependent
defence responses and in which SA in turn feedback‐inhibits CK
signalling (Argueso et al., 2012).
During Pst infection of Arabidopsis, CK is also important to estab-
lish a pre‐invasive defence barrier, which consists of stomatal closure
induced by H2O2 (Arnaud et al., 2017). Also in this case, CK action
required the receptor AHK3 and the transcription factors ARR2 and
ARR10, the same components that are relevant during postinvasive
defence (Choi et al., 2010). similar as in postinvasive defence CK
action was SA dependent. However, in this case, TGA3 was not
required as a partner of ARR2 suggesting that SA dependency might
be achieved in a different way. ARR2 directly activated several genes
coding for apoplastic peroxidases (PRX33, PRX34, and PRX71) generat-
ing H2O2 to induce stomatal closure (Arnaud et al., 2017; Figure 5).
An alternative CK‐dependent but SA‐independent pathway has
been revealed in the defence of tobacco plants against P. syringae pv
tabaci (Großkinsky et al., 2011; Figure 5). The CK‐mediated resistance
strongly correlated with an increased level of bactericidal activities
and up‐regulated synthesis of the two major antimicrobial phyto-
alexins in tobacco (Nicotiana tabacum), scopoletin and capsidiol. These
CORTLEVEN ET AL.
antimicrobial compounds could replace CK treatment for suppressing
infection symptoms rather than for increasing SA levels proving their
functional relevance and SA independence. CK induces phytoalexin
production also in other species (Ko et al., 2010) showing that it might
be a general function of the hormone.
The biological relevance of pathogen‐produced CK and its inter-
action with SA in the establishment of plant–pathogen interaction
was also shown in the rice—Magnaporthe oryzae pathosystem
(Chanclud et al., 2016). The rice blast fungus expressed CK Synthesis
1 (CKS1), a tRNA‐IPT gene synthesising cZ. M. oryzae cks1 mutants
showed reduced CK production by the fungus after infection, which
in turn decreased the fungal virulence. In this case, the role of fungal
CK was to suppress the host's defence system, as host plants chal-
lenged with a cks1 mutant strain displayed an elevated oxidative burst
and defence‐related marker gene expression (Chanclud et al., 2016).
On the other hand, after infection of rice with M. oryzae, CK and SA
together induced defence gene expression in a manner dependent
on the SA receptor OsNPR1 and the downstream transcription factor
WRKY45 (Jiang et al., 2013). Thus, in the rice— M. oryzae interaction
CK has different context‐ or dosage‐dependent roles in modulation
of defence responses.
Yet another variant of modulating plant–pathogen interaction
through CK resulting in a reduced defence response has been
reported from the Pst effector protein HopQ1 (Hann et al., 2014).
HopQ1 is one of several secreted pathogen effector proteins that
enters the host cell to suppress its defence responses. Induced HopQ1
expression in Arabidopsis plants increased CK concentration and sig-
nalling, possibly through a CK‐activating function similar to LOG
enzymes. In turn, enhanced CK levels reduced expression of the
FLS2 receptor gene, which is required for pathogen recognition and
defence signalling. Thus, in this case, overtaking the CK system of
the host plant by Pst was beneficial for the pathogen as the host's
immune response was dampened (Hann et al., 2014).
Taken together, in defence against (hemi)biotrophic pathogens,
CK plays diverse roles: pre‐invasive defence by inducing stomatal clo-
sure (Arnaud et al., 2017), postinvasive defence by activating together
with SA the plant's immune system including callose deposition,
defence marker gene expression, and phytoalexin production (Argueso
et al., 2012; Choi et al., 2010; Großkinsky et al., 2011; Jiang et al.,
2013; Naseem et al., 2012; Figure 5). CK may also be used by the
pathogen to dampen the host's immune response (Hann et al., 2014)
or to hijack the host metabolism to create a favourable feeding situa-
tion (Chanclud et al., 2016).
Most recently, it was shown that also pathogens may recognise
plant‐derived CK to enhance their own protection against the plant's
defence (Wang, Cheng, Wu, Ren, & Qian, 2017). Xanthomonas
campestris, a pathogen infecting Brassica oleraceae, is able to perceive
plant‐derived iP via the CHASE domain of a membrane‐bound recep-
tor histidine kinase named PcrK (Wang et al., 2017). Curiously, iP
decreased downstream signalling of the receptor, which at the end
enhanced bacterial tolerance to oxidative stress. Mutation of PcrK
reduced bacterial virulence, suggesting an important role of CK as sig-
nal for pathogenicity (Wang et al., 2017). In sum, it appears that
Xanthomonas detects CK as part of the plant defence, enabling the
pathogen to enhance its own protection against the plant's immune
CORTLEVEN ET AL. 1009

response involving ROS production. This first report on a CK receptor

in phytopathogenic bacteria will certainly induce further research into
this novel role of CK as a signal outside the plant kingdom (Kabbara,
Schmülling, & Papon, 2018).

4.3 | Links between the CK and the JA pathways

Much less than about CK‐SA interaction is known about the links
between CK and JA signalling. Choi et al. (2010) noted that CK is
required for the probably JA‐mediated resistance of Arabidopsis to
the necrotrophic fungus Alternaria brassicicola. Argueso et al. (2012)
reported that expression of PDF1.2, a marker gene of the JA pathway,
was slightly decreased in RRA mutants of Arabidopsis, which might indi-
cate a positive regulation of the JA pathway by CK. However, the
down‐regulation was not strong, and a modelling approach did not
show a conclusive interaction of CK signalling with the JA pathway
(Naseem et al., 2012). Experimentally, it was found that CK did
promote neither JA accumulation nor JA‐induced susceptibility to Pst
(Naseem, Kaltdorf, Hussain, & Dandekar, 2013). However, genome‐
wide association mapping of loci associated with a differential tran-
scriptional response of Arabidopsis against treatment by combinations
of SA and JA has identified the RRB ARR11 as a main player in SA‐JA
crosstalk (Proietti et al., 2018). Although its role in mediating eventually
a function of CK in this crosstalk is as yet unclear, it indicates that CK
may affect the JA pathway through ARR11.
Also in case of plant‐insect interactions, where the JA pathway
translates information perceived at the plant–insect interface into
defence responses (Erb et al., 2012), it is still unclear how the CK
and JA pathways are linked. As mentioned above, in N. attenuata,
the JA pathway was not required for the increase of CK upon
wounding and simulation of herbivore feeding. JA rather suppressed
NaRRA5 expression, which served as readout for CK responses. This
is consistent with the antagonistic roles of JA and CK in regulating
developmental processes such as leaf senescence (Schäfer, Meza‐
Canales, et al., 2015).
5 | CK AS A PRIMING AGENT
The concept of priming is based on observations that plants, which
experience a first, temporally and intensity‐limited stress stimulus,
show a higher magnitude or faster response towards a future stress
incident as compared with unprimed plants (Hilker et al., 2016;
Figure 6). The advantage of priming for plants is the combination of
low metabolic costs with improved stress protection. CK has been
shown repeatedly to act as a priming agent in preparing plants for a
stronger response to biotic stress, while evidence of priming activity
in abiotic stress is rarer.
Priming for enhanced defence against biotic stress accompanies
SAR and ISR and may be induced by pathogen‐associated molecular
patterns, microbe‐associated molecular patterns, herbivore‐associated
molecular patterns, damage‐associated molecular patterns, pathogen‐
associated effectors or chemicals such as α‐amino butyric acid (BABA;
Conrath et al., 2015; Mauch‐Mani, Baccelli, Luna, & Flors, 2017).
Plants primed for defence against bacterial pathogens showed
FIGURE 6 Cytokinin acts as a priming agent. Treatment with CK
prior to attack of a pathogen (red line) causes a faster and stronger
stress response to a triggering stimulus as compared with nonprimed
plants (black line)
significantly higher levels of fitness than nonprimed plants (van
Hulten, Pelser, van Loon, Pieterse, & Ton, 2006).
The clearest cases of priming by CK have been reported for
defence against microbes. Pretreatment of Arabidopsis leaves with
CK 24 hr before infection with Pst caused a higher expression of the
SA synthesis gene ICS1/SID2 and PR1 and a strong suppression of
pathogen growth (Choi et al., 2010). Pretreatment with CK 48 hr prior
to infection primed also the response of Arabidopsis against Hpa in a
dose‐dependent manner (Argueso et al., 2012). Importantly, in these
cases, CK treatment alone did not lead to high levels of defence acti-
vation, but this was rather dependent on the presence of the patho-
gen or an elicitor functioning as a stress stimulus (Figure 6). Another
case of priming by CK has been shown by the dependence of biocon-
trol by Pseudomonas on the pathogen's ability to produce CK and of
the host to perceive the priming CK signal (Großkinsky et al., 2016).
Notably, in all these cases, priming by CK was dependent on SA as nei-
ther the SA‐deficient eds16 mutant nor npr1 showed priming by CK
(Argueso et al., 2012; Choi et al., 2010; Großkinsky et al., 2016).
Other instances of priming of defence by CK have been noted. In
Phaseolus vulgaris, CK treatment caused a delay of disease symptoms
after infection by white clover mosaic virus (Gális, Smith, & Jameson,
2004). Sheikh et al. (2014) proposed that the priming of defence
responses in N. tabacum by A. tumefaciens sp. strain GV3101 to a sub-
sequent infection by Pst depended on the ability of this Agrobacterium
strain to produce CK, which was absent in the nonpriming strain
LBA4404. In Populus, CK primed defence responses against insect her-
bivores after an artificial wounding stress (Dervinis, Frost, Lawrence,
Novak, & Davis, 2010; Sano et al., 1996). CK strengthened also
defence against the necrotrophic plant pathogen A. brassicicola, which
usually involves the JA signalling pathway (Choi et al., 2010). Together,
this indicates that CK may prime SA‐ and JA‐dependent defence
pathways.
Plants with a constitutively increased CK status may be regarded
as being primed as they show enhanced defence responses (Argueso
et al., 2012; Choi et al., 2010). For example, transcriptional analysis
suggested that RRA mutant plants, which lack a negative feedback
inhibition of CK signalling, are primed for SA‐dependent defence
responses as they showed a higher SA level and SA‐dependent
defence gene expression in the absence of pathogens. After CK treat-
ment, the expression of PR1 was drastically increased in RRA mutants,
suggesting a suppression of SA‐related defence gene expression by
1010
RRAs (Argueso et al., 2012). Similarly, Shanks et al. (2015) showed that
defence genes activated by nematode infection were hyperinduced in
RRA mutants, indicating that elevated CK signalling triggers a height-
ened immune response to nematode infection or, in other words, that
these plants were in a primed state.
These studies clearly show that modulating the CK system has the
potential to establish a more sensitive answer to subsequent pathogen
infections. Thus, CK can be classified as a priming agent in the
response to biotic stress, acting to potentiate defence responses
(Albrecht & Argueso, 2017; Figure 6). However, it is unclear whether
priming is a physiological function of CK. The increase in CK content
that is often accompanying pathogen infection would be in compli-
ance with this possibility. Notably, this parallels the behaviour of
BABA, which is naturally present in plants and is induced by stress
(Thevenet et al., 2017). Like in other cases of priming, the molecular
mechanism underlying priming by CK is not clear. Increased resource
allocation to the site of CK action may be one beneficial activity of
the hormone to prepare and support responses to future stress.
In contrast to the priming of responses to biotic stress, there are
only few reports documenting a priming effect of CK in the response
to abiotic stress. It has probably been best documented for protection
of reproductive tissues from the detrimental consequences of heat
treatment causing flower or kernel abortion. CK treatment during
the reproductive phase increased thermotolerance of maize, rice, and
passion fruit and thus increased yield stability (Cheikh & Jones,
1994; Sobol et al., 2014; Wu et al., 2016, 2017). It is conceivable that
in this case, the protective effect of CK was at least partly due to an
improved sink capacity of the endangered tissue. Preincubation with
CK can also induce enhanced dehydration stress tolerance in plants
(Kang et al., 2012). CK could have additional roles in priming, for
example, during protection from high light stress, but this has as yet
to be tested.
6 | A RO LE F OR C K I N RE G U L A TI N G
G RO WTH ‐ D E F E NC E T RA D E ‐ O F F S
Growth‐defence trade‐offs occur when available resources are limited
and plants have to prioritise either growth or defence, depending on
their environment. It is thought that plants prioritise growth but after
perceiving stress they reallocate resources to defence at the expense
of growth (reviewed by Albrecht & Argueso, 2017; Huot, Yao,
Montgomery, & He, 2014; Vos, Pieterse, & van Wees, 2013). A well‐
documented example is restraint of shoot growth as an adaptive strat-
egy of plants to respond to water deficit. However, in Arabidopsis,
other types of stress such as removal of the primary inflorescence
may cause a decreased, unaltered, or even increased plant fitness
depending on the genotype (Scholes, Rasnick, & Paige, 2017). In any
case, to reach a context‐dependent optimal use of resources, intense
crosstalk between different signalling pathways is indispensable to
fine‐tune the balance between growth and defence.
Although the growth‐defence trade‐off concept is widely
accepted and, for example, the growth inhibitory function of stress
response hormones well documented (Huot et al., 2014; Vos et al.,
2013), it should however be noted that it probably does not hold true
CORTLEVEN ET AL.
in all instances. Transient periods of stress can be compensated by
later growth overcasting the impact of stress. The interpretation of
the impact of stress on plant fitness may also depend on the time
and the parameter(s) used to determine fitness. It has been pointed
out that the trade‐off between growth and defence will be definitively
more complex if analysed at different developmental stages and in a
different and dynamic ecological context, rather than viewing the pro-
cess at a single moment in a static environment as is often the case in
experimental biology (de Vries, Evers, & Poelman, 2017).
The general growth‐defence trade‐off scenario is certainly appli-
cable when plants are source limited. However, often, plants are not
source limited but rather differences in sink demand may govern plant
growth (Körner, 2015). In this case, one might expect that plants will
be able to serve both growth and defence at the same time, which
would cause no or only low growth‐defence trade‐offs. CK has been
suggested to foster growth and defence simultaneously, based on
the positive impact it has on the SA defence pathway during pathogen
response (Choi et al., 2010). In support of such a dual activity,
uncoupling of growth and defence mechanisms was found in CK
receptor mutants, which have a reduced growth and are at the same
time more susceptible to pathogen attack (Argueso et al., 2012; Choi
et al., 2010). Here, the CK pathway is required for both optimal
growth and defence.
Recent work by Campos et al. (2016) has confirmed that it is pos-
sible to genetically uncouple growth‐defence trade‐offs in the case of
JA. Suppressor mutagenesis of jaz quintuple mutants, causing consti-
tutive JA signalling and thus a constitutive defence response but
reduced growth, identified a mutation in the phyB gene being
responsible for reversing the growth suppression while keeping
defence at a high level. This clearly demonstrates that growth limita-
tion must not necessarily be the consequence of a strong constitutive
defence (Campos et al., 2016). In support of this, the Arabidopsis eco-
type C24 expresses constitutively normally repressed SA‐regulated
defence genes causing a constitutive high level of disease resistance,
which however did not negatively affect seed yield (Bechtold et al.,
2010). Additional analyses modified also the sight that growth‐
defence antagonism is managed by a simple metabolic competition
that shunts resources to defence at the expense of growth. Instead,
a transcriptional network causing reduced growth was activated by
JA signalling (Campos et al., 2016). The finding is of great relevance
to design breeding strategies that consider both, improving defence
and increasing yield.
Given the many functions of CK in regulating plant growth, the
hormone will undoubtedly play an important role in regulating
growth‐defence trade‐off and crosstalk with defence hormone path-
ways (Figure 7). Generally, all stress hormones negatively regulate
the CK signalling pathway (Albrecht & Argueso, 2017; Naseem et al.,
2015). In addition, abiotic stress often causes a reduction in CK
content reducing shoot growth. This suggests that stress hormones
negatively affect growth via regulating CK metabolism and/or signal-
ling. Conversely, reducing the CK content or signalling often increases
abiotic stress resistance (Nishiyama et al., 2011). However, there are
exceptions from the reciprocal negative regulation of stress defence
and the CK pathway as was shown by the synergistic action of CK
and SA (Argueso et al., 2012; Choi et al., 2010; Figure 7).
CORTLEVEN ET AL. 1011

FIGURE 7 Model for the role of cytokinin in regulating growth‐defence trade‐offs. The CK signalling pathway interacts in a reciprocal fashion
with signalling pathways of defence hormones. In the absence of stress, CK signalling inhibits stress response pathways; growth is favoured.
Stress activates hormonal defence signalling pathways causing the reduction of CK signalling and thus reduced growth. Black lines indicate a
dominant, grey lines a minor role in the respective condition. Synergistic activity of CK and other hormones is also possible under stress conditions
(see Figure 5) and is depicted as a dotted black line. See Figure 3 for mechanisms of CK‐ABA crosstalk

The crosstalk to fine‐tune the balance between growth and
defence might be best illustrated by the numerous interactions
between the CK and ABA signalling pathways, which are partly shown
in Figure 3. ABA down‐regulates the CK content (Guo & Gan, 2011;
Maruyama et al., 2014; Nishiyama et al., 2011; Todaka et al., 2017)
and modulates the activity of CK signalling proteins such as RRAs
and RRBs by protein interaction and phosphorylation (Huang et al.,
2018). Another mechanism is the transcriptional regulation of CK
genes by stresses involving ABA. Among these, the RRA genes seem
to be particularly responsive to abiotic (Bielach et al., 2017; Huang
et al., 2018; Kang et al., 2012; Nishiyama et al., 2011; Nguyen et al.,
2016; Ramireddy et al., 2014) and to biotic stress (Argueso et al.,
2012; Igari et al., 2008). The regulation of ARR7 and ARR15 by differ-
ent types of stress is noteworthy as these RRA genes have been
shown to be involved in negatively regulating the CK pathway and
shoot growth (Leibfried et al., 2005; Zhao et al., 2010). EIN3, which
transmits the activity of ET in stress responses, represses ARR5,
ARR7, and ARR15 by direct binding to their promoters (Shi et al.,
2012) suggesting that these genes may serve as a pathway switch to
regulate growth‐defence trade‐off.
Reciprocally, CK regulates components of stress response path-
ways. Thus, in the absence of stress, RRBs repress SnRKs to shut off
the ABA signalling pathway (Huang et al., 2018) as part of a regulatory
circuit balancing growth and defence (see Figure 3). Other regulatory
circuits integrating stress responses with growth involve interaction
between ABA and the target of rapamycin pathway (Wang et al.,
2018) or interaction between the JA and GA pathways (Yang et al.,
2012). This illustrates that there are different regulatory mechanisms
to optimise the balance of growth and stress responses.
ROS are formed in response to different stresses and is one of the
main causes for decreases in growth and productivity. It will therefore
be of great interest to analyse in more detail the links between CK and
ROS homeostasis (Tognetti et al., 2017). Analysis of transcriptomic
data sets of CK responses from Arabidopsis and rice revealed that
GO terms associated with oxidative stress were among the most
highly enriched GO biological process terms (Zwack & Rashotte,
2015). This suggests that CK acts on the transcriptional level to mod-
ulate ROS responses. It is generally seen as a negative regulator of
ROS, at least in part acting through CRF6 (Zwack et al., 2016; Zwack,
Robinson, Risley, & Rashotte, 2013).
Taken together, there is an emerging picture by which mecha-
nisms the CK system interacts with stress response pathways to reg-
ulate growth‐defence trade‐offs.
7 | C O NC L U D I N G R E M A RK S
There is increasing evidence that CK has a variety of functions in the
plant responses to different stresses. Components of the canonical CK
signalling pathway and some genes encoding CK metabolism enzymes
have been identified as being functionally relevant in the stress
response, but knowledge on downstream components is scarce. Inter-
estingly, mostly the same components that are known from studies on
CK‐regulated growth are also involved in the response to stress. This
indicates that no specific stress response modules have evolved but
that the response to stress is intimately linked with the regulation of
growth. In this respect, deeper knowledge of the crosstalk of CK with
established stress response pathways will improve our understanding
of the hormone's role in regulating growth‐defence trade‐offs. Refined
genetic approaches and system analysis will be instrumental to get
deeper insight into processes downstream of the canonical CK
signalling pathway and to discover links to classical stress response
pathways. To achieve this, the spatial and temporal resolution of
molecular details needs to be improved.
In order to deepen our understanding of the relevance of CK
action under natural conditions, it will be relevant to analyse plants
under stress conditions occurring in their natural habitats or in agricul-
tural ecosystems. Here, plants experience frequently relatively mild
1012
stress conditions or combinations of different types of stress, which
trigger different responses than the often harsh experimental stress
conditions (Claeys, Van Landeghem, Dubois, Maleux, & Inzé, 2014).
The fact that roots and shoots of plants respond to CK in a different
manner further increases complexity, because organ‐ or even age‐
specific responses may also be found in the hormone's action in stress
responses. Consistent with such distinct functions, CK is required for
stress tolerance in the response to high light in leaves (Cortleven
et al., 2014), whereas plants with a lower CK content or signalling
display higher resistance to drought stress impacting first roots
(Nishiyama et al., 2011; Macková et al., 2013). Furthermore, the
ecological role of CK as a modulator of genotype–environment
interactions is not well understood. Certainly, as a regulator of growth
and stress defence, it will influence plant performance and reproduc-
tive success, thus shaping population structure.
Finally, it has been shown that priming the stress response path-
ways would provide an advantage to the plant as it permits faster
and heightened responses with low energy costs. Applying a similar
rationale to the phase that necessarily follows a growth inhibitory
stress, namely, the phase when regrowth is initiated, it would make
equally sense for a plant to be prepared for fast and efficient
regrowth. This could be achieved, for example, by leaving somatic
epigenetic marks on central growth‐promoting genes as has been
described for stress response genes (Ding, Fromm, & Avramova,
2012). Marking such genes would allow for their faster activation after
the stress has terminated and facilitate the start of regrowth rapidly.
CK‐related genes could have an important function in governing
regrowth after a stress has passed. Indeed, plants with a low CK con-
tent exhibited slow and delayed recovery following a drought period
whereas CK up‐regulation resulted in fast and more vigorous recovery
(Prerostova et al., 2018).
ACKNOWLEDGEMEN TS
We acknowledge funding by Deutsche Forschungsgemeinschaft
(DFG) through Collaborative Research Centre 973 (www.sfb.973)
and project Schm 814/29‐1.
CONF LICT OF INT E RE ST
We declare no conflict of interest.
ORCID
Thomas Schmülling https://orcid.org/0000-0001-5532-9645
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