Journal of Integrative Plant Biology 2011, 53 (6): 412–428
Invited Expert Review
Salicylic Acid and its Function in Plant Immunity
Chuanfu An and Zhonglin Mou
F
∗
Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA
∗
Corresponding author
Tel: +1 352 392 0285; Fax: +1 352 392 5922; E-mail: [email protected]
F Articles can be viewed online without a subscription.
Available online on 3 May 2011 at www.jipb.net and www.wileyonlinelibrary.com/journal/jipb
doi: 10.1111/j.1744-7909.2011.01043.x
Abstract
The small phenolic compound salicylic acid (SA) plays an important
regulatory role in multiple physiological processes including plant immune response. Significant progress has been made during the past two
decades in understanding the SA-mediated defense signaling network.
Characterization of a number of genes functioning in SA biosynthesis,
conjugation, accumulation, signaling, and crosstalk with other hormones
such as jasmonic acid, ethylene, abscisic acid, auxin, gibberellic acid,
cytokinin, brassinosteroid, and peptide hormones has sketched the
finely tuned immune response network. Full understanding of the mechanism of plant immunity will need to take advantage of fast developing
genomics tools and bioinformatics techniques. However, elucidating
Zhonglin Mou
genetic components involved in these pathways by conventional ge(Corresponding author)
netics, biochemistry, and molecular biology approaches will continue
to be a major task of the community. High-throughput method for SA
quantification holds the potential for isolating additional mutants related to SA-mediated defense
signaling.
Keywords:
salicylic acid (SA); systemic acquired resistance; NPR1; crosstalk; SA biosensor; plant defense.
An C, Mou Z (2011) Salicylic acid and its function in plant immunity. J. Integr. Plant Biol. 53(6), 412–428.
Introduction
Salicylic acid (SA) is a secondary metabolite produced by a
wide range of prokaryotic and eukaryotic organisms including
plants. Chemically, it belongs to a group of phenolic compounds
defined as substances that possess an aromatic ring bearing
hydroxyl group or its functional derivative. Long before SA’s
regulatory role in multiple physiological processes of plants
attracted people’s attention, the pharmacological properties of
salicylates (general name of SA and its derivatives) had been
prized.
Salicylates have been known to possess medicinal properties since the 5th century B.C., when Hippocrates prescribed salicylate-rich willow leaf and bark for pain relief
during childbirth (Rainsford 1984; Weissman 1991). However, the utilization of salicylate-containing plants for curing
C
2011 Institute of Botany, Chinese Academy of Sciences
aches and fevers can be traced back to inhabitants of both
the Old and New Worlds. The exploration of the chemical
essence of the folk remedy began in the early 1800s (Raskin
1992a,1992b). In 1828, German scientist Johann A. Buchner
purified a small quantity of the yellowish substance named
salicin (a salicyl alcohol glucoside) from willow bark. Later,
Raffaele Piria converted salicin into a sugar and an acid he
named salicylic acid (SA). More natural sources of SA and
other salicylates were identified, but the demand for SA as a
pain reliever rapidly outstripped production capacity. In 1859,
Hermann Kolbe and coworkers chemically synthesized SA.
Subsequently, the synthetic process was improved, which led
to the large-scale production of cheaply priced SA for greater
medicinal use. In 1897, Felix Hoffmann rediscovered the synthetic derivative acetyl salicylic acid (ASA), a chemical originally
created by Charles Frederic Gerhardt in 1853, which undergoes
Defense Signal Molecule Salicylic Acid
spontaneous hydrolysis to SA but produces less gastrointestinal irritation and has similar therapeutic properties. In
1899, Bayer pharmaceutical company registered the trade
name “Aspirin” for ASA. Today, Aspirin has become one of
the most successful and widely used drugs worldwide.
The primary action of salicylates in mammals is attributed to
disruption of eicosanoic acid metabolism (Mitchell et al. 1990),
thereby altering the levels of prostaglandins and leukotrienes.
SA also affects gene expression by altering the activity of
multiple transcriptional factors and inducing signaling molecule
nitric oxide (Kopp and Ghosh 1994). Further studies showed
that SA appears to modulate signaling through nuclear factorκB (NF-κB), a transcriptional factor that plays a central role
in animal immunity (McCarty and Block 2006). In plants,
exogenous application of SA or its derivates affects diverse
plant processes such as thermogenesis (Raskin et al. 1987),
seed germination (Rajou et al. 2006), seedling establishment
(Alonso-Ramı́rez et al. 2009), cell growth (Vanacker et al.
2001), respiration (Norman et al. 2004), stomatal responses
(Manthe et al. 1992; Lee 1998), senescence (Rao et al. 2001,
2002), thermotolerance (Clarke et al. 2004), and nodulation
(Stacey et al. 2006). In addition, genetic mutant studies in
Arabidopsis suggest that SA is involved in modulating cell
growth (Rate et al. 1999), trichome development (Traw and
Bergelson 2003), and leaf senescence (Morris et al. 2000).
However, its effect on some of these processes may be
indirect, because SA is heavily involved in crosstalk with other
plant hormones (Robert-Seilaniantz et al. 2007; Pieterse et al.
2009).
The most well-established role of SA is as a signaling
molecule in plant immune response (Vlot et al. 2009). Unlike animals, plants lack specialized immune cells and immunological memory. However, each plant cell has developed
the capability of sensing pathogens and mounting immune
responses. Recognition of pathogen-associated molecular
patterns (PAMPs) results in PAMP-triggered immunity (PTI,
formerly called basal resistance) that prevents pathogen colonization. However, during the arms race between pathogen
and plants, pathogens have evolved effectors to dampen
PAMP-triggered signals and host plants in turn have evolved
resistance (R) proteins to detect the presence of pathogen effectors and induce effector-triggered immunity (ETI) (reviewed
in Jones and Dangl 2006). Activation of defense signaling
pathways (PTI or ETI) results in the generation of a mobile
signal(s) that moves from local infected tissue to distal tissue,
inducing systemic acquired resistance (SAR), which is a form
of long-lasting immunity to a broad spectrum of pathogens. SAmediated immune responses are important parts of both PTI
and ETI (Tsuda et al. 2009), and also essential for the activation
of SAR (reviewed in Durrant and Dong 2004). Studies in various
plant species have shown that pathogen infection leads to SA
accumulation not only in infected leaves but also in uninfected
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leaves that develop SAR (Malamy et al. 1990; Métraux et al.
1990), and that SA accumulation often parallels to or precedes
the increase in expression of PR genes and development of
SAR. Consistently, application of exogenous SA and its functional analogs, such as Aspirin, 2,6-dichloroisonicotinic acid
(INA), and benzothiadiazole S-methyl ester (BTH), activates
expression of PR genes and resistance against viral, bacterial,
oomycete, and fungal pathogens in a variety of dicotyledonous
(Malamy and Klessig 1992; Ryals et al. 1996; Shah and Klessig
1999) and monocotyledonous plants (Wasternack et al. 1994;
Gorlach et al. 1996; Morris et al. 1998; Pasquer et al. 2005;
Makandar et al. 2006). Conversely, blocking SA accumulation
through expression of a bacterial salicylate hydroxylase, which
converts SA to catechol, in transgenic tobacco and Arabidopsis
compromises HR and abolishes SAR (Gaffney et al. 1993; Delaney et al. 1994). Similarly, mutation or application of inhibitor
of enzymes involved in SA biosynthesis has been shown to
enhance susceptibility to pathogen, yet the resistance can be
restored through exogenous SA (Mauch-Mani and Slusarenko
1996; Nawrath and Métraux 1999; Wildermuth et al. 2001;
Nawrath et al. 2002).
During the past two decades, significant progress has been
made in understanding SA metabolism, signaling, and its interactions with other defense mechanisms, especially hormones.
As much as these studies have provided insights into the
functioning of SA in plant immunity, they also underscore how
much remains unknown on the complexities of SA signaling.
For example, how SA is synthesized in plants is still not fully
defined. However, through systems biology methods, a better
understanding of robust plant immunity network properties
is emerging. New methods for SA quantification have been
developed for large-scale mutant screening purposes. In this
review, we will address recent advances and discuss the future
perspectives in the above directions.
SA Metabolism
The importance of SA as a key signaling component in disease resistance and a regulator of other important physiological processes have stimulated considerable interest in its
metabolism. By using the classic biochemical radiolabeling
approach and mutant-based genetic analysis, two distinct
enzymatic pathways for SA biosynthesis have been identified
in plants (Lee et al. 1995; Chen et al. 2009). One is the
phenylalanine ammonia lyase (PAL)-mediated phenylalanine
pathway, and the other is the isochorismate synthase (ICS)mediated isochorismate pathway. Both pathways require the
primary metabolite chorismate, which is an intermediate of
plant phenylpropanoid pathway (downstream of shikimic acid
pathway leading to lignin, flavonoid, anthocyanin, and proanthocyanidin biosynthesis).
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Biochemical studies using isotope feeding in the early 1960s
have suggested two possible routes from phenylalanine to SA,
which differ at the step involving hydroxylation of the aromatic
ring. The common and initial enzymatic step of this pathway is
the conversion of chorismate-derived L-phenylalanine to transcinnamic acid by PAL. Subsequently, trans-cinnamic acid is
hydroxylated to form O-coumarate followed by oxidation of
the side chain to yield SA. Alternatively, the side chain of
trans-cinnamic acid can be initially oxidized to give benzoic
acid, which is then hydroxylated to produce SA. Thus, the
difference between the two routes is the hydroxylation of the
aromatic ring before or after the chain-shortening reactions.
Isotope feeding experiments indicate that SA is mainly formed
from benzoic acid in some plant species such as tobacco,
rice, potato, cucumber, sunflower, and pea (Klambt 1962;
Yalpani et al. 1993; Leon et al. 1995; Silverman et al. 1995;
Sticher et al. 1997), while other plant species can synthesize
SA through the route of O-coumarate (Yalpani et al. 1993;
Leon et al. 1995; Silverman et al. 1995). However, feeding
of 14 C-labeled phenylalanine, cinnamate, and benzoic acid
to young Primula acaulis and Gaultheria procumbens leaf
segments all leads to SA formation, suggesting that both
routes are probably utilized in SA biosynthesis (El-Basyouni
et al. 1964). Similarly, SA is formed mostly via benzoic acid in
young tomato seedlings, but after infection with Agrobacterium
tumefaciens, SA biosynthesis is shifted to the route of hydroxylation of cinnamate to O-coumarate (Chadha and Brown
1974).
Phenylalanine ammonia lyase is a key regulator of the
phenylpropanoid pathway and also plays an important role in
regulating SA biosynthesis during the plant immune response.
Expression of PAL is rapidly induced during plant-pathogen
interaction, and inhibition of PAL activity results in the breakdown of an incompatible interaction between Arabidopsis and
Hyaloperonospora arabidopsidis (Mauch-Mani and Slusarenko
1996). However, the incompatibility can be restored by SA
application represented by complementation of the defense
phenotype of PAL-inhibited plants. These results suggest
an important role for PAL in localized defense against this
oomycete pathogen. During the process of catalyzing benzoic
acid to SA, the hydroxylation step is catalyzed by benzoic acid2-hydroxylase (BA2H). The BA2H activity has been detected
in plants including tobacco and rice (Leon et al. 1995; Sawada
et al. 2006). In tobacco, the activity of a partially purified
BA2H is strongly induced by benzoic acid application and in
response to tobacco mosaic virus (TMV) infection, suggesting
that this pathway may be involved in tobacco response to TMV
(Leon et al. 1995). However, none of the enzymes required for
the conversion of cinnamate to SA have been isolated from
plants.
Some bacteria can synthesize SA from chorismate via two
reactions catalyzed by ICS and isochorismate pyruvate lyase
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(IPL) (Serino et al. 1995). Overexpression of these two bacterial
enzymes in plants increases SA accumulation, indicating that
plants do have the capability of synthesizing SA from chorismate (Serino et al. 1995). Genetic study has confirmed the
presence of a similar SA biosynthesis mechanism in Arabidopsis (Wildermuth et al. 2001). The sid2/eds16 phenotype is due
to mutation of the ICS1 gene, which encodes isochorismate
synthase. Upon pathogen infection, the sid2/eds16 mutant
plants accumulate only 5–10% of wild-type levels of SA. These
mutant plants exhibit enhanced susceptibility to pathogens and
are compromised in their ability to activate SAR. SA application
can complement their enhanced disease susceptibility phenotype. All these findings demonstrate that the isochorismate
pathway is the main source of SA accumulated during plantpathogen interaction in Arabidopsis (Wildermuth et al. 2001).
Further, the ICS pathway has recently been shown to be active
in tomato (Uppalapati et al. 2007) and tobacco (Catinot et al.
2008). At the sequence level, the ICS1 protein includes the
highly conserved chorismate-binding domain and shares high
identity with biochemical activity confirmed bacterial ICS protein
(Wildermuth et al. 2001). The ICS1 promoter contains binding
sites for WRKY and MYB transcriptional factors, both of which
are involved in the regulation of plant defense, stress response,
or secondary metabolism (Yang and Klessig 1996; Bender and
Fink 1998; Eulgem et al. 2000).
Two isochorismate synthase genes, ICS1 and ICS2, are
present in the Arabidopsis genome. Similar to ICS1, ICS2
encodes a functional ICS enzyme targeted to plastids. Null
ics1 mutants still accumulate some SA, suggesting a possible
role for ICS2 or the PAL pathway in biosynthesis of residual
levels of SA. Comparison of SA accumulation in the ics1, ics2,
and ics1ics2 mutants has indicated that ICS2 participates in the
synthesis of SA. Upon UV exposure, the ics1 mutant accumulates roughly 10% and the ics1ics2 double mutant accumulates
about 4% of wild-type levels of total SA. Therefore, the majority
of SA (about 95%) is synthesized from the ICS pathway in
UV-treated Arabidopsis plants with the remaining from an
alternative pathway, possibly the PAL pathway (Garcion et al.
2008). Under both biotic and abiotic stress, Nicotiana benthaminana can also activate the ICS pathway for the bulk of SA
biosynthesis, confirming the importance of the ICS-dependent
SA biosynthetic pathway under stress conditions (Catinot et al.
2008). Isochorismate, the product of ICS, is converted to SA
by IPL in bacteria. So far, no gene encoding IPL has been
cloned from plant species (Chen et al. 2009). Thus, how plants
catalyze isochorismate to SA is still unclear.
Though the ICS pathway is responsible for the majority of
SA synthesis in UV-treated or pathogen-infected Arabidopsis
and N. benthamiana plants, evidence for an important role
of PAL activity for pathogen-induced SA formation has been
repeatedly found in multiple plant species. In tobacco, SA
levels in both TMV-inoculated local tissue and uninoculated
Defense Signal Molecule Salicylic Acid
distal tissue of PAL-silenced plants are fourfold lower than
those in control plants. As a result, both TMV-induced PR gene
expression and SAR are compromised in the PAL-silenced
tobacco plants (Elkind et al. 1990; Pallas et al. 1996). Also, the
PAL inhibitor, 2-aminoindan-2-phosphonic acid (AIP), reduces
pathogen- or pathogen elicitor-induced SA formation in potato,
cucumber, and Arabidopsis (Meuwly et al. 1995; Mauch-Mani
and Slusarenko 1996; Coquoz et al. 1998). Further, simultaneous knockout of all four PAL genes (PAL1-PAL4) in the
Arabidopsis genome leads to a production of about 25% and
50% of wild-type levels of basal and pathogen-induced SA,
respectively (Huang et al. 2010). Therefore, both the cinnamic
acid and isochorismate pathway appear to participate in basal
and pathogen-induced SA production. However, the different
roles of these two SA biosynthetic sources and how they are
regulated in different physiological processes remain unclear.
To prevent toxicity caused by high concentrations of SA
(Manthe et al. 1992), plants have evolved systems of converting
infused SA to its derivatives such as SA O-β-glucoside (SAG),
salicyloyl glucose ester (SGE), methyl salicylate (MeSA),
methyl salicylate O-β-glucoside (MeSAG), and amino acid
SA conjugates (Pridham 1965; Pierpoint 1994; Vlot et al.
2009). Significant progress has been made to uncover genes
responsible for different conjugation enzymatic step(s). Among
the above conjugate forms, MeSA is volatile. In addition to
its role in airborne signaling for both intra- and inter-plant
communication (Lee et al. 1995; Shulaev et al. 1997), MeSA
was proposed to be a critical mobile signal for SAR (Park SW
et al. 2007). A gene (BSMT1), which encodes a protein with
both benzoic acid and SA carboxyl methyltransferase activity,
was identified in Arabidopsis (Chen et al. 2003). MeSA can be
hydrolyzed by esterases to release SA. Recently, the tobacco
SA-binding protein 2 (SABP2) was shown to possess MeSA
esterase activity (Park SW et al. 2007). Most importantly, MeSA
is likely the long-sought, phloem-mobile signal that activates
SAR in uninfected tissue following its translocation from the
infection and synthesis site. The high level of SA produced
in infected sites inhibits SABP2’s MeSA esterase activity by
binding to its active site, thereby facilitating buildup of MeSA
for translocation to the systemic tissue (Park SW et al. 2007).
Further study in Arabidopsis and potato suggest that the role
of MeSA and its esterases in SAR is conserved. However,
it is possible that some other molecules could also serve
as long-distance signals for SAR (Truman et al. 2007; Jung
et al. 2009; Vlot et al. 2009). The presence of a plastid transit
peptide and cleavage site in ICS1 indicates that SA may
be synthesized in plastids (Wildermuth et al. 2001). Further,
EDS5/SID1, which is also involved in SA synthesis in pathogeninfected Arabidopsis, is predicted to localize to the chloroplast
(Ishihara et al. 2008). EDS5 is a protein with homology to the
animal multidrug and toxin extrusion (MATE) transporter family
involved in transportation of organic molecules (including phe-
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nolic compounds) across membranes (Nawrath et al. 2002).
Therefore, chloroplast is likely the biosynthesis site of SA. SA
transported from chloroplasts can be converted into less toxic
conjugation forms in cytosol, and the conjugated forms (such as
SAG) are actively transported from the cytosol into the vacuole,
where they may function as an inactive storage form that can be
converted back to SA (Hennig et al. 1993; Dean and Mills 2004;
Dean et al. 2005). Therefore, both long-distance SAR signaling
and subcellular detoxication/storage rely on conjugated forms
of SA.
SA Signaling
During the process of plant immune response, there is a
complex genetic regulatory network that affects SA-mediated
signaling. Here, we discuss the current understanding of the
interaction among genes that regulate the signaling by grouping
into regulation of SA accumulation, NPR1-dependent pathways, and NPR1-independent pathways.
Regulation of SA accumulation
Through mutant screening, a number of regulators affecting
SA accumulation have been identified. Depending on their role
in regulating SA accumulation, these regulators can be divided
into two categories. Loss-of-function mutations in positive regulators lead to reduced SA accumulation and enhanced disease
susceptibility, while in negative regulators, loss-of-function mutations are associated with increased SA accumulation and
disease resistance.
The lipase-like protein EDS1 represents an important node
acting upstream of SA in PTI against viral, bacterial, and
fungal pathogens as well as in ETI initiated by a subset of
R genes (Parker et al. 1996; Aarts et al. 1998; Falk et al.
1999; Chandra-Shekara et al. 2004; Xiao et al. 2005). EDS1
physically interacts with two other positive regulators, PAD4
and SAG101, both of which are putative lipases (Feys et al.
2001, 2005). Exogenous application of SA can rescue defense
gene induction in eds1 and pad4 mutants and induce expression of EDS1 and PAD4 in wild-type plants, suggesting that
SA positively regulates both of them through a feedback loop
(Zhou et al. 1998; Falk et al. 1999; Feys et al. 2001). EDS1
can form different protein complexes with PAD4 or SAG101
at different subcellular locations including cytosolic EDS1 homodimers, nucleo-cytoplasmic EDS1-PAD4 heterodimers, and
nuclear EDS1-SAG101 heterodimers (Feys et al. 2005). EDS1
is needed for PAD4 and SAG101 accumulation, indicating that
EDS1 functions upstream of PAD4 and SAG101. Accumulating
evidence indicates that the three regulators work cooperatively
but PAD4 and SAG101 act in a separate pathway to transduce
EDS1 signaling (Feys et al. 2005). NDR1 is another positive SA
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regulator acting independently of EDS1 since the two proteins
are located downstream of two functionally distinct classes of R
proteins (Century et al. 1997; Aarts et al. 1998). Similar to eds1,
SAR-deficient phenotype of the ndr1 mutant can be rescued
by BTH application (Shapiro and Zhang 2001). Additionally,
ndr1 exhibits suppressed PTI and ETI, whereas overexpression
of NDR1 significantly reduces the growth of virulent bacterial
pathogens (Shapiro and Zhang 2001; Coppinger et al. 2004).
Continuous efforts on mutant screening have identified a growing number of SA positive regulators such as ALD1 (Song et al.
2004), EDS5/SID1 (Nawrath et al. 2002), PBS3/WIN3/GDG1
(Nobuta et al. 2007; Lee et al. 2007; Jagadeeswaran et al.
2007), EPS1 (Zheng et al. 2009), and MOS (Monaghan et al.
2010). Furthermore, SA synthesis may also be influenced by
a signal amplification loop involving reactive oxygen species
(ROS) (Torres et al. 2006). Combining genomics tools (such
as microarray and RNA-Seq technologies) with traditional
epistasis analysis will facilitate revealing the interaction of these
positive SA regulating components.
Salicylic acid synthesis is also under negative feedback
regulation. However, compared to positive SA regulators, negative SA regulators are more difficult to study because their
mutations are often associated with adverse growth phenotypes such as cell death and/or dwarfism. Plants carrying
such mutations are often called lesion mimic mutants (LMM)
(Lorrain et al. 2003; Moeder and Yoshioka 2008). In order to
gain insights into the function of the corresponding genes, an
indirect strategy has been utilized through crossing LMMs to
mutants defective in genes that positively regulate SA signaling.
Analysis of the double or triple mutants not only reveals the
association of SA and phenotypes conferred by different LMM
mutations, but also provides information on the interactions
of SA regulators. This statement is supported by analysis of
multiple LMMs such as lsd1, edr1, and vad1 (Rustérucci et al.
2001; Lorrain et al. 2004; Tang et al. 2005). In addition, a
gain-of-function LMM, acd6-1, has become a powerful tool
for assessing the functional relationship among SA regulators
because of the inverse correlation between the dwarfism and
SA-mediated defense (Lu et al. 2003). Using this convenient
phenotyping approach, the different roles of ALD1 and PAD4
in SA-mediated defense have been confirmed (Song et al.
2004).
A combination of positive and negative regulatory mechanisms ensures tight regulation of SA synthesis and fine-tuning
of plant defense response. Moreover, such feedback regulation
also allows for immune responses to be dampened once the
threat of infection has subsided.
NPR1-dependent SA signaling
NPR1, also known as NIM1 or SAI1, is a master regulator
controlling multiple immune responses including SAR. It rep-
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resents a key node in signaling downstream from SA (Dong
2004; Durrant and Dong 2004; Pieterse and Van Loon 2004).
The npr1 mutant was first identified in screening of Arabidopsis
mutants that were unable to activate the expression of PR
genes or disease resistance (Cao et al. 1994; Delaney et al.
1995; Shah et al. 1997). Like NF-κB/IκB in the mammalian
immune system, NPR1 contains an ankyrin-repeat motif and
a BTB/POZ domain (Cao et al. 1997). The promoter region
of the NPR1 gene contains W-box sequences, which are
binding sites of WRKY family protein. Mutation in the W-box
sequences of the NPR1 gene promoter adversely affects its
expression, suggesting that WRKY transcription factor plays
an important role in mediating signaling between SA and
NPR1 (Yu et al. 2001). In the absence of SA or pathogen
challenge, NPR1 is retained in the cytoplasm as an oligomer
through redox sensitive intermolecular disulfide bonds. Upon
induction, NPR1 monomer is released to enter the nucleus
where it activates defense gene transcription (Mou et al.
2003). Therefore, SA affects NPR1 activity at two stages: first,
it activates NPR1 expression, and second, it stimulates the
translocation of NPR1 into the nucleus. SA-induced changes
in the cellular redox state lead to reduction of two cysteine
residues (Cys82 and Cys216) by TRX-H5 and/or TRX-H3 (Mou
et al. 2003; Tada et al. 2008). Mutation of either Cys82 or
Cys216 elevates the levels of monomeric, nuclear localized
NPR1, and consequently upregulates PR-1 gene expression
(Mou et al. 2003). SA application and pathogen-inoculation
enhance NPR1 expression. Overexpression of Arabidopsis
NPR1 or its homologs confers broad resistance against diverse pathogens in multiple plant species (Cao et al. 1998;
Chern et al. 2001, 2005; Lin et al. 2004; Makandar et al.
2006; Malnoy et al. 2007; Potlakayala et al. 2007; Zhang
et al. 2010; Parkhi et al. 2010). Moreover, overexpression of
monomeric NPR1 by disturbing the formation of disulfide bond
holds the potential to generate transgenic plants with further
elevated disease resistance. However, considering the role of
cytosolic NPR1 oligomer in mediating crosstalk between SA
and other signal molecules, developing disease-resistant crops
through overexpressing monomeric NPR1 requires further
investigation.
NPR1 itself does not have DNA binding capability. Relaying
NPR1-mediated signaling requires interaction with other proteins. Genome-wide expression profiling analysis showed that
members of the WRKY transcription factor family act downstream of NPR1 (Wang et al. 2006). Protein-protein interaction
assays have revealed that NPR1 interacts with seven members
of the TGA family transcription factors and three structurally
related NIMIN proteins (Després et al. 2000; Weigel et al.
2001, 2005). The TGA factors can directly interact with PR-1
gene through binding to the activation sequence-1 (as-1) in its
promoter region (Lebel et al. 1998). In planta analysis showed
that the interaction between NPR1 and TGA1 or TGA4 needs
Defense Signal Molecule Salicylic Acid
the presence of SA. However, interaction between NPR1 and
TGA2 can be detected in the absence of SA but the interaction
is enhanced by SA application (Fan and Dong 2002). Further,
the ability of TGA2 and TGA3 to activate downstream transcription requires both SA and NPR1, suggesting that NPR1
may enhance the DNA binding activity of some TGA proteins
and thus affect expression of PR-1 gene (Durrant and Dong
2004; Rochon et al. 2006). Mutational analysis of TGA genes
indicated their redundancy in SA signaling (Zhang et al. 2003).
Although NIMIN1, NIMIN2, and NIMIN3 are transiently induced
after SA treatment, NIMIN1 appears to negatively regulate
SA/NPR1 signaling (Weigel et al. 2001, 2005). Overexpression
of NIMIN1 results in compromised ETI and SAR, whereas
reduced expression of the same gene enhances induction of
PR-1 expression by SA.
NRR1-independent SA signaling
Accumulating evidence has indicated that certain aspects of
defense are controlled by SA-dependent, NPR1-independent
signaling pathway(s) (Clarke et al. 1998, 2000; Kachroo et al.
2000; Shah et al. 2001; Murray et al. 2002). ETI was suppressed by expression of the NahG gene that encodes salicylate hydroxylase, but not in the npr1 mutant, suggesting the
involvement of an NPR1-independent SA signaling mechanism
in plant defense (Rardian and Delaney 2002; Kachroo et al.
2001; Takahashi et al. 2002). The existence of an NPR1independent mechanism is further supported by studies of
various Arabidopsis mutants, which constitutively accumulate
SA and the transcripts of PR genes even in the absence of a
functional NPR1 gene. A putative negative regulator of SAR,
SNI1, was identified through screening for suppressors of the
npr1-1 mutant (Li et al. 1999). In the npr1-1 background, the
recessive sni1 mutation restores PR gene induction by SA,
and disease resistance, whereas in the NPR1 background,
renders the plant more sensitive to SAR signals. The SNI1
protein appears to be a nuclear protein with limited similarity
to the mouse retinoblastoma protein, a negative transcription
regulator. More components in the NPR1-independent defense
pathway were identified through screening ethyl methylsulfonate (EMS) mutagenized npr1-5 mutant for constitutive PR
gene expression. The ssi mutants, ssi1, ssi2, and ssi4, show
constitutive accumulation of SA and exhibit heightened resistance to a variety of pathogens (Shah et al. 1999, 2001; Shirano
et al. 2002). Evidence of an NPR1-independent signaling
pathway was illustrated by studies of the ssi1 npr1 and ssi2
npr1 double mutant plants (Shah et al. 1999, 2001). The
ssi1 and ssi2 mutant plants containing the wild-type NPR1
allele accumulate greater levels of PR1 gene transcripts than
ssi1 npr1 and ssi2 npr1 double mutant plants, respectively,
indicating an NPR1-dependent pathway functioning additively
with the NPR1-independent pathway (Shah et al. 1999, 2001).
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Another npr1 suppressor mutant, snc1, displays constitutive
SA-dependent, NPR1-independent resistance owing to a mutation in a TIR-NB-LRR type of R protein. The gain-of-function
mutation snc1 leads to constitutive activation of the R protein
and downstream defense responses without the presence of
pathogens. The snc1 mutant plants accumulate high levels of
SA, constitutively express PR genes, and display enhanced
resistance to pathogens (Li et al. 2001). More snc mutants
such as snc2-1D (Zhang et al. 2010) and snc4-1D (Bi et al.
2010) have been identified and characterized. Moreover, a
set of genes that may be involved in SA regulated, NPR1independent defense pathway are transcription factors such as
WHIRLY (WHY) and MYB. The single stranded DNA binding
activity of WHY is stimulated by SA treatment in both wildtype and npr1 mutant plants (Desveaux et al. 2002, 2004),
suggesting their important roles in NPR1-independent expression of PR-1 and resistance against pathogen. AtMYB30 positively regulates the pathogen-induced HR in an SA-dependent,
NPR1-independent manner (Raffaele et al. 2006). Additionally,
the constitutive defense mutants, cpr5, cpr6, and hrl1, all show
NPR1-independent, SA-dependent characters (Clarke et al.
2000; Devadas et al. 2002). However, evidence has shown that
cpr5 and cpr6 activate ethylene (ET) and jasmonic acid (JA)
mediated defense signaling (Clarke et al. 2000). Similarly, ET
is also required for the resistance conferred by hrl1 (Devadas
et al. 2002).
In genetic screening for suppressors of the npr1 mutant
based on its intolerance to SA, our laboratory recently isolated
the elp2 mutant. The elp2 mutation restores SA tolerance to
npr1 and suppresses npr1-mediated hyperaccumulation of SA
(DeFraia et al. 2010). Pathogen infection experiments suggest
that ELP2 regulates an NPR1-independent defense pathway
and does not affect SAR. The immune deficiency in elp2 mutant
may be attributable to the delayed induction of SA biosynthesis
and defense gene expression (DeFraia et al. 2010). ELP2 is
a subunit of the Elongator complex, which is composed of
three core subunits (ELP1-3) and three accessory subunits
(ELP4-6). The Elongator complex interacts with elongating
RNA polymerase II and facilitates transcription through histone
acetylation (Winkler et al. 2002; Close et al. 2006). Recent
genetic studies have demonstrated that Elongator functions in
Arabidopsis development and in response to abiotic stresses
(Nelissen et al. 2005, 2010; Chen et al. 2006; Zhou et al. 2009).
Ongoing studies in the lab are focusing on the role of different
Elongator subunits and their interactions in different aspects of
plant immune responses.
SA and Other Hormones
Plants are subject to attack by a wide variety of microbial
pathogens with a diverse array of effector molecules to colonize
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Journal of Integrative Plant Biology
Vol. 53
their host. Plants have in turn evolved sophisticated innate
immune systems by which they recognize non-self molecules or
signals from injured cells, and respond by activating effective
immune responses through SA signaling cascade and interactions with other phytohormones such as JA, ET, abscisic
acid (ABA), auxin, gibberellic acid (GA), cytokinin (CK), brassinosteroid (BR), and peptide hormones (Bari and Jones 2009;
Pieterse et al. 2009).
SA and JA/ET
Salicylic acid-mediated resistance is generally effective against
biotrophs, whereas JA/ET-mediated responses are predominantly against necrotrophs and herbivorous insects (Glazebrook 2005). Although most reports indicate a mutually antagonistic interaction between SA- and JA/ET-dependent signaling,
synergistic interactions have been described as well (Schenk
et al. 2000; Van Wees et al. 2000; Mur et al. 2006). During
the antagonistic interactions between SA and JA/ET, common
components shared in different signaling pathways serve as
signaling nodes, which play important regulatory roles in the
crosstalk. Mutation or ectopic expression of the corresponding
regulatory genes was shown to have contrasting effects on
SA and JA/ET signaling and on resistance against biotrophs
and necrotrophs (Bari and Jones 2009; Pieterse et al. 2009).
Among these regulatory components are EDS1, EDS4, PAD4,
NPR1, SSI2, WRKY transcription factors, MPK4, and GRX480
(glutaredoxin, a disulfide reductase) (Petersen et al. 2000;
Kachroo et al. 2001; Li et al. 2004; Brodersen et al. 2006;
Ndamukong et al. 2007). EDS1, EDS4, and PAD4 act upstream
of NPR1 affecting SA accumulation. Mutants of genes encoding
these components exhibit enhanced response to inducers
of JA-dependent gene expression, suggesting the negative
interaction between SA and JA (Zhou et al. 1998; Falk et al.
1999; Gupta et al. 2000). In addition, NPR1 regulates the SAmediated expression of WRKY53, WRKY62, WRKY70, and
GRX480, which encode proteins that suppress JA-dependent
gene expression (Li et al. 2004; Li et al. 2007; Ndamukong et al.
2007). Besides functioning as a key transcriptional co-activator
of SA-responsive genes, NPR1 is also a crucial regulator in
SA-mediated suppression of JA signaling. Arabidopsis npr1
plants are compromised in the SA-mediated suppression of
JA responsive gene expression, indicating that NPR1 plays
an important role in SA-JA interaction (Spoel et al. 2003).
Nuclear localization of SA-activated NPR1 is not required for
the suppression of JA-responsive genes, indicating that the
antagonistic effect of SA on JA signaling is modulated through
a function of NPR1 in the cytosol (Spoel et al. 2003; Yuan et al.
2007).
Characterization of mutants in JA/ET signaling has identified regulatory components that function in antagonizing SA
signaling. A loss-of-function mutation in the Arabidopsis MPK4
No. 6
2011
gene, which encodes a mitogen-activated kinase, impaired JA
signaling and simultaneously conferred enhanced resistance
against bacterial and oomycete pathogens due to constitutive
activation of SA signaling (Petersen et al. 2000). Similar to
mpk4, ssi2 plants exhibit impaired JA signaling, constitutive
expression of SA-mediated defenses, and enhanced disease
resistance (Kachroo et al. 2001; Kachroo et al. 2003). The SSI2
gene encodes a steroyl-ACP fatty-acid desaturase, which is
hypothesized to catalyze the synthesis of a fatty-acid-derived
signal involved in mediating both JA signaling and negative
crosstalk between JA and SA pathways. JA-dependent gene
expression is also impaired in double mutant mpk4 nahG and
ssi2 nahG plants, which do not accumulate high levels of SA,
suggesting that the impairment of JA signaling in single mutants
is not due to an inhibitory effect of elevated SA levels (Kunkel
and Brooks 2002). Unlike mpk4 and ssi2, coi1 mutant plants do
not exhibit constitutive expression of SA-dependent defenses.
Rather, the SA-mediated defenses are hyperactivated only in
response to attack by Pseudomonas syringae. COI1 encodes
an F-box protein that is predicted to regulate JA-signaling by
inactivating negative regulators of the JA-mediated pathway
(Feys et al. 1994; Xie et al. 1998; Kloek et al. 2001). The same
negative regulatory interaction can also be found between ET
and SA signaling pathways. Genetic characterization of ein2,
an ET-insensitive mutant, showed that the basal level of SAresponsive marker gene PR-1 expression is significantly higher
than that in wild-type plants. This indicates that the modulation
of the SA pathway by ET is EIN2 dependent and functions
through the ET signaling pathway (De Vos et al. 2006). Characterization of the Arabidopsis elp mutants revealed that the
Elongator complex promotes the initiation of SA signaling but
represses JA/ET signaling (DeFraia et al. 2010; Nelissen et al.
2010). The Elongator may therefore be an important player in
the crosstalk between these pathways (DeFraia et al. 2011).
SA and auxin
Auxin is an important hormone that affects almost all aspects
of plant growth and development. A growing body of evidence
indicates that many plant pathogens can either produce auxin
themselves or manipulate host auxin biosynthesis to interfere
with the host’s normal developmental process (Chen et al.
2007; Robert-Seilaniantz et al. 2007). Conversely, plants have
evolved mechanisms to repress auxin signaling during pathogenesis. Plants overproducing the defense signal molecule SA
frequently have morphological phenotypes that are reminiscent
of auxin-deficient or auxin-insensitive mutants, suggesting that
SA might interfere with auxin response (Wang et al. 2007). SA
application causes global repression of auxin-related genes,
resulting in stabilization of the Aux/IAA repressor proteins and
inhibition of auxin responses (Wang et al. 2007). Similarly,
it was found that the majority of the auxin inducible genes
Defense Signal Molecule Salicylic Acid
are also repressed in systemic tissues after induction of SAR,
indicating that SAR response involves downregulation of auxin
responsive genes (Wang et al. 2007). In contrast, exogenous
application of auxin has been shown to promote disease
(Yamada 1993, Navarro et al. 2006; Chen et al. 2007) and
blocking auxin responses leads to increased resistance (Wang
et al. 2007). The finding that enzymes involved in auxin amino
acid conjugation, and thus inactivation, affect SA-mediated
defenses indicates another possible level of crosstalk between
SA and auxin (Park JE et al. 2007). GH3.5 conjugates both SA
and indole acetic acid, and altered expression of this enzyme
affects disease resistance (Zhang et al. 2007). The loss-offunction mutant of the auxin response factors (ARFs), arf6
arf8, displays reduced expression of genes involved in JA
biosynthesis and low JA levels, suggesting that activation of JA
signaling may play an important role during the interaction of
SA and auxin (Tiryaki and Staswick 2002; Nagpal et al. 2005).
Therefore, SA and auxin signaling is mutually antagonistic.
However, the detailed mechanism of their interaction, especially the regulatory components of the two signaling pathways,
merits further investigation.
SA and ABA
Abscisic acid plays a crucial role in adaptation to abiotic stress.
However, its role in biotic stress responses is less understood.
Generally, ABA is considered as a negative regulator of disease
resistance (Bari and Jones 2009; Ton et al. 2009). Application
of exogenous ABA prevents SA accumulation and suppresses
resistance to P. syringae in Arabidopsis (Mohr and Cahill 2003).
Similar results have been found in other plant species (Mohr
and Cahill 2001; Koga et al. 2004). Recently, Yasuda et al.
(2008) reported that ABA treatment suppresses SAR induction,
indicating an antagonistic interaction between SA and ABA
signaling. Likewise, mutants impaired in ABA biosynthesis or
sensitivity are more resistant to different pathogens compared
to wild-type plants in both Arabidopsis (Mohr and Cahill 2003;
Anderson et al. 2004; Adie et al. 2007; de Torres-Zabala et al.
2007) and tomato (Audenaert et al. 2002; Thaler and Bostock
2004; Achuo et al. 2006; Asselbergh et al. 2008). Furthermore,
increased ABA production and activation of ABA-responsive
genes have been described during the interaction of plants with
invading pathogens (Whenham et al. 1986; de Torres-Zabala
et al. 2007). Therefore, ABA is a negative regulator of plant
defense signaling pathways mainly mediated by SA. It has
been shown that ABA regulates defense response through its
effects on callose deposition (Hernandez-Blanco et al. 2007;
Flors et al. 2008), production of reactive oxygen intermediates
(Xing et al. 2008), and regulation of defense gene expression
(Adie et al. 2007; de Torres-Zabala et al. 2007). It also could
be possible that ABA-SA antagonism results from the indirect
effect of ABA-JA/ET interactions (Anderson et al. 2004; Adie
419
et al. 2007). However, the exact molecular mechanism of
ABA action on plant defense responses to diverse pathogens
remains unclear. Detecting regulatory factors involved in the
crosstalk of ABA with other phytohormones in plant defense
warrants extensive future study.
SA and GA
Gibberellic acid is a well-studied growth promoting phytohormone, yet limited attention has been received in the elucidation
of its role in defense response. Infection with rice dwarf virus
(RDV) represses expression of ent-kaurene oxidase, a GA
biosynthetic enzyme, and results in significant reduction of GA
levels and a dwarf phenotype similar to GA-deficient symptoms
(Zhu et al. 2005). However, the normal growth phenotype can
be restored by exogenous GA application, indicating that RDV
modulates GA metabolism to promote disease symptoms in
rice. Further, modulation of bioactive GA levels through GA
deactivating enzymes, elongated uppermost internode (EUI),
has been shown to affect disease resistance in rice. The lossof-function eui mutants accumulate high levels of GA and
show compromised resistance, whereas EUI overexpressors
accumulate low levels of GA and show increased resistance
(Yang et al. 2008). Together with the studies on exogenous
application of GA biosynthesis inhibitor or GA analogs, it is
clear that GA plays a negative role in basal disease resistance in rice. Mutants defective in GA perception also show
altered immune response. The gid1 mutant of rice, defective
in GA reception, accumulates higher level of GA and shows
enhanced resistance to the blast fungus (Tanaka et al. 2006).
Recent studies on Arabidopsis DELLA proteins revealed its
role in mediating GA-, SA-, JA/ET-mediated defense signaling
pathways in plant immune response. The Arabidopsis quadruple della mutant that lacks four functional redundant DELLA
genes (gai-6, rga-t2, rgl1-1, rgl2-1) is susceptible to fungal
necrotrophic pathogens but is more resistant to biotrophic
pathogens (Navarro et al. 2008). Gene expression analysis
of infected quadruple della mutants showed that SA marker
genes are induced earlier and stronger but JA/ET marker genes
are significantly delayed. This suggests that DELLAs promote
resistance to necrotrophs and susceptibility to biotrophs, partly
by modulating the balance between SA-mediated and JA/ETmediated defense signaling pathways (Navarro et al. 2008).
Since GA stimulates degradation of DELLA proteins, it could be
deduced that GA functions in promoting resistance to biotrophs
and susceptibility to necrotrophs. DELLA proteins are also
found to promote the expression of genes encoding ROS
detoxificaiton enzymes, thereby regulating the levels of ROS
after biotic or abiotic stresses (Achard et al. 2008). Considering
the possible feedback amplification loop between SA and ROS,
the role of DELLAs as a regulatory component during SA-GA
interaction in plant defense signaling seems likely. However,
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Journal of Integrative Plant Biology
Vol. 53
the detailed mechanism of GA action on different plant defense
response signaling remains to be uncovered.
In addition to JA/ET, auxin, ABA, and GA, other hormones
such as CK, BR, and peptide hormones are also involved in
plant defense pathways (Bari and Jones 2009; Grant and Jones
2009; Vlot et al. 2009). However, their role in plant defense, especially the interaction with SA is less well studied. Depending
on the type of plant-pathogen interactions, different hormones
play positive or negative roles against various biotrophic and
necrotrophic pathogens. Plant hormone signaling pathways are
not isolated but rather interconnected with a complex regulatory
network. How plants coordinate multiple hormonal components
in response to different pathogen infections, how the integrated
signal is generated, regulated, and transduced to result in HR
cell death, defense gene expression, and/or SAR, and what
role SA plays in this sophisticated process are questions that
remain to be addressed.
Techniques for SA Quantification
Salicylic acid is a major signal molecule involved in plant
immunity (Raskin 1992a; Durrant and Dong 2004). Unveiling
the SA-mediated signaling pathway, especially understanding
the mechanism underlying SA accumulation, frequently requires the quantification of a large number of samples with
different genetic backgrounds or treatments. High performance
liquid chromatography (HPLC) and gas chromatography/mass
spectroscopy (GC/MS) are two commonly used methods for SA
quantification (Malamy and Klessig 1992; Verberne et al. 2002;
Schmelz et al. 2003; Aboul-Soud et al. 2004). However, both
methods are costly and time-consuming. Identifying mutants
deficient in SA accumulation from mutated populations has
been proved as an effective way to study the mechanisms of SA
biosynthesis or signaling (Nawrath and Métraux 1999; Wildermuth et al. 2001). So far, the most extensive mutant screening
study quantified around 4 500 individual M 2 Arabidopsis plants
by HPLC-based methods (Nawrath and Métraux 1999). However, in order to capture more valuable genetic components
involved in SA biosynthesis or signaling, the population for
mutant screening needs to be increased. Therefore, there is a
great need to develop a high-throughput method with reduced
cost and time requirements for SA quantification.
Huang et al. (2006) developed a biosensor, Acinetobacter
sp. ADPWH_lux, for SA quantification. This strain is derived
from Acinetobacter sp. ADP1, and contains a chromosomal
integration of a salicylate-inducible lux-CDABE operon, which
provides both substrate and enzyme needed for SA-responsive
luminescence. It can proportionally produce bioluminescence
in response to salicylates including SA, methyl-SA, and the
synthetic SA derivative ASA. The well-correlated results between the biosensor and GC/MS method on TMV-infected
tobacco leaves suggest that the biosensor is suitable for SA
No. 6
2011
quantification in an easy, cheap, and fast way. In plants,
SA can be converted to SAG (2-O-β-D-glucosylsalicylic acid),
methyl-salicylate, and a glycosylated form of methyl-salicylate,
which also play important roles in plant immunity (Pridham
1965; Pierpoint 1994; Vlot et al. 2009). DeFraia et al. (2008)
developed a method for biosensor-based SAG measurement
by treating crude extracts with β-glucosidase as well as optimized extraction and quantification steps, which further reduce
cost and time. On the basis of this improved biosensorbased SA quantification method, Marek et al. (2010) simplified
tissue collection and SA extraction procedures, and further
adapted the protocol to a high-throughput format. The efficacy
and effectiveness of the most updated biosensor-based SA
quantification method was confirmed by HPLC and verified
in Arabidopsis npr1 suppressor screening. Using this highthroughput method, our lab is conducting a comprehensive
Arabidopsis npr1 suppressor screen with the objective to isolate
novel SA metabolic mutants. Several mutants with lower or
higher SA levels than npr1 have been identified. Allelism tests
with the known mutants are underway and some possible novel
mutants are in the process of map-based cloning. Preliminary data indicate the great potential of adding new genetic
components to SA biosynthetic or regulation pathways. In
addition to isolating mutants with aberrant SA accumulation,
this high-throughput SA measurement approach can also be
applied to studies on characterization of enzymes involved in
SA metabolism and analysis of temporal changes in SA levels.
Future Perspectives
Our understanding of the role of SA in plant immunity has
increased over the past two decades. Significant progress
has been made in elucidating SA biosynthetic pathways
and new components involved in SA signaling have been
identified. Recent advances have provided exciting new
insights into the understanding of SA-mediated defense
crosstalk with other plant hormones. Furthermore, a rapid
biosensor-based method for SA quantification and a highthroughput procedure suitable for SA metabolic mutant
screening have been established, which hold great potential for isolating additional SA accumulation mutants.
However, SA-mediated defense signaling pathways are not
isolated but rather interconnected to form a complex and
well-regulated network. Elucidating genetic components involved in the pathways will continue to be a major task of
the community. Nonetheless, with the expanding discovery
of additional SA signaling pathway components, there is
a clear need to understand how plants integrate genetic
information with various developmental and environmental
factors into tight control over energetically costly immune
responses. A systems approach, which integrates genetics,
Defense Signal Molecule Salicylic Acid
molecular biology, and biochemistry results into genomewide kinetic gene expression and signaling component
profiling datasets, together with computational biology and
bioinformatics techniques, will accelerate the process towards fully understanding SA-mediated plant immunity.
421
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Bender J, Fink GR (1998) A Myb homologue, ATR1, activates tryptophan gene expression in Arabidopsis. Proc. Natl. Acad. Sci. USA
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Bi D, Cheng Y, Li X, Zhang Y (2010) Activation of plant immune
This work was supported by a grant from the National Science
Foundation (IOS-0842716) to Dr. Z Mou.
responses by a gain-of-function mutation in an atypical receptorlike kinase. Plant Physiol. 153, 1771–1779.
Brodersen P, Petersen M, Nielsen HB, Zhu S, Newman MA, Shokat
Received 14 Feb. 2011
Accepted 14 Apr. 2011
KM, Rietz S, Parker J, Mundy J (2006) Arabidopsis MAP kinase
4 regulates salicylic acid- and jasmonic acid/ethylene-dependent
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(Co-Editor: Yunde Zhao)