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Fungal Production and Manipulation of Plant Hormones The
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Chemistry

BENTHAM
SCIENCE

Sandra Fonseca1,*, Dhanya Radhakrishnan2, Kalika Prasad2 and Andrea Chini1,*

1
Departamento de Genética Molecular de Plantas, Centro Nacional de Biotecnología- Consejo Superior de
Investigaciones Científicas, Madrid, Spain; 2School of Biology, Indian Institute of Science Education and Re-
search Thiruvananthapuram, Kerala, India

ARTICLE HISTORY
Received: October 25, 2016
Revised: January 24, 2017
Accepted: January 25, 2017
DOI:
10.2174/0929867324666170314150827
Current Medicinal Chemistry
Abstract: Living organisms are part of a highly interconnected web of interactions, character-
ised by species nurturing, competing, parasitizing and preying on one another. Plants have
evolved cooperative as well as defensive strategies to interact with neighbour organisms.
Among these, the plant-fungus associations are very diverse, ranging from pathogenic to mu-
tualistic. Our current knowledge of plant-fungus interactions suggests a sophisticated co-
evolution to ensure dynamic plant responses to evolving fungal mutualistic/pathogenic strate-
gies.
The plant-fungus communication relies on a rich chemical language. To manipulate the plant
defence mechanisms, fungi produce and secrete several classes of biomolecules, whose mode-
of-action is largely unknown. Upon perception of the fungi, plants produce phytohormones
and a battery of secondary metabolites that serve as defence mechanism against invaders or to
promote mutualistic associations. These mutualistic chemical signals can be co-opted by

pathogenic fungi for their own benefit.

Among the plant molecules regulating plant-fungus interaction, phytohormones play a critical
role since they modulate various aspects of plant development, defences and stress responses.
Intriguingly, fungi can also produce phytohormones, although the actual role of fungal-
produced phytohormones in plant-fungus interactions is poorly understood. Here, we discuss
the recent advances in fungal production of phytohormone, their putative role as endogenous
fungal signals and how fungi manipulate plant hormone balance to their benefits.

Keywords: Phytohormones, plant-fungus communication, fungal effectors, fungal secondary metabolites, plant
hormones, TAM.

1. INTRODUCTION:
1.1. No Organism is an Island
No organism lives in an exclusive niche. All organ-
isms form part of a large web of life, in dynamic bal-
ance with species nurturing, competing, cooperating
and parasitizing on one another. The sessile plant life-
style may have promoted the evolution of cooperative
strategies with neighbour organisms to accomplish the
tasks that plants cannot achieve by themselves includ-
ing defensive responses. Among the inter-species and
intra-species interactions, the plant-fungus interactions
*Address correspondence to these authors at the Departamento de
Genética Molecular de Plantas, Centro Nacional de Biotecnología-
Consejo Superior de Investigaciones Científicas, Madrid, Spain;
Tel: +34915855430; E-mails: achini@cnb.csic.es;
sfonseca@cnb.csic.es
are very diverse [1, 2]. Fungus can be a boon or bane to
plants. Every year hectares of crop plants are destroyed
due to fungal pathogen infestation resulting in huge
economic losses [1, 3]. On the other hand, mutualistic
associations between fungi and plants can contribute to
the productivity of crop plants and benefit the famers
[2]. Therefore, it is crucial to understand these plant-
microbial interactions, which can be controlled and
exploited to achieve better plant fitness and agricultural
benefits.
Over the course of evolution plants have developed
a robust defence system to protect them from various
microbial invasions. However, co-evolutionary strate-
gies by microbes including fungi have ensured that
these barriers are breached to gain access to the host
plants during pathogenic and symbiotic associations

1875-533X/18 $58.00+.00 © 2018 Bentham Science Publishers

254 Current Medicinal Chemistry, 2018, Vol. 25, No. 2
[4]. Therefore, the emerging consensus is a re-thinking
of plant defence system not as a bulletproof shell but
rather as a “negotiation between parties trying to estab-
lish a trade deal”.
Plant secondary metabolites have been studied as an
integral part of defence mechanism against invaders,
including fungi. However, to attract beneficial fungi,
plants also produce chemical signals that can be co-
opted by fungal pathogens [2]. During the process of
invasion, fungi produce effectors, pathogen-associated
molecular patterns (PAMPs) and biomolecules that
capsize or bypass the plant defence mechanisms. These
include oligosaccharides like glucan and chitin, poly-
saccharide like pectin, other molecules like glycopep-
tides, lipids, toxins, effector proteins, phytohormone
and their analogs, small RNA, reactive oxygen species
(ROS), volatile compounds and other fungal secondary
metabolites (SM) involved in the multipronged ap-
proaches of fungal infection and colonization [5-9].
Several fungi combine different lifestyles, ranging
from pathogenic to mutualistic, the boundaries of
which are often not clearly defined [1]. Depending on
the mode of association, fungi produce different bio-
molecules and to varying extents to achieve selective
advantages in some environments or fungal-plant inter-
actions. For example, biotrophic fungi are poor pro-
ducers of SMs and produce few cell wall degrading
enzymes and effectors to obtain nourishment from liv-
ing plant tissues [10, 11]. However, necrotrophic fungi
employ a large variety of secondary metabolites, pep-
tides and ROS to kill host cells [6, 12]. Similarly,
hemibiotrophic fungi, which use a combination of
biotrophic and necrotrophic lifestyles, actively produce
SMs and toxins mainly during the necrotrophic phase
[12]. Finally, mutualistic fungi also produce several
SMs to establish symbiotic relationships [13].
The molecular mode-of-action of several microbial
virulent effectors are well characterised, whereas the
activity of effectors produced by fungi, ranging from
pathogenic to mutualistic, is only beginning to be deci-
phered [13-15]. In general, necrotrophic fungal effec-
tors affect plants through the exploitation of ROS me-
diated Programmed Cell Death (PCD) [5]. For exam-
ple, the necrotrophic fungus Pyrenophora tritici-
repentis produces PtrToxA that interacts with the host
ToxABP1 in the chloroplasts. PtrToxA-ToxABP1 in-
teraction causes ROS accumulation by interfering with
photosystem activity, eventually leading to PCD [1].
This accumulation of ROS is a light-dependent process,
showing that fungal infestation is influenced at the mo-
lecular level by environmental factors [16]. ROS plays
Fonseca et al.
a primary role as general host defence mechanism and
also during symbiosis and infections by fungal agents
with diverse lifestyle [7]. However, one strategy of ne-
crotroph fungi is the hijacking of host ROS production
to kill host cells and feed on their dead tissues. The ex-
ploitation of ROS mediated PCD by necrotrophic fungi
may also be an example of co-evolutionary strategy
exploited by fungal pathogens; an example of a plant
defence strategy turned against the plant.
In addition, mutualistic fungi also have evolved ef-
fectors to weaken the host defence responses. The ec-
tomycorrhizal fungus Laccaria bicolorthe produces the
Mycorrhizal induced Small Secreted Protein 7
(MiSSP7) to develop within the host poplar roots and
to interfere with the plant defences [15, 17]. The fungal
MiSSP7 is translocated into the plant nuclei where it
interacts with the key JA-repressor PtJAZ6 (JAS-
MONATE ZIM DOMAIN), inhibiting its JA-induced
degradation and consequently the activation of JA-
mediated defences [17]. Therefore, MiSSP7 inhibits the
JA-dependent host defences to promote fungal coloni-
zation and mutualism. The description and mode-of-
action of fungal effectors, as well as their delivery into
the hosts, are emerging hot subjects [13, 18]. The close
knit molecular communication between the host-fungal
partners suggest sophisticated co-evolution that ensures
dynamic plant responses/defences and fungal mutualis-
tic/pathogenic strategies [14, 19].
Recent studies are unravelling an ever-expanding
repertoire of plant-fungus signalling and fungal effector
molecules such as the small RNAs (sRNAs) in Botrytis
cinerea-Arabidopsis interaction. Fungal small RNAs
are delivered into the host cell to form complex with
plant Argonaute1, a key component of plant RNA in-
terference system, leading to the selective silencing of
specific host immunity genes [8]. In addition, plant
produced sRNAs are also transferred into the fungi and
target Botrytis DCLs (Defective chloroplasts and leaves
protein), key components of the sRNA synthesis, at-
tenuating fungal pathogenicity and growth [20]. Over-
all, these results show a bidirectional cross-kingdom
RNAi and sRNA trafficking between plants and fungi
to manipulate the partner responses.
2. FUNGAL SYNTHESIZED PHYTOHORMONES
Among the plant signalling molecules regulating
plant-fungus associations, phytohormones play a criti-
cal role [6, 21]. Phytohormones fundamentally act to
modulate various aspects of plant development and
differentiation, as well as responses to stresses and de-
fences. It is intriguing that fungi can produce phyto-
Fungal Manipulation of Plant Hormones
hormones such as auxins, cytokinins (CKs), gibberellic
acids (GAs), abscisic acid (ABA), jasmonates (JAs),
salicylic acid (SA), ethylene (ET), and phytohormones-
like molecules (Suppl. Fig. 1). Fungal produced phyto-
hormones were first suggested to promote fungal viru-
lence, however, the actual role of fungal-produced
hormonal compounds in plant-fungus interactions is
Hormone, analogs, or
Proposed role in fungi
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Current Medicinal Chemistry, 2018, Vol. 25, No. 2 255
poorly understood [13, 18, 21]. Here we shortly de-
scribe the function of each hormone in plants and we
focus on the comparison between plant and fungal
hormonal biosyntheses, the physiological fungal re-
sponses triggered by the phytohormones and how fungi
manipulate plant hormone balance to their benefits
(Fig. 1).
Proposed plant responses to fungi
hormone modifiers produced phytohormones
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Fig. (1). Fungal produced phytohormones.

In the middle column (white boxes) fungal produced phytohormones are reported, as well as hormone precursors, derivatives,
analogs and enzymes that modify plant hormone stability. The proposed physiological consequences in the fungi as putative
endogenous signals are shown in the yellow boxes. Finally, the proposed alterations in plant physiology as consequence of
hormonal balance/level changes induced by the fungi to promote their own benefits are reported in the green boxes. Orange
arrows highlight production of molecules and modifiers by the fungi; synthesis of hormones by plants are shown in green ar-
rows. Dashed arrows suggest that the activity of hormone, compound or modifier requires further studies. Red characters cor-
respond to enzymes that modify the corresponding hormone, precursor or derivative molecules. (The color version of the figure
is available in the electronic copy of the article).
256 Current Medicinal Chemistry, 2018, Vol. 25, No. 2 Fonseca et al.

2.1. Auxins susceptibility of the host [38, 39]. In the case of rice
blast fungus Magnaporthe oryzae, fungal auxin has
Auxin in conjunction with other phytohormones
been proposed to regulate plant auxin-dependent tran-
plays varied roles in plant development. Indole-3-acetic
scriptional activation, suggesting control over the plant
acid (IAA) is the major endogenous plant auxin and
development or host hormonal balance by the fungal
regulates several development traits at multiple levels
phytohormone [40, 41]. Moreover, A. brassicicola in-
(i.e. cell, tissue and organ) of plant organogenesis [22].
fection promotes increased plant IAA levels and induc-
Synthesis of IAA progresses through multiple path-
tion of the JA pathway, suggesting a synergetic interac-
ways which can be broadly categorised into tryptophan
tion between IAA and JA to increase defence responses
(TRP)-dependent and TRP-independent pathways [23].
against necrotrophic pathogens [42]. Direct evidence to
Four different interconnected tryptophan dependent
show that fungal produced auxins alter host hormonal
pathways have been postulated: (i) the indole-3-
balance is still a pending challenge.
acetamide (IAM) pathway; (ii) the indole-3-pyruvic
acid (IPA) pathway; (iii) the tryptamine (TAM) path- Fungal infection can also directly affect auxin ho-
way; and (iv) the indole-3-acetaldoxime (IAOX) path- meostasis. The plant GH3 proteins regulate IAA (and
way, all based on the intermediate immediately down- also JA) conjugation to aminoacids to inactivate aux-
stream of TRP [22]. ins. Magnaporthe infection promotes transcription of
rice GH3, resulting in the inactivation of free active
It is interesting to note that fungi also produce
IAA and in turn reduced cell wall integrity, facilitating
auxin. Indeed, even before the identification of IAA in
fungal infection [43, 44]. In Botrytis–Arabidopsis in-
plants, it was first detected in the culture filtrate of the
teraction, GH3.2-mediated conjugation of IAA to as-
fungus Rhizopus suinus [6]. As in plants, fungal bio-
partic acid activates pathogenicity genes in the fungus
synthesis of IAA is proposed to proceed through both
making plants more susceptible, whereas down-
TRP-dependent and TRP-independent pathways. Al-
regulation of GH3.2 gene expression leads to higher
though the TRP-independent pathway is not clearly
resistance [45, 46]. Finally, auxin transport was also
defined in fungi, the fungal TRP-dependent production
implicated in successful fungal infection, for example
of IAA is proposed through the IPA and/or the IAM
promoting susceptibility to the pathogenic fungus
pathways [24]. Unequivocal analysis of these pathways
Fusarium oxysporum [47]. In summary, the role of
is difficult because some of the intermediates can be
auxins in the plant-fungus interaction seems to depend
by-products of other metabolic activities, and culture
on the plant and the pathogen involved. Moreover in
media used for in vitro studies may contain plant de-
each case studies are focusing in a part of the overall
rived components resulting in false positive. Fungal
scenario which make difficult to define an unequivocal
genomic and genetic studies are required to confirm the
common role for auxin in plant-fungi defence proc-
in vitro results [6, 25].
esses.
The role of auxins in fungal pathogenicity is well
Since auxin can impact defence, over the course of
described. In F. oxysporum, the overexpression of two
evolution microbes associated with plants have learned
auxin biosynthetic genes induces auxin accumulation
to use this to their advantage. Auxin levels in plants are
and virulence on Orobanche infection [34]. Consis-
increased during mycorrhizal associations [26]. For
tently, silencing of an auxin biosynthetic gene in Puc-
example, increased IAA levels induce lateral root for-
cinia graminis resulted in reduced pustule formation
mation which is mutually beneficial for plants (i.e. fa-
during wheat infection [35]. In addition, infections
cilitating nutrient uptake) and fungi (promoting root
caused by P. brassicae and by Taphrina species pro-
colonisation) [27, 28]. In addition, the auxin precursor
mote severe organ deformation disrupting the host
indole-3-butyric acid (IBA) is also involved in promot-
auxin biosynthesis [36]. Nevertheless, the role of fun-
ing arbuscular mycorrhizal associations although the
gal auxin in promoting virulence and tumour formation
specific origin and effect of this compound requires
during similar organ deformation caused by U. maydis
further analyses [29]. However, the effect of these
in corn is still unclear [37].
hormones may not always guarantee a benefit to host
Besides, fungi can produce auxins to alter the host plant. For instance, the overproduction of auxin by mu-
hormonal balance to their benefits. For example, auxin tants of ectomycorrhizal Hebeloma cylindrosporum
can repress SA levels and signalling, therefore biotro- enhances Pinus pinaster root tissue invasion but it did
phic pathogens, including fungi, may have evolved to not enhance the plant growth [30]. Similarly, a modula-
exploit auxin-mediated suppression of SA to enhance tion of IAA biosynthesis in transgenic Piriformospora
Fungal Manipulation of Plant Hormones
indica, which is a root colonising plant growth promot-
ing basidiomycete, failed to produce any effect on plant
growth [31, 32]. These studies fail to confirm a direct
regulation of plant morphology by auxins produced by
symbiotic fungi. However, in the plant mycoparasitism
of Trichoderma spp. several auxinic metabolites pro-
duced by the fungi induced lateral root development
and plant growth [33].
The activity of auxins in fungi is still uncertain.
Auxin induces several developmental responses in
fungi, such as cellular elongation, hyphal growth and
spore germination [6, 48]. An endogenous role for fun-
gal auxin is suggested by its synthesis even in fungi not
associated with plants. However, understanding the
role of auxins in organisms other than plants still repre-
sents a major challenge.
2.2. Cytokinins
CKs play a role in plant cell cycle, differentiation,
root and shoot formation, senescence and are required
for source-sink nutrient distribution [49, 50]. Free CKs
are considered biologically active whereas the conju-
gated forms are inactive, serving as translocation or
storage forms [51, 52]. CK biosynthesis occurs mainly
through two pathways. Isoprenoid CKs are synthesized
de novo via adenosine phosphate, a reaction in which
the first step is catalyzed by Isopentenyl transferase
(IPT). Aromatic CKs are synthesized through a minor
pathway that requires the modification and catabolism
of specific t-RNA molecules by t-RNA Isopentenyl
transferases (t-RNA-IPT). In both pathways the result-
ing products are then activated by the cytokinin-
activating enzyme LONELY GUY (LOG) [6, 51-54].
Fungi can also produce isoprenoid and aromatic cy-
tokinins identical to the plant hormones. Indeed, the
discovery of CK manipulation by pathogens uncovered
the role for CKs in plant immunity [55, 56]. The best-
described example is that of the gall forming bacteria,
Agrobacterium tumefaciens which transfers an IPT
gene into the host genome and modulates the plant CK
synthesis [57]. CK-mediated pathogenesis modifies
host growth dynamics by inducing tumour gall or
“green island” formation, thereby establishing new
source-sink relationship that remobilizes photoassimi-
lates for feeding. This strategy is largely beneficial for
many biotroph pathogenic fungi although some patho-
genic fungi also induce tumours in a CK-dependent
manner [56]. For example, U. maydis and Claviceps
purpurea produce CKs in infected host areas; CK ac-
cumulation correlates with U. maydis virulence al-
Current Medicinal Chemistry, 2018, Vol. 25, No. 2 257
though no experimental evidence confirm a direct viru-
lent effect of fungal CKs [58].
In contrast, some non-tumour forming CK produc-
tion by the fungi is required for its complete virulence
[55, 59]. In the case of M. oryzae, fungal CK biosyn-
thetic mutant for t-RNA–IPT, the key biosynthetic en-
zyme of plant aromatic CKs, was impaired in CK pro-
duction [60]. The requirement for t-RNA–IPT, in the
fungal CK production also suggests conservation in CK
biosynthesis across species, despite minor variations.
For example, the biotrophic pathogen Claviceps pur-
purea evolved a single enzyme with both the IPT and
LOG functions required for de novo CK biosynthesis
[52]. However, impairment in CK biosynthesis seems
not to affect virulence of C. purpurea, though it exhib-
its a hypersporulating phenotype [52].
An additional fungal strategy for the regulation of
plant CK levels based on the production of the fungal
β-glucosidase cleaving zeatin-O-glucosyde [(OG)Z] by
several biotrophic and hemibiotrophic, but not ne-
crotrophic, fungi. During infection (OG)Z ensure pho-
toassimilate accumulation for fungal growth by releas-
ing stored conjugated CKs [61, 62].
In addition, CKs are involved in mutualistic plant-
microorganism interaction as mycorrization and nodu-
lation. For example, in mycorrizal symbiosis, accumu-
lation of CKs promote the growth of the host and the
fungi [6].
The tremendous diversity of CK-producing fungal
species, ranging from pathogenic to symbiotic, includ-
ing those non-associated with plants, suggests a role of
CKs as endogenous fungal signal [6, 60]. Indeed, CKs
induce hyphal development and nutrient uptake in sev-
eral fungi, whereas in C. purpurea they alter fungal
biology [52]. Recently, CKs have been shown to be
involved in oxidative stress tolerance in the M. oryzae
[6, 59]. However, a possible direct sensing of CKs by
fungi, suggesting a putative endogenous fungal role,
requires further analyses. Beyond plant-fungus bounda-
ries, Mycobacterium tuberculosis, the human obligate
pathogen, is also able to synthesize and secrete CKs
[63]. In agreement, the cytokinin-activating enzyme
LOG is conserved in important human pathogens [64],
suggesting novel roles of CKs in pathogenesis and as
crosskingdom communication compounds [64, 65].
The actual function of CKs in fungi is not clear yet,
although the hypothesis that these non-plant metabo-
lites evolved as signalling hormones only in plants was
recently proposed [65].
258 Current Medicinal Chemistry, 2018, Vol. 25, No. 2
2.3. Gibberellins
Gibberellins are terpenoid derived secondary me-
tabolites first identified from the phytopathogenic fun-
gus Gibberella fujikuroi (renamed Fusarium fujikuroi),
that render rice infected plants abnormally tall (“baka-
nae” or “foolish seedling” disease). Currently more
than 100 GAs have been identified in plants, fungi and
bacteria [66]. GAs synthesis, signalling and action are
well studied in plants: GAs promote growth and devel-
opment, seed germination, stem elongation, flowering
and fruit maturation [67]. In fungi, however, our
knowledge related to GAs is limited to its synthesis [6,
68]. The first steps and final compounds in GA biosyn-
thesis are conserved among plants and fungi, although
different intermediates do occur, suggesting an inde-
pendent and convergent evolution [67-69]. Besides,
higher plants have evolved strategies for GA inactiva-
tion that are absent on fungi, displaying an additional
level of regulation of GA levels. The absence of com-
pound inactivation in fungal GAs has been proposed to
occur since these are secreted to alter the host physiol-
ogy [69].
GA synthesis is mainly restricted to some phytopa-
thogenic fungal species with some species-specific bio-
synthetic steps (e.g. F. fugikuroi and Phaeosphaeria
sp.) and in some cases GA levels correlate with strain
virulence [6, 68, 70]. F. fujikuroi produces a GA4 de-
saturase whose overexpression in plant was sufficient
to induce growth by protecting GA3 from oxidation
[69]. Since the equilibrium of the GA and JA pathways
sets the balance between plant growth and defence,
some pathogenic fungi were proposed to produce GA
to interfere with the host hormonal balance and weaken
defences [71, 72].
Endophytes and arbuscular mycorrhizal (AM) fungi
can also produce several GAs [73, 74]. For example,
the endophytes Phoma glomerata and Penicillium sp.
produce biologically active GAs that improve the
growth and stress responses of host cucumber plant
[74]. In addition, the root endophyte Piriformospora
indica enhanced rice tolerance to root herbivory by al-
tering the balance between GA and JA pathways [75].
In symbiotic arbuscular mycorrhizal fungi, GA sig-
nalling is involved in fungal development after forma-
tion of AM symbiosis [76, 77]. In addition, the DELLA
proteins, key repressors in the host GA pathway, of
several plant species act as positive regulators of arbus-
cule formation [76, 78, 79].
The role of GA in the fungi itself remains elusive to
date. The production of GAs mainly by pathogenic
Fonseca et al.
fungi together with the absence of fungal GA inactiva-
tion enzymes, points to a role in fungus-host interac-
tion. Exceptionally, in the non-pathogenic GA-
producing fungus Neurospora crassa, exogenous GA
treatment enhances hyphae growth, suggesting a direct
effect of GA on fungal physiology [6]. Exogenous GA
affects fungal AM colonization, although it is not clear
if GA acts directly on the fungi or indirectly altering
the host physiology [77].
2.4. Strigolactones
Strigolactones (SLs) play a key role in the associa-
tion between plants and arbuscular mycorrhiza fungi,
since SLs release by plant roots promotes fungal hy-
phal branching to begin the plant-fungus symbiosis [80,
81]. In nature, plants produce around 20 natural SLs
acting as endogenous plant signals, involved in regulat-
ing plant architecture, adventitious rooting, secondary
growth and reproductive development [81, 82]. Re-
cently, a role of SLs in plant defence, through their in-
teraction with the jasmonic acid pathway, has been
proposed [83].
In fungi, SLs promote spore germination, growth
and hyphal branching of AM fungi from the phylum
Glomeromycota, although SLs fail to influence spore
germination or hyphal growth of Fusarium oxysporum
[80, 81, 84-86]. The exact mechanism of detection of
SLs secreted by the plant hosts in fungi is unknown.
However the D14-type proteins that recognizes stri-
golactones in plants have not been discovered in fungi
[84, 86]. The assessment of SL perception in AM fungi
still represents a major challenge.
2.5. Brassinosteroids
Brassinosteroids (BRs) are a class of plant steroid
derivatives with various physiological effects on plants
such as cell elongation, proliferation, vascular differen-
tiation, senescence, fertility, leaf morphology and
light–dark regulation of development [87]. Recently,
tissue specific activities of BRs were also reported,
showing a regulation of root growth and development
as well as a role in plant growth-immunity balance [88,
89]. So far, there is no evidence of BR produced by
fungi; however, the fungal metabolite KM-Ol isolated
from Drechslera avenae was characterized as the first
naturally occurring selective brassinosteroid inhibitor
[90]. Fungal responses to exogenous BRs are very
scarce; for example, mycelial cultures of Psilocybe
cubensis and Gymnopilus purpuratus are promoted by
BRs [91]. In summary, further studies are required to
assess the role, if any, of BRs in plant-fungus interac-
tions.
Fungal Manipulation of Plant Hormones
2.6. Abscisic Acid
Abscisic acid is the key signalling molecule in plant
responses to environmental stresses as drought, high
salinity and extreme temperatures [92]. ABA also regu-
lates plant physiological processes (i.e. seed maturation
and dormancy) preventing precocious germination and
counteracting GAs action [93]. Finally, ABA modu-
lates defence responses such as SAR and ISR, antago-
nizing defence signalling molecules as SA and ET [94-
96].
ABA is a sesquiterpene that is synthesized from
isopentenyl phosphate (IPP) either by direct or indirect
pathways, where mevalonate (MVA) or methylerythri-
tol phosphate (MEP) are the corresponding source of
IPP respectively [97]. Plants can use both pathways;
the indirect plastid-specific pathway is predominant,
whereas the cytosolic MVA pathway seems auxiliary.
Physcomitrella patens is the most ancient land plant
with the complete genome sequenced that retains this
indirect plastid-specific ABA synthesis pathway, sug-
gesting this pathway evolved with land colonization
[98].
Fungi with diverse life strategies (e.g. pathogenic,
symbiotic and saprophytic) can produce ABA, via the
cytosolic MVA pathway [6]. However, as described for
the pathogenic fungi B. cinerea and Cercospora cru-
enta, these pathways can have similar but distinct in-
termediates, pointing to a high diversification of syn-
thesis strategies [97]. In the case of B. cinerea, the
BcABA1-4 genes are responsible for ABA biosynthesis
[99]. So, if fungi synthesize ABA, can they perceive it?
Our current knowledge suggests that well-described
plant ABA receptor PYRABACTIN RESISTANCE
(PYR)/REGULATORY COMPONENT OF ABA RE-
CEPTOR (RCAR) proteins are present only in land
plants, being Marchantia polymorpha the earliest stud-
ied organism harbouring potential PYR/RCAR ho-
mologs [98]. Therefore, PYR/RCAR-mediated ABA
perception was suggested to have evolved with land
conquer. However, since ABA is a molecule common
to unicellular ancestor of eukaryote and their principal
receptors in plant do not exist in other organisms, a
divergent evolution of ABA functions and perception
may be expected [98]. In this context, functions of
transmembrane G-protein coupled receptors and asso-
ciated heterotrimeric GTP-binding proteins have been
associated to ABA signalling across kingdoms suggest-
ing a role for ABA in the producing organism [96, 98].
Intriguingly, fungi encode for transmembrane G-
protein coupled receptors and associated heterotrimeric
GTP-binding proteins similar to those involved in ABA
Current Medicinal Chemistry, 2018, Vol. 25, No. 2 259
signalling. However, the role of ABA in fungi is still
elusive, and only few reports demonstrate a direct ef-
fect of ABA on fungi physiology [98]. For example,
ABA treatment induces hyphal growth in Ceratocystis
fimbriata whereas ABA promotes germination and ap-
pressoria formation in Magnaporthe oryzae, contribut-
ing to the fungal virulence [100]. Moreover, the muta-
tion in ABA4 (homologous to the above-described
BcABA4, a key ABA biosynthetic gene) in M. oryzae
halves the ABA levels and renders the pathogen unable
to infect rice, showing a primary role for ABA in fun-
gal pathogenicity [101]. Other studies suggest that
ABA may interfere with plant defence indirectly. For
example, ABA affects JA biosynthesis and the activa-
tion of defences against the oomycete Pythium irregu-
lare [102]. In addition, ABA acts antagonistically to
SA during M. grisea infection [6, 103]. Although it is
impossible to dissociate the intrinsic plant-specific role
of ABA from the effect of appressoria formation, sev-
eral studies support a direct plant-specific role for ABA
of fungal origin. For instance, in B. cinerea and U.
maydis, the level of ABA present in the fungus corre-
lates with infection levels [58, 104]. In addition, ABA
contributes to susceptibility to B. cinerea and Plec-
tosphaerella cucumerina by suppressing defence re-
sponses in plants [105, 106]. Although the molecular
mode-of-action of fungal produced ABA is still un-
known, in plants ABA and SA antagonistically influ-
ence cellular NPR1 protein levels [107]. ABA pro-
motes NPR1 degradation via the proteasome pathway,
whereas SA may protect NPR1 from ABA-promoted
degradation through phosphorylation, resulting in a
dynamic balance of NPR1 turn-over [107]. In the com-
ing years, we expect the elucidation of the molecular
mechanisms sustaining the hormonal relations involv-
ing fungal produced ABA and plant defences.
2.7. Jasmonates and Additional Oxylipins
Plant jasmonates are key signalling molecules regu-
lating stress and defence responses as well as growth
and fertility [108, 109]. JAs signalling pathway is in
dynamic balance with those of other defence hormones
(SA and ET) and growth promoting hormones (e.g.,
auxins and GAs). JAs are cyclopentanone oxylipins
derived from α -linolenic acid via lipid peroxidation
[108]. This plant biosynthetic pathway involves several
hydroperoxide oxylipins, or structurally similar com-
pounds, conserved in several fungi [110, 111]. In addi-
tion, some fungi can also accumulate cyclopentenone
and cyclopentanone oxylipins such as OPDA, JA and
conjugated JAs [15, 112]. For example, Fusarium ox-
ysporum accumulates JAs via lipoxygenase enzymes
260 Current Medicinal Chemistry, 2018, Vol. 25, No. 2
related to those identified in plants, suggesting that
fungal JAs may be generated in a similar manner as in
plants [113]. Some, but not all, F. oxysporum strains
can produce jasmonates such as JA-Ile and JA-Leu that
require COI1, the plant JA-Ile receptor, to promote in-
fection, suggesting a role for fungal JA-conjugates as
virulent effectors [114]. However, further studies on
the virulence of fungal mutants affected in JAs produc-
tion are required to confirm fungal JAs as virulent ef-
fectors.
A key regulation of JA-Ile-mediated responses is
the hormone catabolic turnover promoted by JA-Ile
oxidation [115, 116]. It was proposed that JA-derivates
resulted from JA-Ile catabolism, such as hydroxylated
JA (12OH-JA), might retain a biological function con-
tributing to switch-off JA signalling [108, 117]. Note-
worthy, the rice blast fungus M. oryzae can convert
endogenous JA into 12OH-JA using an enzyme, the
antibiotic biosynthesis monooxygenase (Abm) [118].
Abm and 12OH-JA are both secreted during host infec-
tion to weaken plant defenses [118]. M. oryzae loss-of-
function mutant for Abm results in higher plant produc-
tion of methyl-JA, that in turn induces stronger plant
defences. On the other hand, exogenous 12OH-JA in-
crease M. oryzae penetration. Therefore, Abm might
have a dual role: (1) reducing the free JA and conse-
quently plant defences, and (2) producing 12OH-JA,
that in turn enhances fungal penetration [118]. How-
ever, the conversion of plant JA into 12OH-JA by Abm
itself to facilitate host colonization awaits further con-
firmation.
JA-Ile acts as “molecular glue” to induce the forma-
tion of the plant co-receptor complex formed by COI1-
JAZ proteins [119-122]. The bacterial phytotoxin coro-
natine (COR) is the best studied JA-Ile mimic that acts
as structural analogue of the plant hormone, inducing
the formation of the plant co-receptor complex COI1-
JAZ [15, 122]. Novel bacterial COR-like compounds,
such as coronafacoyl-isoleucine (CFA-Ile) and related
coronafacoyl-conjugated, have been recently isolated
and suggested to act as structural JA-Ile analogs [123].
So far, COR or CFA-derivates have not been identified
in fungi. However, cinnacidin is a COR-like compound
isolated from the fungus Nectria sp. DA060097 [124].
Plant bioassays suggested that cinnacidin and its ana-
logs might act by mimicking the role of COR and JA-
Ile [124]. The astonishing similarity between cin-
nacidin and COR suggests a putative cinnacidin’s
mode-of-action promoting the formation of the plant
co-receptor complex COI1-JAZ.
Fonseca et al.
In contrast, synthetic COR derivatives that spatially
impede the interaction of the co-receptor COI1 and
JAZ proteins act as competitive antagonists [125]. It is
logical that fungi evolved natural JA-derivates acting
as competitive antagonists, preventing the formation of
the COI1-JAZ co-receptors and consequently weaken-
ing plant JA-mediated defences. For example, Lasio-
diplodia produces in vitro three JA esters (named lasio-
jasmonates A, B and C) whose structural comparison to
JA-Ile suggests a putative ability to bind COI1 but spa-
tially prevent the recruitment of the JAZ co-receptor
[122, 126]. However, the hypothesis that fungal secon-
dary metabolites may act as competitive JA-Ile antago-
nists awaits formal experimental confirmation. Alterna-
tively, fungal JA-derivates may act as a pool of inactive
JAs, easily converted into active molecules whenever
necrotrophic fungi need to induce plant cell death and
necrosis.
Finally, several JAs and oxylipins have a direct ef-
fect on fungal physiology, suggesting that fungi might
be able to sense JAs [127]. Generally, JAs show nega-
tive effects on fungal growth; for example, Me-JA in-
hibits spore germination and mycelium growth of F.
oxysporum, highlighting that fungal responses may re-
semble plant JA-mediated responses [108, 128].
2.8. Salicylic Acid
Salicylic acid plays an essential role in plant immu-
nity against biotrophic and hemibiotrophic pathogens,
including fungi, relying on living host tissue for nutri-
ents [129]. SA also regulates systemic acquired resis-
tance, a broad-spectrum immune response activated by
avirulent pathogens, including fungi [129, 130].
Fungi are not able to produce SA, although few ex-
ceptions, such as Moniliophthora perniciosa and
Oudemansiella mucida, have been reported [131, 132].
The fungal biosynthesis of SA is currently unknown,
whereas the predominant SA biosynthesic pathway in
plants converts shikimate into the intermediate com-
pounds chorismate and isoisochorismate to finally gen-
erate the bioactive plant hormone SA [133]. In contrast,
fungi have evolved several strategies (at least three dif-
ferent molecular mechanisms have been described to
date) to interfere with the plant SA homeostasis and
SA-mediated plant defences [6]. First, the biotrophic
fungus Ustilago maydis was shown to produce and se-
crete the chorismate mutase Cmu1 as a virulence factor
[134]. Cmu1 convert the SA plant precursor chorismate
into prephenate, reducing accumulation of SA. In addi-
tion, genes encoding chorismate mutases were identi-
fied in many additional genomes of biotrophic plant
Fungal Manipulation of Plant Hormones
pathogens and symbionts, suggesting that chorismate
mutase is a widespread fungal mechanism to manipu-
late plant SA levels [134]. Furthermore, fungi have
evolved additional secreted enzymes to degrade a dif-
ferent SA precursor. The necrotrophic fungus Verticil-
lium dahlia produces isochorismatase, which hydro-
lyzes the SA plant precursor isochorismate in order to
decrease SA levels in the plant host and thereby to
promote infection [135]. Finally, the shyA enzymes
encoded by different fungi, such as U. maydis and
Epichloë festucae, are salicylate hydroxylases which
convert the bioactive plant SA into an inactive com-
pound [136, 137]. The SA-degrading activity of several
bacterial salicylate hydroxylases has been long charac-
terised and established [137]. Overall, these studies
show the manipulation of plant host SA levels (or
metabolic priming) is a common strategy evolved by
many fungi with very different lifestyle, from ne-
crotrophs to symbionts, also conserved in bacteria.
Fungi are also able to produce SA-derivate mole-
cules such as 6-methylsalicylic acid (6-MeSA); how-
ever, fungal 6-MeSA is not converted into SA, but it is
rather a well-characterised precursor of the mycotoxin
patulin [138]. In contrast, victorin is a secondary me-
tabolite with a chemical structure un-related to SA pro-
duced by the fungus Cochliobolus victoriae [139].
However, victorin binds to and represses thioredoxins
including TRX-h5 that in turn inhibits the reduction of
NPR1, the key transcriptional regulator of SA-
mediated immune responses [140]. The redox status of
NPR1 regulates its relocation from cytosol to the nu-
cleus, suggesting that victorin may suppress SA-
mediated defences. However, the virulent task of vic-
torin might not require NPR1 manipulation because C.
victoriae, as a necrotrophic pathogen, also employs
victorin to induce plant cell death inducing hypersensi-
tive response triggered by LOV1, a resistance protein
activated by the inhibition of TRX-h5 [140, 141]. This
hypothesis is supported by the evidence that C. victo-
riae only triggers virulence on plants carrying the
LOV1 resistance locus [142]. Nevertheless, victorin
underscores an exciting fungal strategy to manipulate
NPR1 and SA-mediated signalling.
SA was reported to inhibit growth and spore germi-
nation of several fungi, such as Harpophora maydis
and Aspergillus flavus, suggesting that SA might be
sensed by fungi [143, 144]. Recently, it was proposed
that the fungus U. maydis directly perceives SA via
Rss1, a binuclear zinc cluster protein. Rss1 is a tran-
scriptional regulator of genes required for SA and tryp-
tophan degradation as well as a putative SA receptor
Current Medicinal Chemistry, 2018, Vol. 25, No. 2 261
[145]. However, Rss1 fails to act as fungal virulence
factor, suggesting the existence of redundant sensing
mechanisms regulating fungal SA-responsive genes
[145].
2.9. Ethylene
Ethylene regulates many plant development and en-
vironmental responses as well as pathogen responses
[146]. Rather than being the principal regulator, ET
often fine-tunes defence pathways, including those
regulated by JA and SA [147]. ET is also produced by
several fungi belonging to different phyla and with dif-
ferent lifestyles, from pathogenic fungi, such as B. cin-
erea, to symbiotic fungi, such as the ectomycorrhizal
F. oxysporum f. sp. pini [6, 148-150]. The canonical
plant ET biosynthetic pathway, relaying on the conver-
sion of methionine into 1-aminocyclopropane-1-
carboxylic acid (ACC) via ACC-synthase enzymes into
ET, is also conserved in fungi [150, 151]. However,
fungi also evolved two additional biosynthetic path-
ways producing ethylene from 2-keto-4-
methylthiobutyric acid and/or from 2-oxoglutarate [6,
150, 152]. The multiple fungal ET-biosynthetic path-
ways suggest an important role of this phytohormone
for several fungi, although a consensus function of
fungal ET is not established yet [6]. For example, the
production of ET by the necrotrophic fungal pathogen
Cochliobolus miyabeanus increases rice susceptibility,
suggesting a virulent role of the fungal ET [152]. In
addition, truffle Tuber borchii and Tuber melanop-
sorum produce ET to induce alterations in the host root
morphology, suggesting a putative role of ET in fungal
virulence [153]. Nevertheless, only the analysis of fun-
gal mutants affected in ET production will clarify the
role of ET in plant-fungus interactions.
ET, as well as its precursor ACC, affects fungal
spore germination and fungal growth in both patho-
genic (e.g. Alternaria alternata and B. cinerea) and
symbiotic fungi (e.g. Gigaspora ramisporophora and
G. mosseae), suggesting that fungi might be able to
sense ET and ET-related compounds [154]. In addition,
ET produced by ripening tomato fruits is somehow
perceived by the pathogenic Coeotrickhum sp and in-
duces spore germination and the development of ap-
pressorium [155]. These results suggest that these fungi
might have co-evolved a mechanism sensing the plant-
produced ET to establish the most advantageous time
to develop specialized structures for penetration and
infection [155]. Until recently, ET was assumed to be
sensed only by land plants, via a family of five recep-
tors acting as negative regulators of the ET pathway
262 Current Medicinal Chemistry, 2018, Vol. 25, No. 2 Fonseca et al.

[146]. However, the freshwater green algae Spirogyra BRs = Brassinosteroids

pratensis was recently showed to possess an ethylene CFA-Ile = Coronafacoyl-Isoleucine
sensing system similar to land plants [156]. To date,
genomic and transcriptional analyses failed to identify CKs = Cytokinins
a fungal ethylene system similar to the plant; therefore, Cmu1 = Chorismate mutase
the hypothesis that some fungi can perceive ET (and
COI1 = Coronatine insensitive 1
how) await experimental confirmation.
COR = Coronatine
CONCLUSION AND FUTURE CHALLENGES
DCL = Defective chloroplasts and leaves
Fungi, independently on the nature of the fungus- protein
plant association, manipulate plant hormone balance to ET = Ethylene
their benefits. To reach this purpose, fungi evolved dif-
ferent strategies, from altering the plant hormonal bio- FSP = Fungal synthesized phytohormones
synthetic pathways to affecting the plant perception GAs = Gibberellic acids
systems. Besides, fungi can synthesize most phytohor-
IAA = Indole-3-acetic acid
mones as well as many analogues and derivatives, al-
though their biological roles are still not known. Fungal IAM = Indole-3-acetamide
synthesized phytohormones (FSP) have been suggested IAOX = Indole-3-acetaldoxime
to act both as virulent or symbiotic factors by affecting
plant physiology. However, these fungal metabolites IBA = Indole-3-butyric acid
also induce physiological responses within the fungi, IC = Isochorismate
suggesting that fungi can respond to FSP. How fungi
IPA = Indole-3-pyruvic acid
perceive and respond to FSP is still a mystery. Simi-
larly, it is still unclear whether most or only few FSP IPP = Isopentenyl phosphate
can induce physiological responses in fungi. IPT = Isopentenyl transferase
The assessment of FSP as endogenous fungal sig- JAs = Jasmonates
nalling molecules is a primary challenge that might
pave the way to identify the fungal sensing mecha- JAZ = Jasmonate Zim Domain
nisms of FSP. It is currently unknown if fungi evolved LOG = Lonely Guy
receptors to sense FSP; so far, fungal genome-wide LOV1 = Long Vegetative Phase1
sequence analyses fail to identify reliable homolog
genes encoding for the key phytohormone plant recep- MEP = Methylerythritol phosphate
tors. However, sequence analyses showed that green MiSSP7 = Mycorrhizal induced Small Secreted
algae also failed to conserve many key components of Protein 7
phytohormone pathways, suggesting a lack of conser-
MVA = Mevalonate
vation among kingdoms [157]. Ultimately, the under-
standing of how fungi developed phytohormone sens- NPR1 = Nonexpresser of PR genes 1
ing machineries will allow an evolutionary and func- (OG)Z = Zeatin-O-glucosyde
tional comparison to the plant perception systems.
PCD = Programmed Cell Death
LIST OF ABBREVIATIONS PYR = Pyrabactin Resistance
12OH-JA = 12-Hydroxylated JA RCAR = Regulatory Component of ABA Re-
6-MeSA = 6-methylsalicylic acid ceptor
ABA = Abscisic acid ROS = Reactive Oxygen Species
Abm = Antibiotic biosynthesis monooxy- SA = Salicylic acid
genase shyA = Salicylate hydroxylase
ACC = 1-aminocyclopropane-1-carboxylic SLs = Strigolactones
acid
SM = Secondary Metabolites
AM = arbuscular mycorrhizal
sRNAs = small RNAs
Fungal Manipulation of Plant Hormones
t-RNA-IPT = Isopentenyl transferases
TAM = Tryptamine
TRP = Tryptophan
TRX = Thioredoxin
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial
or otherwise.
ACKNOWLEDGEMENTS
We thank Roberto Solano and to Vicente Rubio for
critical reading of the manuscript. SF was supported by
a “Ramon y Cajal” fellowship and by the project
BIO2016-80551-R funded by the Spanish Ministry for
Science and Innovation. Work in AC's laboratory was
funded by the Spanish Ministry for Science and Inno-
vation (grant BIO2013-44407-R and BIO2016-77216-
R).
SUPPLEMENTARY MATERIAL
Supplementary material is available on the pub-
lisher’s web site along with the published article.
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