REVIEW

Intervention of Phytohormone Pathways by PathogenEffectorsOPEN

Kemal Kazan1 and Rebecca Lyons

Commonwealth Scientific and Industrial Research Organization (CSIRO) Plant Industry, Queensland Bioscience Precinct, Brisbane4069, Queensland, Australia

ORCID ID: 0000-0002-5169-8934 (K.K.)

The constant struggle between plants and microbes has driven the evolution of multiple defense strategies in the host as wellas offense strategies in the pathogen. To defend themselves from pathogen attack, plants often rely on elaborate signalingnetworks regulated by phytohormones. In turn, pathogens have adopted innovative strategies to manipulate phytohormone-regulated defenses. Tactics frequently employed by plant pathogens involve hijacking, evading, or disrupting hormonesignaling pathways and/or crosstalk. As reviewed here, this is achieved mechanistically via pathogen-derived moleculesknown as effectors, which target phytohormone receptors, transcriptional activators and repressors, and other componentsof phytohormone signaling in the host plant. Herbivores and sap-sucking insects employ obligate pathogens such as viruses,phytoplasma, or symbiotic bacteria to intervene with phytohormone-regulated defenses. Overall, an improved understandingof phytohormone intervention strategies employed by pests and pathogens during their interactions with plants will ultimatelylead to the development of new crop protection strategies.

INTRODUCTION

Plants possess an innate immune system typified by complexdefense responses activated upon pathogen detection, whichhas evolved over millions of years in parallel with the evolution ofvirulence mechanisms in pathogenic microbes. Membrane pro-teins such as receptor-like kinases, collectively known as patternrecognition receptors (PRRs), play essential roles in detectingmicrobe-derived conserved molecules known as microbe-associated molecular patterns (MAMPs). The current paradigmof plant immunity proposes that host defenses of increasingamplitude and specificity are pitted against counterattacks bypathogens (Jones and Dangl, 2006) (Figure 1). MAMP de-tection initiates basal and broad-spectrum defenses effectivein stopping the invasion by most potential pathogens in a processtermed pattern-triggered immunity (PTI). In return, pathogenshave evolved molecules collectively known as “effectors” that canbe used to overcome PTI by interfering with MAMP detection and/orsubsequent defense signaling. To directly or indirectly detectpathogen effectors, plants have coevolved a large number ofresistance (R) genes, often encoding intercellular proteins (e.g.,nucleotide binding domain leucine-rich repeat containing re-ceptors) (Jones and Dangl, 2006). In resistant or immune hosts,effectors alert the plant to the presence of pathogens, resultingin R protein–mediated defense that inhibits pathogen invasion.This phenomenon is known as effector-triggered immunity orETI. In susceptible interactions, pathogens may either fail totrigger ETI in the host or inhibit ETI via their effector arsenal and

reprogram the host transcriptome, proteome, hormonome, aswell as vesicle trafficking to promote pathogen virulence. Thislatter scenario is known as effector-triggered susceptibility(reviewed in Dodds and Rathjen, 2010; Mengiste, 2012; Xinand He, 2013).This model, which predicts a multilayered-host defense system,

applies particularly well to the interaction of plants with manyoomycete and biotrophic and hemibiotrophic fungal and bacterialpathogens. However, for necrotrophic fungal and bacterialpathogens that produce nonspecific toxins and a large numberof cell wall degrading and defense suppressing enzymes, there isoften little effective resistance, suggesting that these powerfulvirulence functions may override PTI and ETI processes. In somecases, toxin effectors are specifically detected by host proteins,and this may lead to susceptibility rather than resistance(reviewed in Friesen et al., 2008). Thus, in addition to MAMPs, de-tection of damage-associated molecular patterns (e.g., elicitorsreleased from host cells in response to cellular damage)probably plays a major role for cellular defense against ne-crotrophs (Mengiste, 2012). Interestingly, the type III secretionsystem, which is essential for effector delivery and the patho-genicity of hemibiotrophic bacteria such as Pseudomonassyringae (Büttner and He, 2009; Xin and He, 2013), does notseem to be required for the virulence of necrotrophic bacteriasuch as Pectobacteria that cause soft rot disease in many plantspecies (Davidsson et al., 2013).The ability to distinguish friends from foes is another intriguing

feature of the plant’s innate immune system, given that bothpathogenic and symbiotic microbes contain conserved MAMPs(reviewed in Zamioudis and Pieterse, 2012). Emerging evidencesuggests that both the host and the microbe play critical roles inplant–beneficial microbe interactions. An initial host defense

1Address correspondence to kemal.kazan@csiro.au.OPENArticles can be viewed online without a subscription.www.plantcell.org/cgi/doi/10.1105/tpc.114.125419

The Plant Cell, Vol. 26: 2285–2309, June 2014, www.plantcell.org ã 2014 American Society of Plant Biologists. All rights reserved.

response instigated against a “foreign” or potentially pathogenicmicrobe can be swiftly suppressed by the beneficial microor-ganism (Maunoury et al., 2010). Certain beneficial bacteria (e.g.,rhizobacteria) have evolved mutations in MAMPs (e.g., bacterialflagellin), which allow them to evade detection by the plantsurveillance system (Lopez-Gomez et al., 2012; Trdá et al.,2014). The ability of plants to sense pathogen-mediated cellulardamage via host-derived damage-associated molecular patterns(Mengiste, 2012) can also be important to distinguish pathogenicmicrobes from the symbiotic ones.

In contrast to vertebrates, plants do not possess adaptive im-munity, which is acquired through exposure to microbes or mi-crobial derivatives during the lifetime of an individual. However,exposure to microbes acts on the plant innate immune system togenerate a “working memory” known as systemic acquired re-sistance (SAR) (reviewed in Netea et al., 2011). SAR providesa broad-spectrum and long-lasting resistance to multiple patho-gens in tissues not directly exposed to pathogens (Durrant andDong, 2004). Remarkably, memories of microbial exposure canalso be transmitted to the next generation (Luna et al., 2012;Slaughter et al., 2012). Epigenetic processes such as DNAmethylation and chromatin modifications seem to play prominentroles in this phenomenon known as “transgenerational immunity”(Holeski et al., 2012).

INTERVENTION OF PHYTOHORMONE PATHWAYS: AUNIVERSAL STRATEGY ADOPTED BY PATHOGENS

The activation of complex phytohormone signaling networks isa universal defense response employed by plants (Schenk et al.,2000). In particular, essential defensive roles of primary defensehormones, jasmonates (JAs), salicylates (SAs), and ethylene(ET), have been well established. Other phytohormones, such asabscisic acid (ABA), auxins (indole-3-acetic acid [IAA]), cytoki-nins (CKs), brassinosteroids (BRs), gibberellins (GA), and stri-golactones, which are better known for their roles in stresstolerance or plant growth and development, also regulate plantdefense, either alone or in conjunction with the primary defensehormones (Figure 2) (Robert-Seilaniantz et al., 2011; Torres-Veraet al., 2014). Therefore, it is not surprising that pathogens havedeveloped capabilities to manipulate or subvert plant phyto-hormone signaling pathways for their benefit.From a mechanistic point of view, pathogen-mediated phy-

tohormone intervention strategies can be grouped into a fewbroad categories. First, suppression or evasion of host phyto-hormone biosynthesis and/or signaling pathways involved inpathogen resistance appears to be a common tactic employedby multiple pathogens. Various pathogens also manipulatephytohormone signaling pathways to alter the plant host’s es-sential developmental and/or physiological features, such asstomatal opening and senescence that facilitate pathogen entryand disease symptom development, respectively (Melotto et al.,

Figure 2. Complex Signaling Interactions among Phytohormone Path-ways Regulate Both Disease Resistance and Susceptibility in Plants inan Attacker-Dependent Manner.

The plant hormones JA, SA, and ET are primarily involved in plant de-fense, while ABA, auxins (IAA), CK, BR, GA, and strigolactones (STR)also regulate plant defense, either alone or in conjunction with the pri-mary defense hormones. Pathogens have developed strategies via theireffector repertoire to either interfere with or hijack phytohormone path-ways to induce resistance or susceptibility. Forward and blunt arrowsindicate positive and negative interactions, respectively. See text fordetails.

Figure 1. A Simplified View of Plant–Pathogen Interactions.

Pathogen-derived conserved molecules known as MAMPs are detectedby plasma membrane–located PRRs, and this recognition triggers PTI.Pathogens interfere with immune signaling through effectors to inducesusceptibility, and this is known as effector-triggered susceptibility (ETS).In return, plants have evolved effector recognition proteins (R proteins)that trigger an immune reaction following effector recognition to stoppathogen growth, and this phenomenon is known as ETI.

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2008; Kazan and Manners, 2009). In other instances, pathogenstake advantage of phytohormone crosstalk to promote diseasedevelopment (Figure 2). As discussed below, pathogen-mediatedactivation of a phytohormone signaling pathway that promotesdisease by suppressing another phytohormone pathway thatconfers resistance is a typical example of this latter phenome-non (Kazan and Manners, 2009, 2012; Xin and He, 2013).

The lifestyle of a pathogen often dictates the type of phyto-hormone intervention strategy adopted. Activation of a phyto-hormone signaling pathway that negatively regulates cell deathand senescence can be beneficial for biotrophic fungal patho-gens that require living host cells to complete their life cycles. Inaddition or alternatively, biotrophic pathogens may suppresssignaling pathways that promote cell death and necrosis to keepthe host alive as long as needed. By contrast, necrotrophicfungal pathogens manipulate phytohormone pathways that en-able these pathogens to kill and feed on dead cells. Pathogensalso exploit phytohormone crosstalk during their interaction withplants. A well-known example of phytohormone crosstalkhijacked by bacterial, viral, fungal, as well as oomycete patho-gens is the mutual antagonism between the SA and the JApathway. While the SA pathway often confers resistance tobiotrophic pathogens, activation of this pathway attenuatesJA signaling, thereby compromising resistance to necrotrophicpathogens; vice versa, the activation of JA pathway enhancesresistance to some necrotrophs but inhibits the SA pathway andresistance to biotrophic pathogens (reviewed in Thaler et al.,

2012). Pathogens also use “phytohormone mimics,” moleculesthat structurally and/or functionally resemble phytohormones orphytohormone signaling components, to trick the host into be-having inappropriately. Forceful opening of stomata by coro-natine (COR), a bacterial toxin and JA mimic, is a typicalexample of this phenomenon (Melotto et al., 2006; Lee et al.,2013) (Table 1). Most developmental alterations (e.g., stunting,elongation, and flowering time) observed in infected plants canoften be explained by pathogen-mediated alterations in host’shormone homeostasis and/or signaling.Over recent years, significant progress has been made to

understand the mechanistic basis of pathogen-mediated phy-tohormone intervention strategies. In this review, we present anoverview of diverse tactics used by pathogens via their effectorarsenal. We use the term effector, which is often defined asa low molecular weight and cysteine-rich protein secreted bypathogens during their interaction with plants, broadly to refer toboth proteinaceous and nonproteinaceous (e.g., toxins andnucleic acids) pathogen-derived molecules that render the hostenvironment conducive to infection. Many pathogens are ca-pable of producing a wide range of compounds that can act asphytohormone mimics during pathogenesis (Inomata et al.,2004). Pathogen-derived phytohormones are often synthesizedthrough biochemical pathways different from those in plants,suggesting that microbes and plants have evolved phytohor-mone biosynthesis pathways independently. In this review, weconsider pathogen-derived hormone mimics as well as proteins

Table 1. P. syringae Type III Effectors and Toxins Known to Alter Arabidopsis Hormone Physiology and/or Signaling to Cause Susceptibility

Type III Effector Function Reference

AvrRpt2 (cysteine protease) Alters auxin physiology through AUX/IAAdegradation

Chen et al. (2007); Cui et al. (2013)

AvrB (kinase) Activates JA signaling through MPK4,HSP90, and RIN4

Shang et al. (2006); Cui et al. (2010)

HopZ1a (cysteine protease/acetyltransferase) Activates JA signaling by degradingJAZ repressors

Jiang et al. (2013)

HopX1 (cysteine protease) Activates JA signaling by interacting withJAZ repressors and promoting theirdegradation

Gimenez-Ibanez et al. (2014)

Coronatine (toxin) Activates JA signaling through interactionwith the JA receptor COI1

Katsir et al. (2008); Geng et al. (2012)

Syringolin A (toxin) Suppresses SA defense Groll et al. (2008); Misas-Villamil et al. (2013)AvrPto and AvrPtoB Elevate ABA levels to antagonize SA signaling de Torres et al. (2006); de Torres-Zabala et al. (2007)

Promote ethylene signaling and biosynthesis Cohn and Martin (2005)Target brassinosteroid receptor BAK1 Cheng et al. (2011); Shan et al. (2008)

HopF2 Targets BAK1 (currently no direct evidencethat it disrupts BR signaling)

Zhou et al. (2014)

Hopl1 (J domain protein) Disrupts SA accumulation Jelenska et al. (2007) (2010)HopAM1 Promotes ABA signaling Goel et al. (2008)HopM1 Suppresses SA defense DebRoy et al. (2004); Geng et al. (2012);

Nomura et al. (2011)Alters auxin efflux Nomura et al. (2006) (2011)

HopQ1 Activates cytokinin pathway to suppressFLS2-mediated defense signaling

Hann et al. (2014)

AvrE Suppresses SA-dependent callose response DebRoy et al. (2004)

Please note that these effectors may overcome host defense in several different ways, but only roles relevant to hormone manipulation are shown forthe effectors discussed in the text.

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produced by intracellular pathogens such as viruses using thehost-translation machinery as effectors. We will focus mostly onrelatively recent and mechanistically better described exampleswhere specific roles of pathogen effectors in phytohormoneintervention have been demonstrated.

EFFECTOR-MEDIATED MANIPULATIONOF THE SA PATHWAY

The importance of the SA pathway as a regulator of plant de-fense in plants is well established (reviewed in An and Mou,2011; Pajerowska-Mukhtar et al., 2013). SA is required for bothlocal and systemic immunity against a wide range of pathogens.Indeed, the removal of endogenous SA through transgenic ex-pression of the bacterial salicylate hydroxylase (NahG) enzymerenders the plants susceptible to bacterial, fungal, and viralpathogens (Gaffney et al., 1993; Reuber et al., 1998). Further-more, SA induction-deficient (sid) mutants, which lack the iso-chorismate synthase gene involved in SA synthesis, fail toinduce SA upon pathogen challenge and are more susceptibleto bacterial and fungal pathogens (Nawrath and Métraux, 1999;Wildermuth et al., 2001). SA is required for the activation ofgenes encoding pathogenesis-related (PR) proteins such asPR1. SA also potentiates the hypersensitive response triggeredwhen pathogen effectors are directly or indirectly detected by Rproteins (Brodersen et al., 2005; Raffaele et al., 2006). Given thecentral importance of SA for host defense, it is not surprisingthat pathogens have developed innovative strategies to attenuatebiosynthesis and/or signaling of this important phytohormone.

Effectors Targeting SA Biosynthesis

In Arabidopsis thaliana, SA is synthesized in the plastid fromchorismate via the isochorismate pathway and in the cytosolthrough the phenylalanine ammonia-lyase pathway. Of thesetwo pathways, the isochorismate pathway is the predominantsource of both basal and pathogen-induced SA production(reviewed in Dempsey et al., 2011). The SA pathway is known toconfer resistance to the bacterial pathogen P. syringae. To fa-cilitate colonization of its host, P. syringae injects multiple ef-fector proteins into host cells via its type III secretion system (Xinand He, 2013). Hopl1, one of the type III P. syringae effectors,interferes with SA accumulation in Arabidopsis during diseasedevelopment (Table 1). Hopl1 is targeted to chloroplasts where itpresumably interferes with the plastid-specific SA biosynthesispathway. Arabidopsis plants expressing Hopl1 show signifi-cantly reduced levels of both SA levels and PR gene expression,as well as altered chloroplast thylakoid membranes. Hopl1 di-rectly binds to and disrupts the activity of HSP70 (HEAT SHOCKPROTEIN70) in chloroplasts, which may be required for theassembly of components required for SA biosynthesis (Jelenskaet al., 2007, 2010). However, the precise mechanism by whichHopl1 attenuates SA biosynthesis is currently unclear.

The biotrophic fungus Ustilago maydis causes smut disease inmaize. Cmu1, an effector translocated into the cytoplasm ofmaize (Zea mays) plants by U. maydis, interferes with the SApathway during disease development. Cmu1 encodes a cho-rismate mutase, an isomerase enzyme that converts SA precursor

chorismate to prephenate (Djamei et al., 2011). Transgenic strainsof U. maydis lacking Cmu1 trigger increased SA accumulation andshow reduced virulence onmaize plants (Djamei et al., 2011). Cmu1dimerizes with and deregulates a maize chorismate mutase. Thispresumably alters the translocation of chorismate from plastids tocytoplasm, consequently reducing the levels of chorismate avail-able for SA biosynthesis (Djamei et al., 2011; Djamei and Kahmann,2012). U. maydis also contains a gene (Shy1) that encodes acytosolic NahG-like enzyme, suggesting that this pathogen hasevolved multiple effectors potentially targeting SA-regulated hostdefenses (Rabe et al., 2013). SA-degrading ability is also known inthe necrotrophic fungal pathogen Sclerotinia sclerotiorum (Pennand Daniel, 2013). However, further research is needed to establishif such ability contributes to pathogen virulence.

Effectors Targeting SA Signaling

Protein ubiquitination via the 26S proteasome is intimately linkedto the regulation of hormone signaling in plants (Kelley andEstelle, 2012), and plant pathogens often target this essentialcellular process to subvert phytohormone signaling pathways(reviewed in Magori and Citovsky, 2011; Dudler, 2013). SyringolinA (SylA), a virulence factor and a proteasome inhibitor producedby P. syringae pv syringae, plays a role in defense suppression asevidenced by the inability of sylA mutants to inhibit SA accumu-lation and associated resistance responses in bean (Table 1)(Groll et al., 2008; Misas-Villamil et al., 2013). SylA reverts PTI-associated stomatal closure that is also dependent on both SAand NPR1 (NONEXPRESSOR OF PATHOGENESIS-RELATEDGENES1), a master regulator of SA signaling (Figure 3) (Schellenberget al., 2010). This facilitates enhanced entry of the pathogen intothe plant cell via a mechanism that is dependent on its proteasomeinhibitory activity. While sylA mutants fail to reopen stomata ininoculated Arabidopsis plants, addition of SylA or the proteasomeinhibitor MG132 rescues the stomatal opening (Schellenberg et al.,2010).The type III effector XopJ of the bacterial pathogen Xantho-

monas campestris pv vesicatoria also suppresses SA-mediateddefenses and the development of leaf necrosis by inhibitingproteasome activity. Pepper (Capsicum annuum) plants in-oculated with XopJ-deficient X. c. pv vesicatoria strains showincreased SA levels, reduced symptom development, and de-layed necrosis, which can be rescued by treatment with MG132(Üstün et al., 2013). XopJ interacts with the RPT6 (regulatoryparticle ATPase 6) subunit of the proteasome complex at theplasma membrane (Üstün et al., 2013), but exactly how this in-teraction contributes to X. c. pv vesicatoria virulence is yet to bedetermined. NPR1, however, appears to be required for XopJ-mediated disease symptom development (Figure 3). Thus, it hasbeen proposed that both SylA and XopJ may interfere with theproteasome-mediated turnover of NPR1 required for activationof SA responses (discussed below) (Schellenberg et al., 2010;Üstün et al., 2013).In addition to XopJ, X. c. pv vesicatoria suppresses the SA

biosynthesis gene ICS1 (ISOCHORISMATE1) and host defensesthrough XopD, another type III effector produced by this path-ogen (Canonne et al., 2011) (discussed further below in the ETsection). Similar to xopj mutants, a xopd null mutant shows

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reduced growth and symptom development and increased SAlevels and defense gene expression when inoculated onto tomato(Solanum lycopersicum). A XopD homolog from the Arabidopsis-infecting X. c. pv campestris strain directly binds to and repressestranscription of MYB30, a positive regulator of hypersensitiveresponse and other defense responses in Arabidopsis (Vailleauet al., 2002). Reduction of MYB30 transcription also alters ABAand BR signaling, suggesting that MYB30 is a regulator ofphytohormone crosstalk (Raffaele and Rivas, 2013). More re-cently, PopS, a type III effector from the bacterial pathogenRalstonia solanecearum, has also been found to suppress SA-dependent defenses in tomato roots and stems (Jacobs et al.,2013). Together, these examples show that independentlyevolved effectors from diverse pathogens target the SA path-way to promote disease.

Pathogen effectors that suppress SA signaling without af-fecting SA biosynthesis are also known. For example, Ha-RxL96and Ps-Avh163, the two RXLR secretion motif–containing ef-fectors from the oomycete downy mildew–causing pathogenHyaloperonospora arabidopsidis and root rot–causing patho-gen Phytophthora sojae, respectively, suppress the pathogen-mediated induction of SA marker genes, including PR1, whenexpressed in Arabidopsis. Transgenic expression of these effec-tors also causes increased susceptibility to H. arabidopsidis anddecreased MAMP-triggered callose deposition but does notlead to increased SA production, suggesting that these ef-fectors act independently or downstream of the SA bio-synthesis pathway (Anderson et al., 2012). Effectors in theconserved effector loci of P. syringae, including AvrE and hopP-toM (or HopM1), are thought to act redundantly to promote

Figure 3. Effectors from Diverse Pathogens Indirectly Target NPR1, a Master Regulator of SA Signaling, to Promote Disease Development.

An exopolysaccharide produced by the necrotrophic fungus B. cinerea (the causative agent of the gray mold disease) activates SA signaling viaa tomato NPR1 homolog to exploit the antagonistic crosstalk between SA and JA signaling (El Oirdi et al., 2011). Victorin, a toxin produced by thenecrotrophic fungus C. victoriae (the causative agent of Victoria blight disease) indirectly targets NPR1 by binding to TRX-h5, which is required for thenuclear localization of NPR1 (Tada et al., 2008). The 2b protein of CMV targets NPR1 to exploit SA-JA antagonism, while the CMV P6 protein interfereswith the nuclear localization of NPR1 to suppress SA and activate JA signaling (Lewsey et al., 2010; Love et al., 2012). Syringolin A, a toxin andproteasome inhibitor produced by the bacterial pathogen P. syringae pv syringae, has been proposed to inhibit the degradation of NPR1 (Schellenberget al., 2010), which is required for the activation of SA-mediated defenses (Spoel et al., 2009). Unrelated effectors from bacterial (e.g., P. syringae), viral(e.g., Geminivirus), and oomycete (e.g., H. arabidopsidis) pathogens interact with CSN5 (Mukhtar et al., 2011), which in turn interacts with NIMIN1(Weigel et al., 2005), a regulatory protein and interacting partner of NPR1. See text for details.

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disease by suppressing SA-dependent callose deposition andpromoting cell necrosis, allowing increased bacterial proliferationin the P. syringae necrotrophic phase (Table 1) (DebRoy et al.,2004). HopM1 has also been shown to suppress callose depositionvia both SA-dependent and -independent mechanisms (Genget al., 2012). More recently, PR1 induction triggered by the non-host microorganism P. syringae pv phaseolicola in Arabidopsis hasbeen shown to be suppressed by P. syringae DC3000 HopM1 butindependently of SA signaling (Gangadharan et al., 2013).

SA is also required for resistance against plant parasiticnematodes, such as the sugar beet cyst nematode (Heteroderaschachtii) in Arabidopsis (Wubben et al., 2008). The effector10A06 secreted into host cells by H. schachtii disrupts poly-amine metabolism and SA signaling. Arabidopsis plants ex-pressing 10A06 show reduced PR1 expression, increasedsusceptibility to H. schachtii, and bacterial and viral pathogens.10A06 directly binds to Arabidopsis SPDS2 (SPERMIDINESYNTHASE2), a polyamine biosynthetic enzyme, and upregu-lates SPDS2 mRNA levels and enzymatic activity. Arabidopsisplants overexpressing SPDS2 show enhanced susceptibility toH. schachtii, but exactly how altered polyamine levels compro-mise SA defenses is yet to be elucidated (Hewezi et al., 2010).Several species of plant parasitic nematodes also producechorismate mutases, even though they lack other componentsof the shikimate pathway. This suggests that nematodes mayalso have evolved the ability to disrupt host SA biosyntheticpathways during their interaction with plants (Haegeman et al.,2012).

NPR1, A PHYTOHORMNE SIGNALING HUB INDIRECTLYTARGETED BY PATHOGEN EFFECTORS

NPR1 is a key regulator of the SA pathway in Arabidopsis and isfunctionally conserved in diverse plant species (reviewed inPajerowska-Mukhtar et al., 2013). NPR1 and its paralogs NPR3and NPR4 in Arabidopsis recently have been proposed to be SAreceptors (Fu et al., 2012; Wu et al., 2012). In the absence ofelicitation, NPR1 is mainly sequestered in the cytoplasm as anoligomeric complex. In response to elevated SA levels triggeredby pathogen challenge, NPR1 is reduced to its monomeric formand is translocated to the nucleus where it interacts withTGA-bZIP transcription factors, leading to activation of SA-dependent defense gene expression and SAR (Mou et al., 2003;Tada et al., 2008; Pajerowska-Mukhtar et al., 2013). NPR3 andNPR4, which encode proteasomal adaptor proteins, regulateproteasome-mediated turnover of NPR1 in an SA-dependentmanner. In unelicited cells, NPR1-mediated defenses are keptunder wraps by continuous degradation of NPR1 by NPR4. Inresponse to increased levels of SA, NPR4-mediated turnover ofNPR1 is inhibited, and this allows the activation of SAR (Fu et al.,2012). A second model of SA perception suggests that NPR1itself binds SA, leading to the disassembly of the cytoplasmicoligomeric complex and conformational changes that allowNPR1 activation (Wu et al., 2012). NPR1 also interacts withregulatory proteins such as NIMIN1 (NIM1 INTERACTING1),which regulates SA-dependent defenses (Weigel et al., 2005).While the nuclear localization of NPR1 is required for the regu-lation of SA-dependent defenses, the cytoplasmic form of NPR1

plays a key role in the regulation of SA-JA antagonism (Spoelet al., 2003).The elaborate defense-related functions performed by NPR1

make this protein an attractive effector target. Surprisingly,so far no pathogen effector directly targeting NPR1 has beenreported. However, emerging evidence suggests that NPR1function may be indirectly targeted by diverse pathogens (Figure3). For instance, the bacterially secreted proteasome inhibitorsSylA and XopJ mentioned above have been proposed to in-hibit the proteasome-mediated degradation of phosphorylatedNPR1, thereby diminishing its cotranscriptional activity withinthe SA signaling pathway (Schellenberg et al., 2010; Üstün et al.,2013).An intriguing tale of evolutionary one-upmanship involving

NPR1 is the interaction of Arabidopsis with the necrotrophicfungal pathogen Cochliobolus victoriae (Figure 3). LOV1 (LOCUSORCHESTRATING VICTORIN1) is a CC-NB-LRR (COILEDCOIL-NUCLEOTIDE BINDING-LEUCINE RICH REPEAT) proteinthat presumably evolved as a guard protein or R protein againstan unknown pathogen but has been exploited by C. victoriae topromote disease. Victorin, a mycotoxin effector produced by thefungal pathogen C. victoriae, binds to the active site of TRX-h5(THIOREDOXIN-h5; Lorang et al., 2012), a thioredoxin im-plicated in pathogen and SA-mediated reduction of NPR1oligomers to NPR1 monomers in the cytosol (Tada et al., 2008).In lov1 mutants, the TRX-h5–victorin interaction results in re-duced SA-mediated defenses and increased susceptibility tothe biotrophic pathogen P. syringae pv maculicola, similarly towhat is observed in npr1 plants. In wild-type plants, victorin-bound TRX-h5 colocalizes with LOV1 and is required for LOV1activation. Given the importance of TRX-h5 in the reduction ofNPR1 and activation of SA responses, it was proposed thatTRX-h5 is guarded by LOV1 (Figure 3). However, inappropriateLOV1 activation leads to cell death, which promotes C. victoriaedisease (Lorang et al., 2012, 2007).The nuclear effector Ha-RxL44 from the oomycete downy

mildew pathogen H. arabidopsidis has recently been shown tointeract with the mediator subunit MED19a (MEDIATOR19a) andmodulate SA-mediated immunity in Arabidopsis. The RxL44-MED19a interaction leads to the proteasome-dependent deg-radation of MED19a and reduced expression of SA-dependentdefenses (Caillaud et al., 2013). Indeed, the Mediator complex,which fine-tunes transcription by facilitating the interaction be-tween DNA-bound transcription factors and RNA polymerase II(reviewed in Kidd et al., 2011a), has recently emerged as a reg-ulator of plant defense. The MED25 subunit of the ArabidopsisMediator complex has been shown to be an interaction partnerof several defense-related transcription factors such as ERF1(ETHYLENE RESPONSE FACTOR1), ORA59 (OCTADECANOIDRESPONSIVE ARABIDOPSIS AP2/ERF59), and MYC2 (Çeviket al., 2012). A few other subunits of the Mediator complex alsoplay important roles in phytohormone-regulated expression ofplant defense genes and disease resistance (Dhawan et al.,2009; Kidd et al., 2009; Canet et al., 2012; X. Zhang et al., 2012;Zhang et al., 2013; Lai et al., 2014). Effectors from animalpathogens, and in particular viruses, often target Mediatorsubunits to disrupt cellular homeostasis (Yamamoto et al.,2009). Given defense-related functions performed by the plant

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Mediator complex, it is expected that plant pathogens havesimilarly evolved strategies to target Mediator subunits to alterphytohormone pathways.

(COP9 SIGNALOSOME5), a protein targeted by diverseeffectors (Mukhtar et al., 2011; discussed below), interacts withNIMIN1 and NIMIN2, which in turn interact with NPR1 (Weigelet al., 2005), suggesting that CSN5-NIMIN1 interaction may af-fect NPR1-regulated defense responses (Figure 3). Finally, theP6 protein of cauliflower mosaic virus inhibits SA-dependentdefenses while enhancing JA-dependent defenses by affectingNPR1 function. Arabidopsis plants transgenically expressing P6show increased susceptibility to P. syringae but increased re-sistance to Botrytis cinerea, which is sensitive to JA-dependentdefenses. P6 is thought to act by altering the expression and lo-calization of NPR1 (Figure 3) as P6 expressing plants accumulatehigh levels of NPR1 in the nucleus even in unelicited plants. Thus,it was proposed that an inactive form of NPR1 disrupts NPR1-mediated SA defense gene transcription in the presence of apathogen that activates SA signaling (Love et al., 2012).

EFFECTOR-MEDIATED MANIPULATIONOF THE JA PATHWAY

Plant defense responses regulated by JA promote resistanceagainst necrotrophic pathogens and herbivorous insects (re-viewed in Glazebrook, 2005; Kazan and Manners, 2008; Mengiste,2012). JA signaling can also promote susceptibility to viruses (Okaet al., 2013) as well as biotrophic and hemibiotrophic pathogens,which have evolved effectors to hijack this pathway and topromote disease. Disruption or activation of JA signaling bysuch pathogens often promotes disease by exploiting JA-SAantagonism. Examples of key effectors known to target com-ponents of JA signaling are outlined in the section on SA-JAantagonism below.

Effectors Targeting JA Signaling

Activation of JA pathway promotes susceptibility to P syringae inArabidopsis. One of the P. syringae effectors involved in alteringJA signaling in the host is the type III effector AvrB, a kinase-likeprotein that activates JA signaling (Table 1). AvrB associates withRAR1, which encodes a critical defense signaling component(Shang et al., 2006). AvrB also phosphorylates MPK4, a mitogen-activated protein kinase that acts as a positive regulator of JAsignaling. An avrB mutant unable to phosphorylate MPK4 fails toinduce the expression of the JA marker gene PDF1.2. Similarly,AvrB was unable to elicit PDF1.2 expression in mpk4 mutantplants, suggesting that MPK4 is required for AvrB-mediatedpromotion of JA signaling. AvrB also interacts with the guardprotein RIN4 (RPM-INTERACTING4), which acts downstream ofMPK4 to promote JA signaling (Cui et al., 2010). Finally, AvrB-mediated defense suppression seems to require the JA receptorCOI1 (CORONATINE INSENSITIVE1) as overexpression of AvrB inthe coi1 mutant background fails to enhance susceptibility toP. syringae (Shang et al., 2006). Thus, AvrB seems to target the JApathway redundantly.

The JA pathway also promotes susceptibility to the rootinfecting hemibiotrophic fungus Fusarium oxysporum based on

the analysis of Arabidopsis loss-of-function mutants coi1, myc2,and pft1/med25, all of which show increased resistance to thispathogen (Anderson et al., 2004; Kidd et al., 2009; Thatcheret al., 2009). The F. oxysporum effector Fo-SIX4 (SECRETED INXYLEM4) contributes to F. oxysporum disease developmentwhen transgenically expressed in Arabidopsis, whereas six4mutants show reduced virulence on Arabidopsis (Thatcher et al.,2012a). Arabidopsis plants inoculated with six4 mutants exhibita reduced induction of JA-responsive genes, suggesting thatSIX4 promotes pathogen virulence via the host JA pathway(Thatcher et al., 2012a).Two recent studies revealed that bioactive JAs are produced

by tomato- and Arabidopsis-infecting F. oxysporum isolates(Brodhun et al., 2013; Cole et al., 2014). The tomato-infectingF. oxysporum f. sp lycopersici produces JAs using a lipoxygenaseenzyme related to that found in plants, suggesting that JA bio-synthesis in pathogenic fungi occurs via a pathway similar tothat in plants (Brodhun et al., 2013). The Arabidopsis-infectingF. oxysporum strains F. oxysporum f. sp conglutinans andF. oxysporum f. sp matthioli produce bioactive JAs (e.g., JA-isoleucine) (Cole et al., 2014), and Arabidopsis JA-insensitivemutants show increased resistance against these fungi. Incontrast, JA-insensitive Arabidopsis and tomato mutants do notshow any altered resistance against the JA nonproducingstrains F. oxysporum f. sp raphani and F. oxysporum f. splycopersici, respectively (Cole et al., 2014). It was suggested thatfungally produced JAs in the roots activate the JA pathway topromote symptom development in aboveground part of theplant (Thatcher et al., 2009). Several other fungi (Miersch et al.,1999; Tsukada et al., 2010) are capable of producing JA-likeoxylipins, but the biosynthesis pathway and known action ofthese oxylipins on host plants is elusive.In contrast to JA-mediated susceptibility to certain hemi-

biotrophic pathogens, the JA pathway provides resistance tovarious necrotrophic fungal pathogens, some of which haveevolved abilities to suppress this pathway. For instance, SSITL(SCLEROTINIA SCLEROTIORUM INTEGRIN-LIKE) protein, asecretory effector produced by the necrotrophic fungal patho-gen S. sclerotiorum, suppresses JA-dependent defenses (Zhuet al., 2013). The mechanism by which SSITL suppresses JA-dependent defense is currently unknown. However, it was pro-posed that SSITL might mimic plant integrin-like proteins (e.g.,NONRACE-SPECIFIC DISEASE RESISTANCE1 [NDR1]) in-volved in plant defense (Zhu et al., 2013) to interfere with hostresistance. Further supporting the roles of NDR1-like proteins inplant defense, P. syringae effectors AvrB2 and AvrD1 directlyinteract with a soybean (Glycine max) NDR1-like protein calledGmNDR1a (Selote et al., 2014).Plant viruses have also evolved effectors targeting the JA

pathway. For instance, the C2 protein from the geminivirusTomato yellow leaf curl virus and Tomato yellow leaf curl Sardiniavirus or the homologous protein L2 from Beet curly top virus areviral pathogenicity factors that interact with the ArabidopsisCSN5 (Lozano-Durán et al., 2011). This interaction interfereswith the CSN5-mediated ubiquitination process, which is knownto be an integral part of the JA signaling pathway (Hind et al.,2011). Arabidopsis plants expressing C2/L2 show reduced JA-mediated defenses that seem to confer resistance against these

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viruses (Lozano-Durán et al., 2011). Other viral effectors thateither manipulate SA-JA crosstalk or are exploited by insectpests are discussed below.

EFFECTOR-MEDIATED MANIPULATION OFSA-JA CROSSTALK

As shown in Figure 2, extensive crosstalk is known to occur be-tween phytohormone signaling pathways (Kazan and Manners,2008, 2012; Robert-Seilaniantz et al., 2011; De Vleesschauweret al., 2012; Naseem and Dandekar, 2012; B. Kim et al., 2013;Nahar et al., 2013). Of these, the antagonistic crosstalk betweenthe SA and JA pathways is particularly well characterized (Thaleret al., 2012; Gimenez-Ibanez and Solano, 2013; Lyons et al.,2013a). Given that SA and JA pathways are effective againstdifferent groups of pathogens and insects, the antagonisticcrosstalk between these two pathways may have evolved toenable the plant to invest greater resources in one of the path-ways at a time, depending on the type of the attacker. However,pathogens exploit this crosstalk to rewire host defenses for theirown benefits (Spoel and Dong, 2008; Robert-Seilaniantz et al.,2011; Pieterse et al., 2012; Denancé et al., 2013; Grant et al.,2013). Below, we briefly review effector-mediated mechanismsused by diverse microbes that interfere with SA-JA crosstalk.

Bacterial Effectors

Arabidopsis and tomato mutants impaired in JA signaling suchas coi1 (Feys et al., 1994; Kloek et al., 2001) and jasmonateinsensitive1 (Laurie-Berry et al., 2006) exhibit enhanced re-sistance to P. syringae, suggesting that JA promotes suscepti-bility to P. syringae. Promotion of host JA signaling by P.syringae effectors enhances disease by antagonizing SA-baseddefenses (discussed further below) and by SA-independentpathways (Laurie-Berry et al., 2006).

The phytotoxin COR produced by P. syringae promotes vir-ulence by manipulating SA-JA crosstalk (reviewed in Xin and He,2013) (Table 1). COR, a structural mimic of JA-Ile, binds to theJA coreceptor COI1 and activates the JA pathway (Weiler et al.,1994). The COR-bound COI1 receptor complex (SCFCOI1-CORE3 ubiquitin ligase) degrades JASMONATE ZIM DOMAIN (JAZ)proteins acting as negative regulators of the JA pathway andallows the master regulator MYC2 to activate JA-responsivegene expression while attenuating SA responses and SA accu-mulation (Katsir et al., 2008; Melotto et al., 2008; Lee et al., 2013;Zheng et al., 2012; reviewed by Kazan and Manners, 2013). CORpromotes susceptibility to P. syringae, and P. syringae mutantsdefective in COR production cause reduced disease on Arabi-dopsis plants. However, when inoculated onto Arabidopsismutantscompromised in SA biosynthesis or signaling, cor- P. syringaeaccumulates to a similar level as the wild type strain, supporting thehypothesis that COR promotes disease by suppressing SA sig-naling (Brooks et al., 2005). Additionally, cor- P. syringae strains areunable to inhibit MAMP-induced stomatal closure mediated by SAand ABA (Melotto et al., 2006).

Interestingly, in addition to previously described suppressiveeffects of this toxin on SA signaling through JA-SA antagonism,COR also seems to interfere directly with SA-independent

defenses. Thus, P. syringae COR-deficient mutants elicit in-creased callose deposition relative to the wild-type strain, evenin SA-deficient plants, suggesting that COR inhibits callosedeposition via an SA-independent pathway. Furthermore, CORcould inhibit callose deposition and promote bacterial growthindependently of COI1. COR-mediated inhibition of callose bio-synthesis seems to occur through suppression of indoleglucosinolate biosynthesis via a PENETRATION2-dependentpathway, but precise targets for COR other than COI1 are yetto be determined (Millet et al., 2010; Geng et al., 2012).The P. syringae type III effector HopZ1a, a cysteine protease/

acetyltransferase, activates the JA pathway by targeting JAZproteins (Table 1), which act as repressors of JA signaling.During bacterial infection, HopZ1a directly binds to and acety-lates JAZ proteins, and this leads to their degradation in a COI1-dependent manner (Figure 4). This results in the activation of JAand repression of SA-dependent transcription (Jiang et al.,2013). Interestingly, HopX1, another P. syringae effector withcysteine protease activity (Table 1), also physically interacts withmost JAZ proteins via their ZIM domains, and this promotes JAZdegradation and the activation of JA signaling, which in turnpromotes susceptibility to P. syringae by downregulating SAresponses (Gimenez-Ibanez et al., 2014). The P. syringae strainsecreting HopX1 does not produce COR, suggesting that thispathogen has evolved multiple strategies to interfere with SA-JAantagonism of the host plant (Gimenez-Ibanez et al., 2014).

Fungal and Oomycete Effectors

b-(1,3)(1,6)-D-glucan, an exopolysaccharide (EPS) effector se-creted by B. cinerea, was the first fungal effector shown tocontribute to disease development by exploiting the SA-JAantagonism. Tomato plants pretreated with this EPS showedincreased susceptibility to B. cinerea, repression of JA-regulateddefense genes encoding protease inhibitors, and increasedaccumulation of SA. Since NPR1 is required to promote disease,it was proposed that EPS acts by activating the SA pathway,which then represses JA signaling through NPR1 (El Oirdi et al.,2011).The COP9 signalosome, a hub protein targeted by multiple

effectors, as described earlier, interacts with COI1 to regulate itsactivity and the JA response (Feng et al., 2003). Silencing ofthe COP9 subunit CSN5 in tomato causes a reduction in JA lev-els and JA-responsive gene expression, resulting in increasedsusceptibility to the insect pest Manduca sexta and the ne-crotrophic fungus B. cinerea (Hind et al., 2011). Althoughthe expression of genes encoding pathogenesis-related SA-responsive genes such as PR-1a, PR2-a, and PR-5 are in-creased in CSN5 silenced plants, SA levels and response totobacco mosaic virus (TMV) remains unchanged, suggesting thatin this case, JA inhibition can reduce SA defenses independentlyof SA biosynthesis (Hind et al., 2011).

Insect, Viral, and Nematode Effectors

Similar to pathogenic microbes, herbivores manipulate SA-JAcrosstalk, although currently very little is known how this isachieved mechanistically. For example, Colorado potato beetle

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larvae (Leptinotarsa decemlineata) secrete bacteria onto the leafwhile feeding. This induces SA-mediated defense and antago-nizes the JA pathway, allowing enhanced Colorado potatobeetle larval growth, although actual effectors involved in thisphenomenon are unknown. Attenuation of the JA defense re-sponses are dependent on SA-JA antagonism since the bacteriafail to disrupt JA defenses in NahG plants (Figure 5) (Chunget al., 2013). More recently, SA has been detected in the mucussecreted by the slug Deroceras reticulatum, suggesting that theslug exploits SA-JA antagonisms to attenuate JA-dependentdefenses that are effective against this herbivore (Kästner et al.,2014).

It is remarkable that a number of viruses exploit the antago-nistic interactions between SA and JA pathways either for theirown benefit or the benefit of insect vectors that transmit them.For instance, tobacco spotted wilt virus (TSWV), which is vec-tored by western flower thrips (WFT) Frankliniella occidentalis,promotes WFT infection and, thus, virus transmission by exploitingJA-SA antagonism. TSWV induces increased SA levels and SA-mediated defenses, leading to a suppression of JA-mediated

defenses. Consequently, WFT prefer feeding on TSWV-infectedplants because the JA pathway provides resistance to WFT(Figure 5) (Abe et al., 2012). However, in contrast to the previouslydiscussed P6 effector of cauliflower mosaic virus, which maymodulate SA-JA antagonism via NPR1, the mechanism involvedin TSWV-mediated modulation of this phenomenon is currentlyunknown.These examples suggest exploiting SA-JA antagonism may

be widespread among pests and pathogens. Adding to thecomplexity, however, pathogen effectors that suppress both JAand SA pathways are also known. For instance, the calreticulinMi-CRT secreted by the root-knot nematode Meloidogyne in-cognita plays a role as a suppressor of both JA- and SA-dependent defenses. Arabidopsis plants expressing the secretedapoplastically located form of Mi-CRT show increased sus-ceptibility to bothM. incognita and the root-infecting oomycetepathogen Phytophthora parasitica and a suppression of PTI.In response to MAMP treatment, Mi-CRT–expressing Arabi-dopsis plants show attenuated induction of both SA and JApathways (Jaouannet et al., 2013). Although possible plant

Figure 4. Pathogen Effectors Target Phytohormone Repressors to Activate Phytohormone Pathways.

Under low phytohormone levels, JA, IAA, and GA phytohormone signaling pathways are suppressed by JAZ, AUX/IAA, and DELLA repressors, re-spectively. Binding of JA, IAA, and GA to their respective receptors COI1, TIR1, and GID1 leads to proteasome-dependent degradation of repressorsand subsequent activation of the respective signaling pathways. HopZ1a and HopX1, type III effectors from the pathogenic bacterium P. syringae,physically interact with JAZ repressors to activate the JA pathway (Jiang et al., 2013; Gimenez-Ibanez et al., 2014), which confers susceptibility to thispathogen. Similarly, the type III effector AvrRpt2, a cysteine protease, stimulates proteasome-mediated degradation of AUX/IAA repressors to activatethe auxin pathway (Cui et al., 2013), which directly and/or indirectly (e.g., in crosstalk with the SA pathway) provides susceptibility to this pathogen.Similarly, diverse microbes target DELLA proteins to manipulate plant defense and development (Navarro et al., 2008; Jacobs et al., 2011), althougheffectors that interact with DELLA repressors are currently unknown. See text for additional information.

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targets of Mi-CRT are currently unknown, it was suggestedthat the Ca binding properties may be important for defense-suppressing effects of this protein (Jaouannet et al., 2013).

HIRING A HITMAN: INSECT PESTS EMPLOY OBLIGATEPATHOGENS AND SYMBIOTIC BACTERIA TOATTENUATE JA-DEPENDENT DEFENSES

As stated above, the JA pathway confers resistance againstherbivorous insects. One of the remarkable strategies adoptedby such insects to disable JA-dependent defenses is to employobligate pathogens that are able to suppress JA-dependentdefenses. Plant viruses are obligate pathogens often transmittedby insects and exploit host cells to reproduce. During theirinteraction with plants, viruses employ effector molecules tomanipulate host phytohormone signaling (Figure 5). For in-stance, the tomato yellow leaf curl China virus (TYLCCNV) andtobacco curly shoot virus (TbCSV) are whitefly (Bemisia tabaci Bbiotype)–transmitted viruses that cause disease on tomato and

other crops. When placed on TYLCCNV- or TbCSV-infectedtobacco plants, the invasive B. tabaci B biotype shows in-creased growth rates, compared with when placed on un-inoculated plants (Jiu et al., 2007). The viral satellite bC1 proteinis required for TYLCCNV pathogenicity. bC1-expressing Arabi-dopsis plants show attenuated expression of JA-responsivedefense genes such as PDF1.2 and PR4 and reduced pro-duction of JA in response to wounding (Yang et al., 2008;Salvaudon et al., 2013). No experimental evidence that JA isrequired for defense against TYLCCNV currently exists. How-ever, JA inhibits B. tabaci B survival (T. Zhang et al., 2012),supporting the view that the whitefly employs TYLCCNV toprotect itself from JA-dependent defenses.The 2b RNA silencing suppressor from cauliflower mosaic

virus (CMV) is another viral effector that interferes with the JAsignaling pathway, seemingly to act as a decoy to promote itsown transmission by the aphid Myzus persicae (Figure 5). Arabi-dopsis plants expressing 2b show reduced expression of JA-responsive genes upon CMV infection (Lewsey et al., 2010),

Figure 5. Insect Pests Employ Effectors from Obligate Pathogens to Interfere with Host Phytohormone Pathways.

Diverse insects have adopted common strategies in complex tritrophic (insect-microbe-plant) interactions to disable host jasmonate-dependentdefenses that confer resistance to insect pests. See text for additional information.

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leading to the hypothesis that 2b-mediated suppression of JA-dependent defenses is beneficial for the aphid. Indeed, aphidsurvival is increased on tobacco (Nicotiana tabacum) plants in-fected with CMV, whereas it is reduced on tobacco plants infectedwith a CMV strain lacking the 2b protein (Ziebell et al., 2011).

Insects also exploit phytoplasma, which are obligate bacterialpathogens, to interfere with JA-dependent defenses. SecretedAY-WB protein 11 (SAP11), an effector produced by the AsterYellows Witches’ Broom (AY-WB) phytoplasma, interferes withJA biosynthesis in Arabidopsis by binding and destabilizing classII CIN-TCP (CINCINNATA-RELATED-TEOSINTE BRANCHED1,CYCLOIDEA, PCF) transcription factors acting as positive regu-lators of the LOX2 (LIPOXYGENASE2) gene involved in JA bio-synthesis (Schommer et al., 2008) (Figure 5). Arabidopsis plantstransgenically expressing SAP11 as well as wild-type plants in-fected with AY-WB show downregulated LOX1 expression andreduced JA levels when wounded. Consequently, the leafhopperpestMacrosteles quadrililineatus, which transmits the phytoplasma,produces more progeny on AY-WB–infected, SAP11-expressing orlox2-silenced plants (Sugio et al., 2011) (Figure 5). These examplessuggest that independently evolved complex tritrophic interactions,where insects exploit microbes to disarm plant defenses whilemicrobes (e.g., viruses) gain increased dispersal to host plantswhich may not be possible in the absence of an insect.

EFFECTOR-MEDIATED MANIPULATION OFTHE AUXIN PATHWAY

The plant hormone auxin, which regulates many aspects of plantgrowth and development, is also increasingly associated withplant biotic and abiotic stress tolerance (Kazan and Manners,2009; Kazan, 2013) (Figure 6). Auxin promotes susceptibility todiverse pathogens including P. syringae, Xanthomonas oryzae,and Magnaporthe oryzae. Several gall-producing bacteria se-crete pathogen-synthesized auxins and cytokinins into the hostto enable tumor or gall production and infection (reviewed in Fuand Wang, 2011; Patten et al., 2013; see below). Conversely,auxin signaling promotes resistance to the necrotrophic fungalpathogens B. cinerea, Plectosphaerella cucumerina, and Alter-naria brassicicola (Llorente et al., 2008). However, the effect ofdifferent auxins on different B. cinerea strains seems to be dif-ferent (González-Lamothe et al., 2012). Suppression of the SApathway by auxin during the Arabidopsis–P. syringae interactionhas been reported (Wang et al., 2007; Iglesias et al., 2011).However, more recent work indicates that auxin-mediated sus-ceptibility to P. syringaemay be independent from auxin-mediatedsuppression of the SA pathway (Mutka et al., 2013). Auxin sig-naling may also affect disease development through synergisticcrosstalk with JA signaling (Kazan and Manners, 2009; Kidd et al.,2011b; Qi et al., 2012), although additional work is required todissect these complex phytohormone interactions.

Effectors Targeting Auxin Biosynthesis or Signaling

The activation of auxin signaling by pathogens often seems tobe achieved by effector-mediated disruption of AUXIN/INDOLEACETIC ACID (AUX/IAA) proteins that act as repressors of theauxin signaling pathway (Dharmasiri et al., 2005). Auxin signaling

Figure 6. Pathogens Manipulate the Signaling and Transport Pathway ofAuxin to Promote Disease on Plants.

Top panel: Sensing of flg22, a conserved MAMP from the bacterial pathogenP. syringae, activates Arabidopsis miR393, which then attenuates the ex-pression of auxin receptor genes such as TIR1 to suppress the auxin pathway,which promotes susceptibility to this bacteria (Navarro et al., 2006). In return,AvrRpt2, a type III effector from P. syringae, activates the auxin pathway bypromoting 26S proteasome-mediated degradation of AUX/IAA repressors (Cuiet al., 2013). The TAL effector AvrBs3 from the pathogenic bacteria X. cam-pestris pv vesicatoria activates auxin responses by binding to the promoter ofa transcription factor involved in the regulation of auxin responses (Kay et al.,2007). Finally, the effector TENGU produced by insect-transmitted phyto-plasma pathogens suppresses auxin responses to alter plant developmentduring disease progression (Hoshi et al., 2009). Bottom panel: PSE1, an RXLReffector secreted by P. parasitica, interferes with root auxin transport duringpathogenesis by altering the distribution of PIN4 and PIN7 auxin efflux pro-teins (Evangelisti et al., 2013). The effector 19C07 produced by cyst nema-todes interacts with the Arabidopsis auxin transport protein LAX3 to exploitroot auxin transport processes and induce feeding structures. The root imageshown in the bottom panel is from an Arabidopsis seedling expressing theauxin reporterDR5-GUS construct (Ulmasov et al., 1997). The blue color (GUSstaining) corresponds to auxin rich root regions. See text for details.

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is downregulated during the defense response to P. syringae.The MAMP flg22 induces a host microRNA (miR393), whichdownregulates the auxin receptor TIR1 (TRANSPORT INHIBITORRESPONSE1) and related auxin receptors ABF2 (AUXIN SIG-NALING F-BOX PROTEIN1) and ABF3 (Figure 6, top panel)(Navarro et al., 2006). Upon auxin binding, auxin receptors me-diate the removal of AUX/IAA proteins (Dharmasiri et al., 2005).Therefore, downregulation of auxin receptors during defense re-sults in the stabilization of AUX/IAA proteins and the suppressionof the auxin pathway conferring susceptibility to P. syringae.

The P. syringae type III effector AvrRpt2 encodes a cysteineprotease that interferes with the auxin pathway in Arabidopsis(Table 1). AvrRpt2-expressing Arabidopsis plants exhibit in-creased sensitivity to exogenously applied auxin and increasedendogenous free auxin levels during pathogenesis (Chen et al.,2007). AvrRpt2 also activates the auxin pathway by promotingthe proteasome-dependent destabilization of AUX/IAA proteinsand promotes susceptibility to this pathogen (Figure 6) (Cuiet al., 2013). Similarly, TMV infection activates host auxin sig-naling by targeting AUX/IAA proteins. The TMV replicase proteininteracts directly with AUX/IAA family members in Arabidopsisand tomato, disrupting their subcellular location and stability.Plants infected with TMV mutants compromised in their ability tointeract with AUX/IAA targets accumulate less virus and showreduced disease symptoms. Furthermore, Arabidopsis IAA26(INDOLE-3-ACETIC ACID INDUCIBLE26) knockdown mutantsdisplay developmental alterations that are similar to those in-duced by TMV (Padmanabhan et al., 2005, 2008), further sup-porting the idea that viral effectors activate auxin signaling topromote disease symptoms.

Bacterial effectors also target auxin signaling components.For instance, to successfully infect pepper plants, X. c. pvvesicatoria secretes the type III effector AvrBs3, which encodesa TAL (TRANSCRIPTION ACTIVATOR-LIKE) protein. AvrBs3contains a DNA binding domain and regulates auxin responsivegenes by binding their promoters (Figure 6, top panel) (Maroiset al., 2002; Kay et al., 2007). Presumably, this increases thevulnerability of pepper to infection by this pathogen.

Auxin levels also increase during colonization of wheat (Triti-cum aestivum) plants by the stem rust fungus Puccinia graminisf. sp tritici (Pgt) (Yin et al., 2014). Increases in auxin levels cor-relate with the induction of the Pgt gene Pgt-IaaM in fungalhaustorial cells. Pgt-IaaM encodes a putative tryptophan2-monooxygenase involved in the production of the IAA precursorindole-3-acetamide (IAM). Interestingly, transient inactivationof Pgt-IaaM by host-induced gene silencing compromises fun-gal virulence, while overexpression of Pgt-IaaM in Arabidopsisleads to developmental alterations and reduced resistance toP. syringae, suggesting that Pgt-IaaM–mediated auxin productionacts as a virulence factor for the rust fungus (Yin et al., 2014).

Phytoplasma, which causes witches’ broom disease charac-terized by severe developmental alterations in infected plants,also appears to alter the plant’s hormone balance. TENGU,a phytoplasma effector, contributes to symptom development bysuppressing the auxin pathway (Figure 6, top panel) (Hoshi et al.,2009). Several parasitic nematodes including the root knot nem-atode Meloidogyne javanica (Lambert et al., 1999), H. schachtii(Vanholme et al., 2009), and the soybean cyst nematode

Heterodera glycines (Bekal et al., 2003) secrete chorismate mu-tase, an enzyme implicated in SA degradation, as discussedabove (Djamei et al., 2011), into the host cells. Soybean hairyroots expressing the M. javanica chorismate mutase (MjCM-1)show altered root morphology that can be rescued by exogenousauxin treatment, suggesting that MjCM-1 reduces auxin levels inthe roots. How this might promote nematode infection requiresfurther investigation (Doyle and Lambert, 2003).Diverse bacterial and fungal pathogens are capable of pro-

ducing auxins via multiple pathways (reviewed in Reineke et al.,2008; Fu and Wang, 2011; Spaepen and Vanderleyden, 2011;Tsavkelova et al., 2012; Patten et al., 2013). A nitrilase enzymefound in P. syringae pv syringae catalyzes the production ofauxin from indoleacetonitrile, but whether this affects pathogenvirulence is yet to be determined (Howden et al., 2009). Gall ortumor-inducing phytobacteria synthesize and secrete auxinsand cytokinins into the host to facilitate gall initiation and/ordevelopment. Gall-forming bacterial species harbor a horizon-tally transferred gene cluster that controls auxin biosynthesis viathe IAM pathway. Mutants of Pseudomonas savastanoi, thecausal agent of olive and oleander knot, which lack this operon,show reduced auxin biosynthesis and attenuated knot symp-toms on olive plants (Aragón et al., 2014). Pantoea agglomerans(previously known as Erwinia herbicola) pv gypsophilae harborsmachinery to produce auxins via both the IAM and indole-3-pyruvate (IpyA) pathways. These pathways differentially con-tribute to pathogen virulence and infection strategies. WhileP. agglomerans mutants deficient in the IAM pathway exhibitedreduced gall formation, P. agglomerans mutants deficient in theIpyA pathway showed reduced epiphytic colonization (Manuliset al., 1998).Secretion of auxins into the host by Xanthomonas spp and

M. grisea induces host auxin production, increasing susceptibilityto these pathogens (Fu et al., 2011). The root wilt bacterialpathogen R. solanacearum produces auxin and ET (Valls et al.,2006). R. solanacearum mutants lacking components of the Hrptype II secretion system fail to induce root lateral structures ontheir petunia host. Since auxin promotes lateral root production,R. solanacearum–derived auxin may promote this morphologicalchange to facilitate efficient colonization and multiplication ofthe host roots (Zolobowska and Van Gijsegem, 2006).

Effectors Targeting Auxin Transport

Auxin transport plays an integral role in maintaining cell andtissue homeostasis of this phytohormone and diverse patho-gens seem to manipulate host auxin influx and efflux pathwaysto promote disease on plants. For example, the HopM1 effectorfrom P. syringae perturbs auxin transport (Table 1). HopM1binds to and promotes the proteasome-mediated degradationof Arabidopsis MIN7 (HopM INTERACTOR 7), a protein from theADP ribosylation factor guanine nucleotide exchange factorfamily that acts as a regulator of the host vesicle traffickingpathway (Nomura et al., 2006). HopM1 does not show any ho-mology to proteases. Thus, it is thought that HopM1 recruitscomponents of the host proteasome to degrade MIN7 andpromotes defense against P. syringae, possibly by regulating thesecretion of defense-associated proteins (Nomura et al., 2006,

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2011). MIN7 enables PIN1 to efflux auxin (Tanaka et al., 2009),suggesting that degradation of MIN7 by HopM1 may promotedisease via modulation of auxin accumulation.

Another effector that perturbs auxin efflux is PSE1 (PENE-TRATION SPECIFIC EFFECTOR1), an RXLR secretion motif-containing effector from the oomycete pathogen P. parasitica(Figure 6, bottom panel). Arabidopsis plants constitutively ex-pressing PSE1 show increased susceptibility to P. parasitica aswell as developmental alterations similar to those observed inmutants affected in auxin physiology. 2,4-D treatment partiallyrescues the enhanced susceptibility of PSE1-expressing plantsto P. parasitica, suggesting that reduced auxin levels promote P.parasitica infection. The developmental alterations displayed byPSE1-expressing plants such as coiled roots and impaired roothair development were not rescued by exogenous auxin appli-cation but were restored by treatment with 2,3,5-triiodobenzoicacid and N-1-naphthylphthalamic acid, chemical inhibitors ofauxin efflux. Furthermore, PSE1-expressing plants show alteredaccumulation of the two members of the PIN family of auxinefflux proteins, PIN4 and PIN7 at the root apex, suggesting thatPSE1-mediated alterations in root auxin transport is responsiblefor these developmental changes (Evangelisti et al., 2013).

Cyst nematodes, obligate biotrophic parasites that penetrateplant roots and establish specialized feeding structures calledsyncytia, also require the host plant’s auxin signaling andtransport pathways to efficiently colonize plant roots. Arabi-dopsis pin1 plants support reduced cyst formation by the beetcyst nematode H. schachtii (Grunewald et al., 2009). The H.schachtii effector Hs19C07 interacts with the Arabidopsis LAX3(LIKE AUX13) auxin influx transporter and may stimulate its ac-tivity. LAX3 presumably promotes auxin influx into the de-veloping syncytia (Figure 6, bottom panel). However, a directrole for LAX3 in H. schachtii infestation is unclear since lax3plants show similar levels of resistance to wild-type plants (Leeet al., 2011). Recent revelation that many Arabidopsis ARF (auxinresponse factors) transcription factors show distinct expressionpatterns in the synctium is also consistent with the view thatcomponents of host auxin pathway are essential for synctiumdevelopment (Hewezi et al., 2014).

EFFECTOR-MEDIATED MANIPULATION OF THEABA PATHWAY

ABA is the major phytohormone involved in responses to abioticstresses, including drought, salt, and cold (Raghavendra et al.,2010), but also regulates aspects of plant immunity. ABA providessusceptibility to a wide range of pathogens including B. cinerea(Audenaert et al., 2002), F. oxysporum (Anderson et al., 2004),M. grisea (Koga et al., 2004; Yazawa et al., 2012), P. sojae(McDonald and Cahill, 1999), and the bacterial pathogen X. oryzaepv oryzae (J. Xu et al., 2013), while it promotes resistance topathogens such as the rice-infecting fungal pathogen Co-chliobolus miyabeanus (De Vleesschauwer et al., 2010) and theoomycete pathogen Pythium irregular (Adie et al., 2007). ABA-mediated resistance or susceptibility is often thought to bea consequence of crosstalk with defense hormones such as JA,SA, or ET (Anderson et al., 2004; De Vleesschauwer et al., 2010;Z.Y. Xu et al., 2013). During drought stress, ABA promotes

stomatal closure. This response restricts water loss as well asentry of pathogens such as P. syringae into leaves (reviewed inSawinski et al., 2013). The JA analog COR produced by P. syringaeis capable of reverting both pathogen- and ABA-induced stomatalclosure (Melotto et al., 2006). Similarly, X. c. pv campestris canrevert stomatal closure, but the identity of the effector(s) re-sponsible for this process remains elusive (Gudesblat et al., 2009).More recent evidence also implies that an oxylipin-dependent butABA-independent pathway controls stomatal closure during plantdefense against bacterial pathogens (Montillet et al., 2013).ABA both negatively and positively regulates resistance to

P. syringae, depending on the stage of infection. ABA-deficientmutants show increased susceptibility to P. syringae upon sprayinoculation onto Arabidopsis plants, presumably due to the in-hibition of MAMP-triggered stomatal closure (Melotto et al.,2006). On the other hand, ABA-deficient plants show enhancedresistance to syringe-inoculated P. syringae (Thaler and Bostock,2004; de Torres-Zabala et al., 2007), and ABA-treated tomato andArabidopsis plants show increased susceptibility to this pathogen(Mohr and Cahill, 2003; de Torres-Zabala et al., 2007). The dif-ferent effects of ABA on P. syringae were explained based on theproposal that ABA is required to prevent initial infection byP. syringae, but once inside the plant, ABA signaling is hijacked bythe pathogen to maintain a high water potential in the apoplast,which is necessary for P. syringae colony growth (Beattie, 2011).Indeed, ABA concentration increases upon P. syringae infection,and this is dependent on a functioning type III secretion system.The type III effector AvrPtoB (Table 1) seems to be specificallyinvolved in this response as transgenic expression of this effectorprotein in Arabidopsis elevates ABA levels and enhances sus-ceptibility to P. syringae (de Torres et al., 2006; de Torres-Zabalaet al., 2007). Possible mechanisms of how AvrPtoB affects ABAlevels are not clear. However, by increasing ABA levels, P. syringaeseems to antagonize the SA pathway required for resistance to thispathogen (de Torres-Zabala et al., 2009).HopAM1, another type III effector of unknown function produced

by P. syringae, promotes pathogen virulence on plants exposedto water stress (Table 1). HopAM1-expressing Arabidopsis plantsshow enhanced disease symptoms and hypersensitivity to ABA-mediated stomatal closure when infected with P. s. pv maculicola,suggesting that HopAM1 modulates ABA signaling downstream ofABA perception (Goel et al., 2008). The AvrB AvrC domain of theAvrXccC8004 from the bacterial pathogen X. c. pv campestris elicitsABA accumulation by inducing the ABA biosynthesis geneNCED5 (NINE-CIS-EPOXYCAROTENOID DIOXYGENASE5) whenexpressed transgenically in Arabidopsis. Compared with the wild-type strain, an X. c. pv campestris mutant strain deficient inAvrXccC8004 triggers reduced ABA levels when inoculated ontoArabidopsis. Furthermore, exogenous ABA application allowsincreased growth of the AvrXccC8004-deficient strain, sug-gesting that X. c. pv campestris mediated ABA induction pro-motes virulence (Ho et al., 2013).

EFFECTOR-MEDIATED MANIPULATION OF THEETHYLENE PATHWAY

ET is a gaseous hormone that regulates a large number of plantprocesses, including defense against pathogens (Broekaert

Phytohormone Intervention by Pathogens 2297

et al., 2006). ET signaling often works synergistically with JA topromote resistance to necrotrophic pathogens such as B. cinereaand Rhizoctonia solani in Arabidopsis (Thomma et al., 1999) andMedicago, respectively (Anderson et al., 2010). In tomato, the ETpathway inhibits symptom development of the bacterial patho-gens P. syringae and X. c. pv vesicatoria (Lund et al., 1998).However, similar to other phytohormones, the involvement of ETin disease susceptibility, either alone or in combination with otherphytohormones, has also been documented (Chen et al., 2009;Jia et al., 2013; Pantelides et al., 2013; Wang et al., 2013). Inabilityof Arabidopsis and tomato to perceive ET due to a mutation in thereceptor encoding gene ETR1 (ETHYLENE RECEPTOR1) makesthe plants resistant to F. oxysporum (Pantelides et al., 2013).Furthermore, pathogen-mediated activation of ET signaling pro-motes systemic susceptibility to herbivores (Groen et al., 2013),indicating the complexity of signaling crosstalk triggered by dif-ferent attackers.

Arabidopsis flg22 perception activates ET biosynthesis viaMPK6-mediated phosphorylation of the ET biosynthesis enzymeACS (1-AMINOCYCLOPROPANE-1-CARBOXYLIC ACID SYN-THASE) (Liu and Zhang, 2004). MPK6 also interacts withERF104, a transcription factor acting as a positive regulator ofET signaling. It is proposed that flg22 perception results in theloss of MPK6-ERF104 interaction and subsequently allowsERF104 to activate its targets (Bethke et al., 2009). In addition,the expression of the FLS2 (FLAGELLIN SENSING2) gene en-coding a flg22 receptor is controlled by ET signaling regulatorsEIN3 (ETHYLENE INSENSITIVE3) and EIL1 (ETHYLENE-INSENSITIVE3-LIKE1) (Boutrot et al., 2010; Mersmann et al.,2010). Further supporting the importance of ET in basal plantdefense, EIN2, a master regulator of ET signaling, is required forsensitivity to bacterial MAMPs flg22 and elf18 (elongation factor18) (Tintor et al., 2013). Given that PTI triggers ethylene bio-synthesis and signaling in Arabidopsis, it seems somewhatparadoxical that the P. syringae type III effectors AvrPto andAvrPtoB, which are known to repress PTI by targeting MAMPPRRs (as discussed in the next section), promote the expressionof ET biosynthesis and signaling genes and production of ET intomato (Cohn and Martin, 2005) (Table 1).

XopD from X. o. pv oryzae encodes a small ubiquitin-like mod-ifier protease with helix-loop-helix and EAR (ERF-AssociatedAmphiphilic Repression) DNA binding domains (Kim et al.,2008). The latter motif acts as a transcriptional repressor inplants (reviewed in Kazan, 2006). xopd mutants lacking either ofthese domains show reduced virulence, suggesting that XopDrepresses host defenses by repressing defense genes via tran-scriptional repressor activity and/or by degradation of keytranscriptional regulators (Kim et al., 2008). Indeed, as dis-cussed further below, the type III effector XopD from the relatedbacterial species X. c. pv vesicatoria has recently been shown totarget tomato ERF4 (ETHYLENE RESPONSE FACTOR4) tosuppress ET responses (J.G. Kim et al., 2013).

In plants, ET is produced using the 1-aminocyclopropane-1-carboxylic acid pathway (Kende, 1993). Several phytopatho-genic microbes, including R. solanecearum, P. syringae pvsglycinea and phaseolicola, and B. cinerea have evolved alter-native biochemical pathways to produce ET (Weingart andVolksch, 1997; Cristescu et al., 2002; Valls et al., 2006). The

R. solanacearum type III effector RSp1529 is a putative ET formingenzyme. A mutant R. solanacearum strain lacking RSp1529triggers a marked reduction in ET-regulated defense gene ex-pression, but pathogen growth is not affected (Valls et al., 2006).In addition, bacterial wilt symptoms caused by R. solanacearumare reduced in ET signaling mutants, suggesting that R. sol-anacearum–derived ET may be used to activate the host ETsignaling pathway. Although B. cinerea can produce ET (Inomataet al., 2004), a role for B. cinerea–derived ET in manipulating hosthormone homeostasis would seem counterproductive since ETbiosynthesis and signaling promotes resistance to B. cinerea intomato and Arabidopsis (Thomma et al., 1999; Díaz et al., 2002).

EFFECTOR-MEDIATED MANIPULATION OF THECYTOKININ PATHWAY

Although CK have long been implicated in the modulation ofplant defense, currently relatively little is known about theirpossible mechanism of action (Choi et al., 2011; Grosskinskyet al., 2011; Argueso et al., 2012; Reusche et al., 2013). HopQ1,a type III effector from P. syringae, induces CK signaling inArabidopsis to promote disease development (Table 1), and thisseems to be correlated with reduced FLS2 accumulation andattenuated FLS2-mediated defenses, suggesting that effector-mediated increase in host CK levels negatively regulate PTI(Hann et al., 2014). CK treatment of plants also suppresses FLS2accumulation and promotes pathogen susceptibility. HopQ1seems to be conserved in other pathogenic bacteria, such asXanthomonas and Ralstonia (Hann et al., 2014). However, it iscurrently unknown whether HopQ1 homologs in these bacteriawould perform functionally similar roles to HopQ1.CK secreted by biotrophic fungal pathogens alters the sen-

sitivity of tissue to senescence promoting signals (reviewed inWalters and McRoberts, 2006; Walters et al., 2008). Several gall-producing bacteria produce CK and auxins, as previously dis-cussed, to modulate plant development to suit their requirements.For instance, Rhodococcus fascians, the causal agent of leafygall disease, requires CK for disease development (reviewed byStes et al., 2011). The Arabidopsis double mutant ahk3 ahk4defective in CK receptors does not cause leafy gall disease wheninoculated with R. fascians, a CK-producing microbe (Pertry et al.,2009). Some forms of CK synthesized by R. fascians are some-what recalcitrant to host-mediated degradation, allowing themto accumulate in the plant and reprogram development, resultingin disease symptoms (Pertry et al., 2009).

EFFECTOR-MEDIATED MANIPULATION OF THEBRASSINOSTEROID PATHWAY

Given that hormone receptors control a large number of down-stream responses, interfering with hormone receptor functionwould be an efficient approach for a pathogen to disrupt thephytohormone pathway. However, so far only two hormonereceptors, the JA receptor COI1 and the BR coreceptor BAK1(BRI1-ASSOCIATED KINASE1), have been shown to be directtargets of pathogen effectors (Katsir et al., 2008; Shan et al.,2008; Cheng et al., 2011). BAK1 was originally described as

2298 The Plant Cell

a coreceptor for the brassinosteroid receptor BR1 but was sub-sequently found to be associated with the PAMP receptors FLS2and EFR upon PAMP binding (Chinchilla et al., 2007; Roux et al.,2011), suggesting that BAK1 functions both in plant defense andhormone signaling. BRs and BR signaling can promote resistanceor susceptibility against different pathogens (Nakashita et al.,2003; Kemmerling et al., 2007; Kørner et al., 2013), but whetherthe roles of BAK1 in PTI and BR signaling are genetically separateis not completely understood. Although flg22 treatment fails toelicit or suppress BR signaling pathways, overexpression of BR1or BR application in Arabidopsis suppresses PTI (Belkhadir et al.,2012). Activation of the BR-activated transcription factor BZR1affects the expression of WRKY and other defense genes, whichgoes some way to explaining how BR suppresses PTI (Lozano-Durán et al., 2013). However, inhibition of FLS2-mediated immunesignaling by BR perception independently from BAK1 or BAK1-associated phosphorylation pathway has also been reported(Albrecht et al., 2012).

The P. syringae type III effectors AvrPto and AvrPtoB targetBAK1 (Table 1), interfering with its ability to bind FLS and triggerPTI. AvrPtoB/AvrPto-deficient P. syringae strains show reducedvirulence on Arabidopsis, and transgenic Arabidopsis plantsexpressing AvrPto show morphological phenotypes such asstunting that is reminiscent of BR-insensitive mutants. AvrPtoBis known to interact with the BAK1 kinase domain, inhibiting itsability to bind with FLS2/EFR (ELONGATION FACTOR) and elicitPTI, while the mechanism of how AvrPto interferes with BAK1-FLS2 remains unclear (Shan et al., 2008; Cheng et al., 2011).More recently, BAK1 has also been identified as one of thetargets of HopF2 (Table 1), another type III effector from P. sy-ringae (Zhou et al., 2014). Xoo2875, a type III effector from thebacterial pathogen X. o. pv oryzae also interacts with OsBAK1 toinhibit innate immunity as well as BR signaling. Consistent withthis, transgenic rice (Oryza sativa) plants expressing Xoo2875display, in addition to increased X. o. pv oryzae susceptibil-ity, a semi-dwarf plant phenotype that is reminiscent of riceplants with silenced OsBAK1 (Yamaguchi et al., 2013). BIK1(BOTRYTIS-INDUCED KINASE1), which is required for PTI, interactswith the flagellin receptors FLS2 and BAK1. BIK1 is also phos-phorylated by BAK1. The P. syringae type III effector AvrPphB,which encodes a cysteine protease, degrades BIK1, inhibitingPTI. Interestingly, although BIK1 is a positive regulator of de-fense signaling, it negatively regulates BR signaling (Lin et al.,2013). Furthermore, it appears that BR-mediated plant growthand plant defense are negatively correlated (Albrecht et al.,2012). These examples clearly demonstrate the complex natureof interactions between defense and BR signaling.

EFFECTOR-MEDIATED MANIPULATION OF THEGIBBERELLIC ACID PATHWAY

GAs promote plant growth and also promote susceptibility toseveral pathogens in rice (reviewed in Yang et al., 2013). Thus,the GA-insensitive dwarf mutant gid1, which hyperaccumulatesendogenous GA shows increased susceptibility to the rice blastfungus Pyricularia grisea (Tanaka et al., 2006), whereas riceplants compromised in GA biosynthesis show increased re-sistance to M. oryzae and X. o. pv oryzae (Qin et al., 2013). GAs

produced as secondary metabolites in the rice-infecting path-ogenic fungus Fusarium fujikuroi are well known examples ofphytohormone mimics (Bömke and Tudzynski, 2009). Riceplants infected with this fungus display spindly and elongatedstems and chlorotic leaves caused by fungally secreted GA. AGA nonproducing F. fujikuroi strain is not compromised in initialinfection of rice cells but is restricted in subsequent invasion ofthe host (Wiemann et al., 2013). Interestingly, other Fusariumspecies seem to have lost the ability to synthesize GA, sug-gesting that this provides an advantage for F. fujikuroi over otherpathogens (Wiemann et al., 2013).

PHYTOHORMONE SIGNALING HUBS, TRANSCRIPTIONALACTIVATORS, AND REPRESSORS TARGETED BYPATHOGEN EFFECTORS

Recent genome-wide protein–protein interaction studies haveidentified proteins that are commonly targeted by effectors fromtwo diverse pathogens: namely, the bacterial pathogen P. sy-ringae and the oomycete pathogen H. arabidopsidis (Mukhtaret al., 2011). Interestingly, among the 17 so-called “hub” pro-teins identified to interact with effectors from both pathogens,relatively few proteins directly involved in plant hormone sig-naling were found (Mukhtar et al., 2011). This seems to suggestthat hormone signaling pathways may often be indirectly tar-geted by pathogen effectors. Indeed, LSU1 (RESPONSE TOLOW SULFUR1) is a common effector target that interacts with80 other plant proteins including the JA signaling componentsJAZ1 and JAZ9 (Arabidopsis Interactome Mapping Consortium,2011). Two other common effector targets, CSN5a (COP9SIGNALOSOME5a) and CSN5b, two separate subunits of theCOP9 signalosome multimeric protein complex involved incullin-RING E3 ubiquitin ligase regulation, interact with 39 and148 plant proteins, respectively. The auxin signaling proteinsIAA7 and IAA8, as well as the SA signaling components SCN4(SUPPRESSOR OF NPR1-1 CONSTITUTIVE4) and NIMIN2(NIM1-INTERACTING2), were found to interact with the HUBproteins LSU1 and CSN5A, respectively (Arabidopsis Inter-actome Mapping Consortium, 2011). As stated earlier, CSN5aand CSN5b are targeted by the geminivirus 2C protein (Lozano-Durán et al., 2011), further suggesting that CSN5 protein isa direct target of diverse pathogen effectors.Phytohormone responses often are regulated by a large

number of transcription factors. Therefore, a potential way forpathogens to disrupt phytohormone pathways is to targettranscription factors. As stated above, the Xanthomonas effectorXopD interacts with ERF4 in tomato and the MYB transcriptionfactor MYB30 in Arabidopsis. The latter is a key regulator ofmultiple hormone signaling pathways, including SA, ABA, andBR signaling (reviewed in Raffaele and Rivas, 2013). In addition,ERF19 in Medicago truncatula is targeted by a secreted effector(SP7) from the arbuscular mycorrhizal fungus Glomus intra-radices. The physical interaction between SP7 and ERF19 fa-cilitates increased mycorrhizal colonization by G. intraradicesand prolongs the biotrophic phase in rice roots when SP7 isexpressed in the hemibiotrophic rice blast fungus M. grisea(Kloppholz et al., 2011). Host transcription factors also seem tobe indirectly targeted by pathogens. For instance, a recent study

Phytohormone Intervention by Pathogens 2299

showed that flg22 induces alternatively polyadenylated forms ofArabidopsis ERF4 (Lyons et al., 2013b). The full-length At-ERF4isoform, which contains an EAR domain, is involved in tran-scriptional repression, while the flg22-induced ERF4 isoformthat does not contain the EAR domain performs novel defense-related roles (Lyons et al., 2013b).

In addition to the members of the ERF and MYB transcriptionfactor families, various members of the NAC (NAM/ATAF1/2/CUC2) family transcription factors involved in disease resistanceor susceptibility (Delessert et al., 2005) have recently beenshown to be targeted by pathogen effectors. For example, HopD1from P. syringae targets the Arabidopsis NAC transcription factorNTL9 (NAC TRANSCRIPTION FACTOR-LIKE9) (Block et al.,2014). An RxLR effector from P. infestans interferes with nuclearlocalization of the two tobacco (Nicotiana benthamiana) NACtranscription factors called NTP1 (NAC TARGETED BY PHY-TOPHTHORA1) and NTP2 (McLellan et al., 2013). Turnip crinklevirus coat protein binds to the Arabidopsis NAC transcriptionfactor TIP (TCV-INTERACTING PROTEIN1, also known asANAC091) to interfere with defense response (Donze et al.,2014). More recently, Cs-LOB encoding a LOB (LATERALORGAN BOUNDRIES) domain transcription factor in citrus hasbeen identified as a susceptibility gene whose product is tar-geted by the TAL effector pthA from Xanthomonas citri, thebacterial pathogen that causes bacterial canker disease incitrus (Hu et al., 2014; Z. Li et al., 2014). Other LOB domaingenes that potentially are involved in hormone signaling havebeen identified as TAL effector targets (Pereira et al., 2014).The involvement of Arabidopsis LBD20 in JA signaling andFusarium wilt susceptibility is also known (Thatcher et al.,2012b). Given the large number of transcriptional regulatorspotentially involved in pathogen defense (McGrath et al., 2005),future research will probably identify additional phytohormone-related regulators that are directly or indirectly targeted bypathogen effectors to promote disease susceptibility.

Recent research has also established that transcriptionalrepressors play a major role in regulating phytohormone re-sponses. Therefore, repressors present a convenient target forpathogens that benefit from the improper activation of hormonalresponses. For instance, P. syringae targets DELLA repressorsof GA signaling to promote disease development (Figure 4)(Navarro et al., 2008), although a specific bacterial effector di-rectly or indirectly involved in targeting DELLAs has not yet beenidentified. Examples of pathogen effectors that target repressorsof phytohormone pathways are discussed earlier and includeviral and bacterial effectors (e.g., AvrRpt2) targeting repressorsof auxin signaling (Cui et al., 2013). As discussed above, the P.syringae effector and HopX1 and HopZ1a target JAZ repressorsto activate the JA pathway (Jiang et al., 2013; Gimenez-Ibanezet al., 2014) (Figure 4). More recently, an interaction betweenMiSSP7 (Mychorriza-Induced Small Secreted Protein 7) from thebeneficial fungus Laccaria bicolor and the Populus trichocarpaJAZ6 protein has been identified. This interaction inhibits JAZ6degradation, leading to the repression of the JA pathway andthe promotion of symbiosis in P. trichocarpa colonized roots(Plett et al., 2014). Therefore, effector-mediated targeting ofphytohormone repressors appears to be a common theme inboth pathogenic and beneficial plant–microbe interactions.

CONCLUSIONS AND FUTURE PROSPECTS

In recent years, great progress has been made toward discov-ering specific targets of effectors produced by bacterial, viral,fungal, and oomycete pathogen effectors. In this review, theterm “effector” was used to broadly refer to pathogen derivedmolecules that make the host environment conducive to in-fection. In fact, in the light of recent evidence indicating thatsmall RNAs produced by the fungal pathogen B. cinerea targetshost’s signaling pathways (Weiberg et al., 2013), the coverageof this term should probably be extended to any pathogen-produced molecule that contributes to disease development.In addition to relatively well-characterized MAMPs and many

virulence factors, pathogen genomes seem to encode a largenumber of uncharacterized effectors, and potential plant targetshave been reported for only a few of these effectors to date.Most effectors make only subtle contributions to overall path-ogen virulence, and these small effects may be difficult to detectusing pathogen knockouts. It is also becoming increasinglyevident that a single pathogen species can produce a largenumber of effectors that can simultaneously target multiple hostprocesses, including phytohormone pathways that regulateboth defense and development. Numerous studies have sug-gested a tradeoff between plant growth and development anddefense. Effector-mediated manipulation of host hormone bi-ology to promote plant growth may benefit pathogens by re-ducing resources available for the plant to mount an effectivedefense response (Kazan and Manners, 2009; De Bruyne et al.,2014; Huot et al., 2014). Furthermore, the versatility of pathogeneffectors is evidenced by the demonstration that a single ef-fector can interfere with multiple host targets (Cui et al., 2010;Lindeberg et al., 2012; Raffaele and Rivas, 2013; Zhou et al.,2014). A more complete understanding of the complex inter-actions of phytohormone signaling networks triggered by patho-gen effectors may require the adoption of systems biologyapproaches (Kim et al., 2014; Naseem et al., 2014).Identification of conserved protein motifs for nuclear locali-

zation, gene suppression, cellular entry, and subcellular target-ing would certainly be helpful for future studies examiningeffector mode of action. The biosynthesis of many phyto-hormones takes place in the chloroplast. Therefore, interferingwith chloroplast function may be a common strategy used bymany pathogens. As reviewed here, the P. syringae effectorHopl1 targets chloroplasts to reduce SA biosynthesis (Jelenskaet al., 2007). More recently, two type III effectors, HopK1 andAvrRps4 from P. syringae, were also found to be localized toArabidopsis chloroplasts, and this seems to be mediated bya cleavable transit peptide found in these effectors (G. Li et al.,2014). Loss of chloroplast function can also lead to chlorosisthat contributes to disease symptom development. For in-stance, host-selective toxins, produced by the necrotrophicpathogen Alternaria alternata, disrupt chloroplast function topromote disease development (reviewed in Tsuge et al., 2013).Given the importance of transcription factors in the regulation

of genes involved in plant hormone biosynthesis and signaling, itis plausible that pathogen effectors target members of planttranscription factor gene families, although so far only few suchtranscription factors directly targeted by pathogen effectors

2300 The Plant Cell

have been identified. It is expected that future research willidentify new pathogen effectors that either directly or indirectlytarget transcriptional activators and repressors of the host’shormone signaling pathways.

A number of secreted pathogen effectors contain nuclear lo-calization signals indicating that they may interfere with tran-scription (Canonne and Rivas, 2012; Stam et al., 2013), althoughdirect targets of these effectors remain to be determined. Bac-terial effectors that act as plant transcription factors, such asthose belonging to the TAL family, activate host target genes, buttheir precise mode of action remains unclear (Boch and Bonas,2010). Computational analyses to identify TAL targets in plantgenomes may go some way toward uncovering this question(Noël et al., 2013; Pereira et al., 2014). Synthetic TAL or TAL-EAReffectors designed to modulate the expression of TFs involved indefense-associated phytohormone pathways should also haveutility in biotechnological applications (Mahfouz et al., 2012).

To date, effector targets have been mainly investigated forbacterial, biotrophic, and hemibiotrophic fungal pathogens andoomycetes. Necrotrophic fungal pathogens potentially secretelarge numbers of effectors that affect a variety of cellular tar-gets. Host-specific toxins secreted by necrotrophic pathogens(Friesen et al., 2008) can activate a variety of cellular responses,including phytohormone pathways. Host-selective toxins (ToxAand ToxB) of Pyrenophora tritici-repentis, the necrotrophic fun-gal pathogen that causes tan spot disease in wheat, acti-vate the JA pathway (Pandelova et al., 2012). More recentlyPR1-5, a wheat PR1-like protein, which physically interacts withToxA from Stagonospora nodorum, another necrotrophic wheatpathogen, has been identified as a potential ToxA target, sug-gesting that this interaction may be responsible for ToxA-induced necrosis on wheat (Lu et al., 2014). Other mycotoxinssuch as oxalic acid and necrosis and ethylene-inducing peptide(NEP1) secreted by S. sclerotiorum and various pathogenicfungi, respectively, act as effectors to alter phytohormone-regulated host defenses (Qutob et al., 2006; Liang et al., 2009).Similarly, the fungal toxin deoxynivalenol (DON) produced by thewheat head blight pathogen F. graminearum (reviewed in Kazanet al., 2012) acts as an effector, eliciting plant host defenses andcell death (Desmond et al., 2008), although exact cellular targetsof DON remain elusive.

The role of herbivore- or microbial-induced plant volatiles aselicitors of plant defense and pathogen protection have beenrelatively well studied (reviewed in Arimura et al., 2011). Thesecompounds can have antimicrobial and/or defense-inducingeffects and can also attract enemies of predatory insects (Leroyet al., 2011). However, one relatively unexplored area is the ef-fect of microbially produced volatiles as effectors. Indeed, thereis evidence that certain volatiles, such as 1-hexanol releasedby several plant-infecting bacteria, suppress the flg22-inducedproduction of ET and reactive oxygen species, suggesting thatpathogen produced volatiles can manipulate hormone defensesignaling pathways (Blom et al., 2011).

In conclusion, recent studies reviewed here reveal diversemechanisms used by pathogens to target phytohormone sig-naling pathways. Host phytohormone signaling hubs and theirassociated networks directly or indirectly targeted by pathogeneffectors constitute “susceptibility factors.” A better understanding

of effector mode of action would enable us to engineer suscepti-bility factors so that vulnerability to pathogens in crop plants couldbe reduced without causing unintended effects on plant growth anddevelopment.

ACKNOWLEDGMENTS

We apologize from colleagues whose work could not be reviewed dueto space restrictions. We thank John Manners, Nancy Eckardt, andanonymous reviewers for useful suggestions on the article.

Received March 27, 2014; revised May 16, 2014; accepted May 24,2014; published June 10, 2014.

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Phytohormone Intervention by Pathogens 2309

DOI 10.1105/tpc.114.125419; originally published online June 10, 2014; 2014;26;2285-2309Plant Cell

Kemal Kazan and Rebecca LyonsIntervention of Phytohormone Pathways by Pathogen Effectors

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