tick tock: circadian regulation of plant innate immunity · tick tock: circadian regulation of...

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Annual Review of Phytopathology

Tick Tock: CircadianRegulation of PlantInnate ImmunityHua Lu,1 C. Robertson McClung,2 and Chong Zhang1

1Department of Biological Sciences, University of Maryland–Baltimore County, Baltimore,Maryland 21052; email: [email protected] of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755

Annu. Rev. Phytopathol. 2017. 55:287–311

First published as a Review in Advance on June 7,2017

The Annual Review of Phytopathology is online atphyto.annualreviews.org

https://doi.org/10.1146/annurev-phyto-080516-035451

Copyright c© 2017 by Annual Reviews.All rights reserved

Keywords

biological rhythms, disease resistance, stomata, reactive oxygen species,timed defense, defense signaling network

Abstract

Many living organisms on Earth have evolved the ability to integrate en-vironmental and internal signals to determine time and thereafter adjustappropriately their metabolism, physiology, and behavior. The circadianclock is the endogenous timekeeper critical for multiple biological processesin many organisms. A growing body of evidence supports the importanceof the circadian clock for plant health. Plants activate timed defense withvarious strategies to anticipate daily attacks of pathogens and pests and tomodulate responses to specific invaders in a time-of-day-dependent manner(gating). Pathogen infection is also known to reciprocally modulate clockactivity. Such a cross talk likely reflects the adaptive nature of plants to coor-dinate limited resources for growth, development, and defense. This reviewsummarizes recent progress in circadian regulation of plant innate immunitywith a focus on the molecular events linking the circadian clock and defense.More and better knowledge of clock-defense cross talk could help to improvedisease resistance and productivity in economically important crops.

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ANNUAL REVIEWS Further

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http://www.annualreviews.org/doi/full/10.1146/annurev-phyto-080516-035451

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INTRODUCTION

Many living organisms on Earth have evolved the ability to measure time, using the endogenouscircadian clock to anticipate day and night and seasonal changes and to subsequently coordinatetheir metabolism, physiology, and behavior with changes in the environment. A precisely tunedcircadian clock is critical for the growth and development of many organisms, including photosyn-thetic bacteria, archaea, fungi, animals, and plants, and confers fitness and competitive advantagesto the organisms under both benign and stressful conditions (44, 69). Circadian oscillation is alsoan integral component of the human immune system and influences human health (7, 120). Likeanimals, plants encounter various pathogens and pests with different lifestyles on a daily basis. Al-though plants lack adaptive immunity involving antibodies, plants use sophisticated mechanismsto anticipate and counter the incursions of pathogens and pests. Emerging evidence has establishedthe circadian clock as integral to plant defense against pathogen and pest challenges. The circadianclock coordinates immune responses to pathogens and pests, and circadian dysfunction disruptsresponses to invasion. Interestingly, pathogen challenge can reset the plant circadian clock. Thisreciprocal regulation of the circadian clock and plant innate immunity is likely important for thereallocation of limited resources to ensure proper growth and development of plants and theirtimely responses to biotic stresses. It could also offer a strategy for pathogens and pests to manip-ulate plant innate immunity. There are excellent reviews covering topics related to the circadianclock and plant innate immunity (22, 27, 44, 56, 107). This review examines recent progress inour understanding of the cross talk between the circadian clock and plant innate immunity. Wespecifically focus on the molecular events linking these two important biological processes.

PLANT INNATE IMMUNITY

Among various defense mechanisms employed by plants, some are preformed physical or chem-ical barriers and others are induced by the invaders. Plant surface structures, such as trichomes,cuticles, epidermal cells, and stomata, provide a frontline of physical barriers to prevent inva-sion by pathogens and pests. Preexisting secondary compounds can also be used to deter andrepel the invaders. In addition, plants can actively recognize pathogens using at least two majorsurveillance systems and subsequently mount an induced defense. In the first system, plants usepattern recognition receptors to detect pathogen-associated molecular patterns (PAMPs), whichare conserved molecules or structures present in groups of related microbes (12). Such recognitionactivates PAMP-triggered immunity (PTI), a basal level of defense, against nonadapted pathogens.A common counteracting strategy of pathogens is to suppress PTI using pathogen effectors. Forinstance, bacterial pathogens can produce and deliver effector proteins to the vicinity of or insidea plant cell via the type three secretion system (137). These effectors employ various biochem-ical mechanisms to compromise host innate immunity, causing effector-triggered susceptibility(ETS). In response, plants have evolved the second surveillance system, employing resistance (R)proteins to specifically recognize cognate pathogen effectors and subsequently activate effector-triggered immunity (ETI). ETI, also termed R gene–mediated resistance, is a much stronger formof defense. ETI is typically associated with hypersensitive response (HR), a process characterizedby programmed cell death (42), and systemic acquired resistance (SAR), which leads to enhancedand long-lasting disease resistance at the whole-plant level (33). The activation of induced defenseis often associated with increased defense signaling, activating pathways mediated by the smallmolecules, such as salicylic acid (SA), jasmonic acid ( JA), and reactive oxygen species (ROS), re-programming of genome-wide transcription and global metabolism, and further strengthening ofthe cell wall. Networks of defense genes act in concert to orchestrate PTI, ETI, and SAR to ward

288 Lu · McClung · Zhang

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Geneexpression

Enzymeactivity

Metabolismand nutrients

Photosynthesis

Hormonesignaling

Stomataactivity

Floweringand growth

Coldresponse

ROS

Plant innateimmunity

Phase

Period (24 h)

2× amplitude

Zeitgebers

a b

Figure 1The circadian clock regulates many biological processes. (a) Basic concepts of the circadian clock, period, phase, amplitude, andzeitgebers. Although it is endogenous, the circadian clock can be reset by external and internal time cues (zeitgebers). Examples ofzeitgebers shown from left to right are light, temperature, metabolic status, and infection of pathogens, such as Pseudomonas syringae,Hyaloperonospora arabidopsidis, and Botrytis cinerea. Zeitgebers can affect clock period, phase, and amplitude (red dashed lines). (b) Thecircadian clock regulates many biological processes as outputs. Activation of some biological processes (red), such as increased signalingin defense, reactive oxygen species (ROS), and hormones and activation of cold response as well as the nutrient status of an organism, isknown to feedback-regulate clock activity. It is worth mentioning that the position of each biological process on the circle does notimply the time of day when it occurs.

off invaders. However, it remains challenging to identify the genes that play roles in regulatingdefense responses and how these genes function together in defense control.

THE CIRCADIAN CLOCK

The circadian clock is an internal timekeeper that sustains itself under free-running conditions(in the absence of environmental time cues) and exhibits temperature compensation, meaning thatthe pace of the clock (period) remains constant over a range of ambient temperatures. The periodof the circadian clock is approximately 24 h (Figure 1a), coinciding with the period of Earth’srotation around its axis. Although the period of the clock does not vary seasonally, the phase andamplitude of some aspects of clock function may vary seasonally in response to changes in theduration of day and night. The circadian system can be rather simplistically organized into threeinterconnected parts: the input pathways, the central oscillator (clock), and the output pathways.Although it is endogenous, clock activity can be reset by the input pathways with zeitgebers (“timegivers” in German), which are environmental and internal time cues. Light, temperature, andmetabolic state in an organism are examples of zeitgebers that can influence rhythmic parameters,including clock period, amplitude, and phase (Figure 1a). The circadian clock has a profoundinfluence on numerous biological processes in plants, some of which often display distinct andovert circadian rhythms (Figure 1b). Some clock output pathways feed back and serve as inputs tomodulate clock activity (Figure 1b, red) (45, 48, 54, 73, 111, 155) and some cross talk with eachother (51, 112, 150).

www.annualreviews.org • Circadian Regulation of Plant Innate Immunity 289

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CCA1

LHY

LUX

ZTLPRR7 PRR5

ELF3ELF4

CHE TOC1

PRR9

GI

0 4 8 12 16 24ZT (hours)

LNK2

RVE8 LNK1

RVE4

Figure 2A simplified model of the transcription-translation feedback loops (TTFLs) of the Arabidopsis circadianclock. Details of the interactions among the TTFL genes illustrated in this cartoon can be found in the maintext. Blue lines with an arrow indicate activation of target genes by a TTFL gene, and red lines with a circleindicate repression of target genes by a TTFL gene. The dashed line with an arrow indicates an indirectregulation of CCA1/LHY by the evening complex. The line underneath the TTFL network shows times ofday. Each TTFL gene is roughly positioned according to its time-of-day expression. Color circles depictgenes that functionally work together. It is worth mentioning that this cartoon illustrates only a fewexamples of TTFL gene interactions mentioned in this review but does not mean to provide acomprehensive view of the TTFLs of the circadian clock. Abbreviation: ZT, zeitgeber time.

Although the central oscillators of different organisms do not share conserved core molecularcomponents, the architecture of eukaryotic circadian clocks is conserved and consists of networksof interlocked transcription-translation feedback loops (TTFLs) (7, 44, 56, 120). Indeed, the cen-tral oscillator of the model plant Arabidopsis contains many core clock genes that are expressed andact at different times of day to affect activities of other clock proteins and/or themselves (44, 56,107). For instance, CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) and LATE ELONGATEDHYPOCOTYL (LHY) are morning-phased Myb transcription factors that are involved in mul-tiple TTFLs (Figure 2). They directly repress expression of other morning-phased genes, suchas PSEUDO-RESPONSE REGULATOR 9 (PRR9), PRR7, and PRR5, the evening-phased genes,such as TIMING OF CAB EXPRESSION 1 (TOC1; also known as PRR1), and the evening complex(EC) genes [LUX ARRHYTHMO (LUX; also known as PHYTOCLOCK1), EARLY FLOWERING3 (ELF3), and ELF4]. CCA1 and LHY can also negatively regulate expression of each other andthemselves. In addition, expression of CCA1 and LHY can be negatively regulated by multiple clockproteins, including TOC1, the TOC1 interactor CCA1 HIKING EXPEDITION (CHE), PRR9,PRR7, and PRR5. TOC1 is a negative regulator of LUX, ELF4, GIGANTEA (GI), and PRR5. TheEC directly represses expression of PRR7, PRR9, TOC1, GI, and LUX (58). Because PRR9, PRR7,and TOC1 are direct repressors of CCA1 and LHY, the repression of the corresponding encodinggenes by the EC relieves their repression of CCA1 and LHY, making the EC also an indirect activa-tor of CCA1 and LHY. The CCA1/LHY relatives REVEILLE 8 (RVE8) and RVE4, together withthe transcriptional coactivators NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATEDGENE 1 (LNK1) and LNK2, activate transcription of the evening-expressed clock genes ELF4,LUX, PRR5, and TOC1 (55, 111, 116, 151). Along with transcriptional-translational control ofthe circadian clock, post-translational modifications are also key to clock function (121, 128). For


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example, alternative splicing was shown to be important for the function of several clock genes. Inaddition, the evening gene ZEITLUPE (ZTL) encodes an F-box protein in a complex that targetsTOC1 and PRR5 for ubiquitination and subsequent degradation (5, 82). ZTL also interacts withGI to control the stability of GI and itself (68). Such complicated regulation of the circadian clockat multiple levels is critical to ensure the precision of the circadian clock.

REGULATION OF PLANT INNATE IMMUNITY BY THECIRCADIAN CLOCK

The Circadian Clock Genes and Disease Resistance

The circadian clock integrates environmental signals with internal cues to enable proper growth,development, and response to stimuli in organisms (44, 56, 69). Light, one of the main clockzeitgebers, has long been known to affect plant responses to biotic stress (57, 64, 113). In thepresence of pathogens, light conditions influence plant defense responses, including HR, SAR,and defense signaling. Some photosynthesis-related genes and photoreceptors were revealed aspart of the plant immune system. In addition, constitutive defense and cell death phenotypesconferred by some mutations are light-dependent (13, 62, 83, 154).

Most previous defense assays were conducted under diurnal conditions, which would makeit difficult to distinguish the effects caused by light from those caused by the circadian clock.To address this problem, Bhardwaj et al. (10) infiltrated Arabidopsis leaves with the bacteriumPseudomonas syringae at different times of day and subjected the infected plants to the free-runningcondition of continuous light. They found that plants showed a temporal variation over the dayin their resistance to P. syringae with a peak resistance at dawn. This temporal resistance patternwas disrupted when a clock gene, CCA1 or ELF3, was misexpressed. More studies with additionalclock mutants provide further support of the direct role of the circadian clock in disease resistanceagainst various pathogens and pests (Table 1).

Several points regarding the role of the circadian clock in plant innate immunity are clear fromTable 1. First, the defense role of a clock gene is not associated with a specific expression phase.Mutations in clock genes expressed in the morning (CCA1 and LHY ) or evening [CHE, TIME FORCOFFEE (TIC), and ELF3] conferred enhanced disease susceptibility (eds) to P. syringae. Second,the change of clock activity caused by a clock mutation does not predict pathogen resistanceof the mutant. Both short-period mutants (e.g., cca1 and lhy) and arrhythmic plants [e.g., plantsoverexpressing CCA1 (CCA1ox) or LHY (LHYox)] were more susceptible to P. syringae infection.Both the short-period mutant cca1 and the long-period mutant ztl1 showed eds to the oomycetepathogen Hyaloperonospora arabidopsidis (Hpa). Third, the synergistic or antagonistic relationshipbetween two TTFL genes in clock regulation does not determine the defense phenotypes causedby each mutation. Mutations in mutual repressors CCA1 and CHE enhanced susceptibility toP. syringae (157). These observations suggest that although TTFL genes work together to maintainclock precision, some clock genes could affect the specific output to defense and perhaps also otherbiological processes. However, what defense mechanisms are deployed by individual clock genesand how these clock genes orchestrate the integration of temporal information with defenseresponses remain to be addressed. More discussion of how the circadian clock regulates plantdefense (see below) could clarify some aspects of these important questions.

The Circadian Clock Regulates Stomata-Dependent and -Independent Defense

Although they are important for photosynthesis and water transpiration, the plant surface struc-tures known as stomata also provide a portal for some pathogens to break into plant tissue and


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Table 1 Circadian clock genes are direct regulators of plant defense

Gene name Gene IDExpression

phase

Clockphenotypesconferred byfunction loss Defense-related phenotypes References

CCA1 (partiallyredundant withLHY )

AT2G46830 Morning Short period A cca1lhy mutant shows enhanced diseasesusceptibility (eds) to Pseudomonas syringae,Hyaloperonospora arabidopsidis, and Botrytiscinerea, and CCA1ox plant is moresusceptible to P. syringae and Trichoplusia nibut more resistant to H. arabidopsidis

CCA1 affects stomata-dependent andstomata-independent defense, reactiveoxygen species (ROS) homeostasis andresponse, and defense gene expression.

CCA1 acts independently of salicylic acid(SA)

Expression of CCA1 is affected by flg22,RPP4, and infection of P. syringae,H. arabidopsidis, and B. cinerea

10, 37, 38, 52,60, 73, 99,143, 155

LHY (partiallyredundant withCCA1)

AT1G01060 Morning Short period A cca1lhy mutant shows eds to P. syringae,H. arabidopsidis, and B. cinerea, and anLHYox plant is more susceptible toP. syringae

LHY affects stomata-dependent andstomata-independent defense and ROShomeostasis and responseLHY acts independently of SASA increases the amplitude of LHYexpression

60, 73, 155

TOC1 (PRR1) AT5G61380 Evening Short period A toc1 mutant shows higher SA-inducedresistance to P. syringae than Col-0

TOC1 affects stomatal opening and closure,ROS response, and defense geneexpression

The amplitude of TOC1 expression isincreased by SA and suppressed bymutations disrupting ICS1, NPR1, or ROSsignaling

The TOC1 promoter is bound by NPR1 andTGA proteins

26, 59, 73,158

TIC AT3G22380 Evening Short period A tic mutant shows eds to spray-inoculatedP. syringae and is compromised instomata-dependent defense

TIC is a negative regulator of jasmonic acid( JA) response and affects ROS response

70, 73, 124

ELF3 AT2G25930 Evening Arrhythmic An elf3 mutant shows eds to P. syringae andB. cinerea

ELF3 affects ROS response

10, 60, 73

(Continued )


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Table 1 (Continued )

Gene name Gene IDExpression

phase

Clockphenotypesconferred byfunction loss Defense-related phenotypes References

ELF4 AT2G40080 Evening Arrhythmic ELF4 affects ROS response 73

LUX AT3G46640 Evening Arrhythmic A lux mutant is compromised in temporalexpression of some defense phenotypesinduced by flg22 or P. syringae infectionand in phase-dependent resistance to T. ni

LUX affects ROS response

38, 70, 73

ZTL AT5G57360 Evening Long period A ztl mutant shows eds to H. arabidopsidis 143

CHE AT5G08330 Evening No phase andperiod change

A che mutation disrupts the diurnaloscillation of SA and ICS1 transcription ina light/dark cycle and compromisesP. syringae–caused systemic acquiredresistance (SAR), SAR-induced SAaccumulation, and expression of ICS1 andtwo ICS1 regulators

CHE binds to the ICS1 promoter

157

GRP7 AT2G21660 Afternoon No phase andperiod change

A grp7 mutant shows eds to P. syringaeGRP7 affects stomata-dependent andstomata-independent defense

GRP7 directly interacts with P. syringaeeffector HopU1 and transcripts ofpathogen-associated molecular pattern(PAMP) receptors FLS2 and EFR

66, 106, 155

gain access to rich nutrients for proliferation as well as space for colonization (89, 139). A stomateconsists of two guard cells connected at the ends to form a pore that exhibits rhythmic variation inits aperture, opening during the day and closing at night. This process is regulated by the circadianclock in anticipation of the change of light and humidity in a diurnal cycle (144).

Studies show that some clock genes regulate plant defense via a stomata-dependent path-way. Correlating with the rhythmicity of stomata aperture, Arabidopsis plants spray-infected withP. syringae showed more resistance at night than in the morning. Plants misexpressing clock genes(e.g., CCA1, LHY, TOC1, LUX, and TIC) exhibited disrupted diurnal stomatal opening and clo-sure (26, 70, 155). Some of these plants also lost the temporal variation in resistance to P. syringae(10, 70, 155). However, open stomata during the day are not just a passive portal for P. syringaeto access the leaf interior. In fact, plants can actively close stomata to restrict pathogen entrythrough sensing the invader as nonself. This sensing can be achieved by plant receptors to recog-nize PAMP molecules of P. syringae, such as flg22 and elf16, which are conserved peptides fromflagellin and elongation factor Tu, respectively (71, 159). Although the mechanisms by whichTOC1, LUX, and TIC affect stomata-dependent defense remain to be elucidated, CCA1 andLHY were shown to impose time-of-day dependence on (gate) the plant response to P. syringae–induced stomatal closure (155). CCA1 and LHY likely act through a potential downstream gene,GRP7 (At2g21660; also known as COLD AND CIRCADIAN REGULATED 2), which encodes anRNA binding protein (34). GRP7 is likely a direct target of CCA1 and LHY based on the over-representation of two CCA1 binding motifs, evening element (EE) and CCA1 binding site (CBS),


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in the GRP7 promoter. Expression of GRP7 is circadian regulated and dependent on CCA1 (41).Because loss of function in GRP7 does not affect clock activity, GRP7 is not considered as partof the clock TTFLs but rather as part of a slave oscillator (129). GRP7 was previously shown toregulate stomatal defense, possibly partly through its direct interaction with transcripts of PAMPreceptors FLS2 and EFR (66, 155). The P. syringae effector HopU1 binds to the GPR7 protein,likely blocking this interaction and thereby interfering with host stomatal defense (34, 71, 106,159). Thus, functional TTFL genes (CCA1 and LHY ) and their output pathway target (GRP7) arerequired for the normal function of at least some PAMP receptors to keep P. syringae from dis-rupting stomatal defense. Additional clock genes have also been shown to affect stomatal openingand closure in a diurnal cycle (76, 125). Further investigation is needed to reveal whether clockgenes could broadly gate P. syringae entry into the plant interior via stomata.

Spraying P. syringae onto the plant surface mimics the natural process of foliar bacterial infectionand has been used to study stomata-dependent defense in plants. In contrast, pressure infiltrationforces bacteria into plant tissue, largely bypassing stomatal restriction on initial bacterial invasionand providing an opportunity to study stomata-independent defense. Interestingly, plants havethe opposite sensitivity to P. syringae when infected with these two methods at different times ofday, showing more susceptibility to infiltrated bacteria in the evening and to sprayed bacteria inthe morning (Figure 3) (10, 70, 155). These observations suggest that plants activate differentdefense mechanisms at different times of day to deal with pathogens with varying invasion tactics.The core clock gene CCA1 was shown to be required for plant resistance to P. syringae deliveredby both methods, underscoring the importance of the circadian clock in plant defense throughoutthe day.

Although stomata-dependent defense is critical to prevent the initial invasion of foliar bacterialike some P. syringae strains that proliferate aggressively in the apoplast of plant cells, the virulenceof many other pathogens of different lifestyles is less dependent on the limitations imposed bystomata (6, 75). For instance, epiphytic bacteria can complete their life cycles on the leaf surfacewithout entering the plant interior (6, 75). Some oomycete and fungal pathogens do not use stomataas the main passage to host internal tissue. Instead, they produce hyphae to directly penetrate intoor between host epidermal cells to interfere with host immunity, obtain nutrients and water, andeventually kill host cells (18, 90, 146). Thus, like stomata-dependent defense, stomata-independentdefense is a major mechanism for plant resistance to pathogens. How the circadian clock regulatesstomata-independent defense against a broad spectrum of pathogens with different lifestyles is notwell understood. Stomata-independent defense overlaps with induced defense, the regulation ofwhich by the circadian clock is discussed further in the next section.

The Circadian Clock Regulates Induced Defense

Besides restricting pathogens with physical barriers like stomata, plants can actively recognizeand subsequently mount induced defense against the invaders. Accumulating evidence indicatesthe importance of the circadian clock in activating induced defense. This section focuses oncircadian regulation of defense gene expression, different layers of defense responses, and keydefense signaling pathways.

Circadian regulation of defense gene expression. The recognition of molecular control ofplant defense by the circadian clock was first made via observations that expression of some defensegenes oscillated in a circadian manner. This individual gene–based notion was quickly validatedby large-scale studies. A genetic screen with the enhancer trapping experiment revealed that 36%of Arabidopsis genes were circadian regulated (92). Time-series transcriptomics studies suggest


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ZT0

ZT12

ZT6ZT18

SA

JA

ROSOther

Figure 3Timed defense in Arabidopsis. Microbial pathogens demonstrate timed virulence whereas insects have timedfeeding behavior (outer black text). In response to attacks from pathogens and pests, plants mount a defense toanticipate the time when the invasion of a certain pathogen or pest is most likely to occur and to gateimmune responses to specific invaders in a time-of-day-dependent manner. Many of the anticipatoryresponses oscillate with relatively low amplitude and peak at a certain time of day. Examples of suchresponses (from inside to outside) are production and/or signaling of salicylic acid (SA) (red ), jasmonic acid( JA) (blue), reactive oxygen species (ROS) ( purple), and plant growth hormone, expression of genes involvedin RPP4-mediated defense and phenylpropanoid biosynthesis, and stomata opening/closure ( green). Thegrowth hormones include auxin (IAA), cytokinins (CKs), brassinosteroids (BRs), ethylene (ET), and abscisicacid (ABA). The position of each label represents the phase of an event, which is the peak activity during aday. Abbreviations: Hpa, Hyaloperonospora arabidopsidis; ZT, Zeitgeber time.

that one-third of Arabidopsis genes cycle under certain circadian conditions (21, 30, 49), whereasas much as 89% of Arabidopsis transcripts oscillate under one or more environmental cyclingconditions (e.g., light-dark or warm-cool) (93). Together, these studies unequivocally support theoverarching transcriptional control of Arabidopsis genes by the circadian clock, which is consistentwith the fact that many core clock genes encode transcription factors. Indeed, such widespreadtranscriptional control by the circadian clock is a common theme in other organisms, includingmouse, Drosophila melanogaster, Neurospora crassa, and cyanobacteria (86, 96, 109, 148). Similarly,biotic stress conditions induce global transcriptional reprogramming (133). It is possible that manygene transcripts change because of modifications in the chromatin structure under cycling and/ordefense conditions. It is critical to distinguish which gene transcripts are passively affected by


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Table 2 Gene Ontology (GO) analysis of target genes of circadian clock proteins

GO analysis CCA1 TOC1 PRR5 PRR7 PRR9All

combinedb

Wholegenome

(all genes)c

Whole genome(protein coding

genes)c

Number oftarget genesa

2,318 772 1,021 1,096 132 4,121 33,602 27,416

Response tobiotic andabiotic stimulid

358(15.4%)

164(21.2%)

192(18.8%)

278(25.4%)

41(31.1%)

720(17.5%)

3,174(9.4%)

3,174 (11.6%)

Developmentalprocessesd

254(11.0%)

98(12.7%)

174(17.0%)

179(16.3%)

23(17.4%)

499(12.1%)

2,989(8.9%)

2,989 (10.9%)

aThe target genes were identified from ChIPseq experiments with the indicated clock proteins (top row) (59, 76, 77, 99, 100).bThe number of genes targeted by all five clock proteins.cRepresents similar GO analysis with all Arabidopsis genes or with protein coding genes only and was included as controls.dTop numbers are the count of genes in each GO category. Percentages were calculated as follows: the count of genes in each GO category/total numberof gene targets of a clock protein × 100.

these conditions and which ones operate at the intersection of the circadian clock and defense toregulate these processes.

To support a role of the circadian clock in defense control, bioinformatics analyses predictthat some defense genes are potential targets of the core clock component CCA1, based onthe enrichment of the two CCA1 binding motifs, the EE and CBS motifs, in the promoters ofthese genes (143, 155). To further identify direct gene targets for the circadian clock, chromatinimmunoprecipitation coupled with deep DNA sequencing (ChIPseq) experiments were conductedwith several core clock proteins, including CCA1, TOC1, PRR5, PRR7, and PRR9 (59, 76, 77,99, 100). Target genes of these clock proteins were enriched with functions related to biotic andabiotic stress as well as to development-related processes (Table 2). Thus, multiple core clockcomponents are likely linked directly to stress outputs. It is worth noting that these ChIPseqexperiments were performed with nonchallenged samples and thus may miss additional clocktargets that respond only under stress conditions. Further experiments are needed to reveal thebiological relevance of circadian control of defense gene expression under both basal and bioticstress conditions.

Circadian regulation of PAMP-triggered immunity and effector-triggered immunity. Thebest-characterized PTI in plants is induced when the PAMP receptor FLS2 recognizes the elicitorflg22. This recognition leads to the internalization and degradation of FLS2, activation of aMAPK cascade and WRKY transcription factors, and global transcriptional reprogramming (12,114). As a result, plants mount a basal defense, associated with a series of physiological changeshappening within minutes to days after the recognition. Several studies suggest a role of thecircadian clock in regulating PTI. An in silico analysis of microarray data revealed that severalkey genes involved in flg22-FLS2 PTI, including FLS2, MKK4/MKK5, MPK3 and MPK6, andWRKY22, exhibit circadian-regulated expression (10). However, it is not yet known whetherany flg22-FLS2 PTI genes are under the direct transcriptional control by a core clock protein(s).Korneli and colleagues showed that flg22 treatment caused temporal induction of ROS productionand defense marker gene expression, depending on the time of day of flg22 treatment; this temporalpattern of induction was disrupted by the lux mutation (70). In addition, the two core clock proteinsCCA1 and LHY are potential PTI regulators because their downstream target gene GRP7 was


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shown to affect PTI, at least through regulating two PAMP receptors, FLS2 and EFR (106). Itis unknown, however, whether misexpression of CCA1 and/or LHY could affect PTI. If so, howCCA1, LHY, LUX, and other core clock components regulate PTI would be an interesting topicfor further investigation.

In addition to PTI, the circadian clock also controls ETI during biotic stress. The resistanceprotein RPP4 belongs to a large protein family with two conserved domains: a nucleotide bindingsite (NBS) and a leucine-rich repeat (LRR) (87). Although its cognate avirulence effector(s) havenot been identified, RPP4 specifically recognizes and activates strong defense against the avirulentoomycete Hpa isolates Emoy2 and Emwa1 (18). Hpa strains cause downy mildew in Arabidopsis,sporulating mainly at night and disseminating spores at dawn (Figure 3). An elegant study byWang and colleagues showed that the circadian clock controls RPP4-mediated Hpa resistance(143). RPP4 and some RPP4-dependent genes are enriched with CCA1 binding motifs in theirpromoters. Expression of these genes displayed a circadian pattern with a peak overlapping thatof CCA1 at dawn, and this pattern was disrupted by a cca1 mutation. Although wild-type plantsshowed more resistance to Hpa Emwa1 when infected at dawn than at dusk, the cca1 mutant lostthis temporally regulated resistance and showed more susceptibility than wild-type plants in themorning. However, CCA1ox was more resistant to the strain. These data led to the conclusionthat plants can use the core clock gene CCA1 to anticipate Hpa infection in the morning when Hpaspore dissemination is the highest. Challenging of a cca1lhy double mutant with a different avirulentHpa isolate, Emoy2, supports this role of CCA1 and further implicates a similar role of the closeCCA1 homolog LHY in RPP4-mediated resistance (155). In addition, the cca1lhy mutant was moresusceptible to the avirulent P. syringae strain expressing avrRpt2, which is recognized by anotherNBS-LRR protein, RPS2 (155). Thus, CCA1 (and perhaps also LHY) may act through multipleR gene–mediated pathways to regulate ETI. Consistent with this idea, some other NBS-LRR genesalso have CCA1 binding motifs in their promoters and thus are potential transcriptional targets ofCCA1 (C. Zhang & H. Lu, unpublished results). Further studies are necessary to establish directCCA1 regulation of its target genes, such as RPP4, RPP4-dependent genes, and other R genes,and the biological relevance of such a regulation in ETI. It would also be interesting to determinewhether other core clock genes are involved in ETI and, if so, to elucidate how they affect specificR gene–mediated disease resistance.

Circadian regulation of hormone signaling. Although SA and JA have long been recognized asdefense hormones, the role of the six major plant growth hormones, auxin, cytokinins, ethylene,gibberellic acids, abscisic acid, and brassinosteroids, in plant defense regulation has only recentlybeen demonstrated, highlighting the importance of balancing growth and defense during the plantlife cycle (112, 126). Circadian control of plant growth hormones has been manifested in dailyrhythmic hormone accumulation and diel expression of genes related to hormone biosynthesis,signaling, and response (Figure 3). Some of these hormone genes are directly controlled by coreclock proteins (2). The circadian clock also gates plant responses to some growth hormones.Whether the circadian clock regulates defense through controlling the rhythmicity of growthhormones is unknown. Recent studies, however, indicate that the defense role of the circadianclock is at least partly coordinated through the regulation of the two defense hormones SA and JA.

Circadian regulation of salicylic acid and systemic acquired resistance. SA is a small phenolicmolecule that plays an important role in signaling different layers of plant defense, from stomata-dependent defense to multiple induced defense responses (47, 89, 117, 138). SA is synthesizedthrough several pathways (23, 79); the major one is catalyzed by ISOCHORISMATE SYNTHASE 1(ICS1) (103, 104, 145). ICS1 is localized to the chloroplast (130), the primary site of SA biosynthesis


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(32). SA and possibly some SA precursors can be further transported by EDS5 to the cytoplasm foraction and/or further modifications (102, 122, 152). Additional genes, such as ACCELERATEDCELL DEATH 6 (ACD6) and EDS1 (31, 80), also affect SA accumulation, but their functions havenot been completely understood. SA perception is mediated by the SA receptors NPR1, NPR3,and NPR4 (149, 153). NPR1 exists as an oligomer in the cytoplasm under an unchallenged state.Higher SA levels change redox status and stimulate the release of the NPR1 monomer fromthe oligomer for nuclear translocation (97, 131). The cytoplasm-nucleus shuttling of NPR1 isimportant for SA signaling, SA cross talk to other signaling pathways, and NPR1 stability (33, 51).

Circadian regulation of the SA pathway is supported by several studies (Figure 3). Goodspeedand colleagues showed that basal SA levels oscillate daily, with a peak at night (38). Consistent withthis, expression of major genes affecting SA levels, including ICS1, EDS1, EDS5, and ACD6, alsoshows circadian oscillations (10, 95, 157). Although the NPR1 transcript level remains constant,NPR1 monomer accumulates rhythmically, with a peak at night (141, 158). Direct circadiancontrol of SA biosynthesis was further demonstrated by Zheng and colleagues (157); the clockprotein CHE binds to the promoter of ICS1 and affects the basal oscillation of ICS1 transcript andSA. CHE is also required for the induction of two transcription factors known to directly regulateICS1 expression, SYSTEMIC ACQUIRED RESISTANCE DEFICIENT 1 and CALMODULINBINDING PROTEIN 60g (142, 156, 157). Thus, these studies strongly establish that SA productionand signaling under non-pathogen-challenged conditions are outputs of the circadian clock.

Besides affecting basal SA oscillation in the absence of pathogens, a che mutation also com-promises SAR induction in response to P. syringae infection, suggesting a role for CHE in SARregulation (157). Interestingly, P. syringae infection is known to induce in the local infected tissuethe acute synthesis of bulk SA and expression of SA key regulatory genes, both of which couldincrease more than tenfold higher than the basal levels within 24 h post infection without maintain-ing the circadian pattern (46). The che mutant is not known to affect local resistance to P. syringaeand acute local defense responses, including SA synthesis. Mutations in the two core clock genesCCA1 and LHY conferred lower local defense to P. syringae but did not affect bulk SA biosynthesisbased on a genetic study (155). Thus, CCA1 and LHY may act independently of SA in defenseregulation. It is possible that the circadian clock gates the immune response under biotic stressconditions rather than through its regulation of diel synthesis of endogenous SA, using the TTFLgene CHE. This idea is supported by the work of Zhou et al. (158) showing that the TTFL genesTOC1, CCA1, and PRR7 are upregulated by NPR1 under stress conditions, and they potentiallyfunction to gate immune responses at a specific time of day. Nevertheless, because SA plays a keyrole in plant innate immunity, it remains an interesting topic to determine which, if any, clockgenes exert a major impact on SA synthesis and/or signaling under biotic stress conditions.

Circadian regulation of jasmonic acid–mediated defense. Jasmonic acids ( JAs) are a collectionof lipid-derived molecules that play key roles in plant defense. Cross talk between JA and SAsignaling is important for plants to balance their defense against different pathogens and pests(14, 112). In general, higher JA levels inhibit SA accumulation and signaling and favor resistanceagainst most insect herbivores and necrotrophic microorganisms, whereas higher SA levels inhibitJA accumulation and signaling and promote resistance against most biotrophic pathogens.

Biotic challenges and wounding induce rapid JA biosynthesis, with jasmonoyl-L-isoleucine( JA-Ile) being the most active form of JA. In the absence of JA-Ile, JA repressors, JASMONATEZIM-DOMAIN ( JAZ) proteins, bind to the transcription factor MYC2 to inhibit JA signaling (16,134). Upon JA-Ile binding to the receptor complex, consisting of the JA receptor CORONATINEINSENSITIVE1 (COI1; an F-box protein) and JAZ coreceptors, JAZ proteins are targeted for


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ubiquitination and degradation, releasing repression of MYC2 and leading to the activation of JAsignaling (16, 25, 123, 134).

The JA pathway is circadian regulated, as demonstrated in several studies. The JA level oscillatesduring a day with a peak at midday (39) (Figure 3). Expression of some key JA biosynthetic genesis circadian regulated (20), including those directly targeted by CCA1 (99). Expression of somecore JA signaling genes, e.g., COI1, MYC2, and the JAZ genes, also showed circadian cycling thatis dependent on the clock protein TIC (124). TIC interacts with the MYC2 protein and inhibitsMYC2 accumulation. Consistent with the central role of TIC in JA regulation, a tic mutant washypersensitive to JA treatment in a MYC2-dependent manner, suggesting that TIC gates JAsignaling as a negative regulator. This tic mutant was also more susceptible to P. syringae infection,possibly due to increased JA signaling that suppresses SA signaling.

As opposed to P. syringae defense, JAs activate plant defense against insect feeding (14). Themidday peak accumulation of JA is consistent with plants’ anticipation of midday feeding insects,such as the cabbage looper (Trichoplusia ni ) (Figure 3). Chewing of T. ni increased but did notdisrupt the rhythmic timing of JA accumulation in Arabidopsis. JA mutants and plants whose clocksare not in phase with T. ni feeding behavior suffered more tissue loss in the presence of theinsect. Arabidopsis resistance against the necrotrophic pathogen Botrytis cinerea is also time-of-daydependent (Figure 3) and requires several core clock genes and intact JA signaling (52, 60). Inaddition, Arabidopsis activates a series of different defense responses chronologically over the timecourse of B. cinerea invasion (147). Together, these findings support the importance of the circadianclock and the JA pathway in plant defense against herbivores and necrotrophic fungal pathogens.They also highlight that plants activate timed defenses to anticipate attacks from pathogens andpests before the attacks occur and to gate immune responses against specific invaders in a time-of-day-dependent manner. However, whether core clock genes other than TIC activate plant defensethrough a direct control of the rhythms of JA accumulation and/or JA signaling remains to bedetermined.

Circadian regulation of reactive oxygen species. ROS are small molecules produced as by-products during photosynthesis and respiration (35). ROS regulate cell and organ growth andcellular communication, and thus they are important for plant development. ROS productioncan also be induced rapidly and/or abundantly during biotic and abiotic stresses, as describedby the term oxidative bursts (127). ROS can act as signaling molecules to activate defense andstrengthen the cell wall through cross-linking. At high concentrations, ROS are toxic to both hostand pathogen cells, causing lipid peroxidation, protein modification, nucleotide and cell membranedamage, and eventually cell death. The multifunctional role of ROS makes it particularly importantto balance ROS homeostasis in plant cells.

The circadian clock has been implicated in regulating ROS production, scavenging, and sig-naling. The basal level of H2O2, a major type of ROS, showed a circadian pattern with a peak at7 h after dawn (ZT7, where ZT stands for zeitgeber time and indicates the time after lights on)(Figure 3). The peak of H2O2 accumulation is preceded by the expression of many photosyntheticgenes at ZT4 (49), consistent with ROS being by-products of photosynthesis. In addition, the ac-tivity of the ROS-scavenging enzyme catalase, the oxidation and reduction cycle of peroxiredoxinproteins, and the levels of the metabolic redox coenzymes NADP+ and NADPH showed specifictime-of-day peaks (29, 73, 158) (Figure 3). The circadian clock also controls the expression ofROS-related genes (73). Of 517 ROS-related Arabidopsis genes, including genes involved in ROSproducing, scavenging, and signaling, 39% show rhythmic expression under circadian conditions.The cycling expression of these ROS genes is largely dependent on CCA1, ELF3, LUX, andTOC1. Even some of the noncycling ROS genes are regulated by these core clock components.


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In particular, CCA1 binds to some ROS gene promoters that are enriched with EE and CBSmotifs. Mutations in CCA1 and LHY led to higher ROS accumulation, reduced catalase activity,and altered response to some ROS-inducing reagents (73). Like CCA1 and LHY, several otherTTFL components, including ELF3, ELF4, LUX, TIC, PRR5, PRR7, PPR9, and GI, were alsoshown to gate responses to ROS stress (72, 73). Although these studies unequivocally establish arole of the TTFL clock in ROS control under nonchallenged conditions, a recent study showedthat the redox cycle of the highly conserved peroxiredoxin proteins persists even in the absence offunctional TTFL genes in all three domains of life: bacteria, archaea, and eukaryota (29). Thus,sensing and responding to oxidative cycles could be intrinsic metabolic processes independentof clock TTFLs. Redox status in the unstressed cellular environment depends on the intimatecoordination between the metabolic clock and the TTFL clock.

Although its role in regulating ROS homeostasis and signaling under unchallenged conditionsis relatively well understood, how the circadian clock affects oxidative bursts during plant-pathogeninteractions is less clear. Whereas whether the metabolic clock could affect oxidative bursts re-mains to be determined, the TTFL clock likely has such a role on the basis of prevailing tran-scriptional control of diel expression of ROS-related genes by TTFL components in non-stressedplants. However, how TTFL proteins affect the expression of ROS-related genes under pathogenchallenge is still an open question. Some cycling ROS genes, e.g., AtrbohD and PEROXIDASE(Figure 3), are known to be part of defense networks (1, 135, 136). Whether TTFL componentsdirectly control these ROS-related defense genes remains to be determined. ROS distribution atthe subcellular level shows a distinct spatial, temporal, and quantitative pattern during PTI, ETI,and ETS, possibly due to differential activation of different ROS production and/or scavengingenzymes (46). It is unknown whether the circadian clock affects such a ROS distribution patternunder stress conditions. Further research is needed to address these questions and gain insightsinto circadian regulation of ROS during plant-pathogen interactions.

RECIPROCAL REGULATION OF THE CIRCADIAN CLOCKBY PATHOGEN INFECTION

The circadian clock is an endogenous timekeeper that can be reset by zeitgebers such as light,temperature, nutrient status, and hormone signaling (45, 48, 54, 111, 119). A growing body ofevidence indicates that pathogen infection can also reciprocally regulate clock activity in plants(Figure 1a). For instance, infection with both virulent and avirulent P. syringae strains can shortenthe plant circadian period as measured by luciferase activity driven by the CCA1 or GRP7 promoter(CCA1:LUC or GRP7:LUC) (155). Rhythmic expression of CCA1 can also be disrupted by infec-tion with the oomycete pathogen Hpa and is dependent on the R gene RPP4 (143). In addition,infection by the necrotrophic pathogen B. cinerea dampens oscillations of a number of core clockgenes, including CCA1, although neither the expression phase nor the period of these genes isaltered (147). Thus, a change in clock activity appears to be a common host response to pathogeninfections. It is worth mentioning that all these infections are associated with programmed celldeath in the infected tissue, which may account for the altered clock activity. However, whetheran acute pathogen attack without causing host cell death could perturb clock activity remains tobe determined. Pathogen-induced host clock change could be a host mechanism to balance costlydisease resistance with primary metabolism, thereby maximizing host growth and development ofplants. It could also offer a strategy on the part of the pathogens to manipulate the host immunesystem to acquire resources.

How does pathogen challenge affect the host circadian clock? There is a paucity of data to di-rectly link pathogen manipulation of the central oscillator. Instead, studies suggest that pathogens


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could use PAMPs, effectors, and other molecules to at least indirectly hijack the plant circadianclock. For instance, P. syringae could use its PAMP molecules, such as flg22, to shorten cyclingof CCA1:LUC or use the effector HopU1 to target GRP7 and thus affect CCA1-mediated clockoutputs (34, 155).

Pathogen-induced host clock change could also be caused by the manipulation of hormonesignaling. For instance, P. syringae effectors could activate the production and/or signaling ofauxin and abscisic acid in Arabidopsis (15, 24, 101). Although they are clock regulated, these twogrowth hormones also reciprocally regulate clock activity and thus could be targeted by pathogensto influence the plant clock and defense. Besides growth hormones, the two defense hormonesSA and JA are also frequent targets of pathogens for manipulation. P. syringae strains employseveral mechanisms to manipulate host defense signaling mediated by JA, using the toxin chemicalcoronatine to mimic JA or effectors to interfere with JA signaling (8, 36, 63, 65). Although JA isnot known to affect clock activity, these studies support the hypothesis that pathogen infectionaffects at least some clock outputs. As with JA, SA production and signaling can be modulatedby various pathogens (132). SA may reciprocally regulate the circadian clock, depending on plantdevelopmental stage, because this role of SA was shown only with soil-grown 3-week-old plantsbut not with plate-grown 10-day-old seedlings (48, 155, 158). Because SA induces redox changesin plants and the master immune regulator NPR1 and its interacting TGA transcription factors arealso important redox sensors in Arabidopsis (51, 97, 131), the role of SA in clock regulation couldstem from cross talk between SA and redox state. Indeed, Zhou et al. (158) showed that NPR1exerts redox-sensitive transcriptional regulation of several TTFL genes, including LHY, PRR7,and TOC1, in the absence of pathogen challenge. In particular, NPR1 and some TGA proteinsbind directly to the TOC1 promoter to regulate its expression. In response to acute perturbationin the redox status triggered by SA, the upregulation of both morning (LHY and PRR7) andevening (TOC1) clock genes by NPR1 reinforces rather than disrupts circadian rhythmicity. Thereinforced clock is critical in gating of immune responses in a time-of-day-specific manner tominimize interference with other cellular processes, for example, confining a robust immuneresponse in the morning could minimize costs on growth at night. Thus, reciprocal regulation ofthe circadian clock and defense could confer enhanced fitness to plants.

PATHOGEN CLOCK

One fascinating idea for host-pathogen coevolution would be that the coordination of circadianclocks from pathogens, pests, and their hosts could shape the outcome of interactions at theorganismal level. Although much is known about host circadian clocks, especially in the modelplant Arabidopsis, studies on pathogen and pest clocks lag behind.

It is not known whether P. syringae has a circadian clock, although its genome contains severalconserved clock genes found in other organisms. Many fungal and oomycete pathogens exhibittime-of-day-dependent hyphae development, sporulation, and spore dissemination, suggestingthe involvement of the circadian clock (11, 74, 110, 118). Indeed, some clock genes identifiedin fungal species were shown to be important for the virulence and development of fungi. Forinstance, a mutation in the bcfrq1 gene of B. cinerea, a homolog of the core clock gene frq inN. crassa, adversely affected the reproduction and virulence of B. cinerea (52). The N. crassa whitecollar-1 (wc-1) ortholog in Magnaporthe oryzae, the causal agent for rice blight disease, regulatesblue-light-specific asexual development, conidia release, and light-dependent disease suppression(67, 74). The fungal causal agent of gray leaf spot disease in maize, Cercospora zeae-maydis, also hasa wc-1 homolog, crp1, which regulates stomatal tropism, appressoria formation, conidiation, andpathogenicity of the fungus (67). In addition, insects can use their circadian clocks to keep pace


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with oviposition, feeding, hatching, and locomotor activities (17, 19, 88, 108, 115). Interestingly,a recent study showed that it is the circadian clock of B. cinerea, but not that of its host Arabidopsis,that dictates the outcome of B. cinerea–Arabidopsis interactions (52). However, the paucity of data onpathogen and pest circadian clocks makes it difficult to assess whether the coordination of circadianclocks between plants and their invaders generally determines the outcomes of interactions at theorganismal level. This clearly represents fertile ground for further study.

TIMED DEFENSE AND PLANT FITNESS

Plant growth, development, and responses to environmental stimuli are energy-costly processesthat can be in conflict through competition for limited resources or via other forms of interference,such as the generation of an intermediate in one pathway that interferes with a second process.Resolution of such potential conflicts can entail spatial segregation of conflicting processes intodifferent cells or subcellular compartments or, alternatively, can entail a temporal separation.Thus, a properly tuned circadian clock has a profound influence on the fitness of Arabidopsis andnatural populations related to Arabidopsis during development and response to abiotic stresses (26,28, 40, 41, 94, 105). This role of the circadian clock has not been well understood in plants underbiotic stresses.

Because plants encounter different pathogens and pests at different times of day, it is conceivablethat plants have evolved the ability to time defense responses to anticipate when the invasion of acertain pathogen or pest most likely occurs and to gate immune responses to individual invaders ata specific time of day. The amplitude of such anticipated defense responses is usually much smallerthan that induced by biotic challenges. Such low and rhythmic responses likely reflect the rhythmicregulation of chromatin accessibility to some transcription factors. In the presence of pathogensand pests, the open chromatin structure permits the access of defense-related transcription factorsand thus primes plants to mount much stronger defense responses. The circadian clock couldgate the priming response at the peak of the basal oscillation as shown in T. ni–induced JAaccumulation (38). This priming mechanism by the circadian clock appears to be widespread forother clock outputs and in other organisms (4, 50, 91). Alternatively, induced defense could beacute and independent of circadian oscillation as shown in P. syringae–induced SA accumulation(46). Whether such acute defense responses are also directly regulated by the circadian clockremains to be addressed. Defense activation could also reinforce the circadian clock, leading tomore restricted immune responses at a specific time of day and subsequently minimizing costlyeffects associated with defense (158). Thus, timed defense likely reflects the adaptive nature ofplants to their pathogens and pests.

The importance of such timed defense with the right strategy has already been demonstratedin Arabidopsis because clock dysfunction results in compromised resistance to broad-spectrumpathogens and pests (Table 1). Activating defense at the wrong time is detrimental (158), andconstitutive defense activation could be at the cost of shortening the plant life cycle and/or reducingbiomass (3, 78, 140). In natural populations related to Arabidopsis, hybrid plants show growth rigorwhen their stress genes are expressed in a timed manner, whereas necrosis occurs when thesegenes are constitutively expressed (95). Together, these observations indicate that the circadianclock-timed defense confers a fitness advantage in Arabidopsis plants.

Our understanding of the mechanisms of plant timekeeping and defense is largely derivedfrom studies of Arabidopsis. It is broadly assumed that the Arabidopsis model applies to plants ingeneral, but the degree to which this Arabidopsis-centric view of the circadian clock and defensecan be extrapolated to other plants has not been tested in detail. As in Arabidopsis, widespreadcircadian regulation of gene expression is found in most plants, including important crop species


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such as poplar, soybean, rice, and maize (53, 61, 81, 84). Orthologs of Arabidopsis clock genes areidentified in other species, but few studies have established the importance of those orthologs toclock function or defense regulation (9, 85, 128). For instance, Arabidopsis orthologs of GI, eachof the PRRs, and the evening complex genes ELF3, ELF4, and LUX/NOX are known to serve asimportant determinants of flowering time in a number of crops, including beet, soybean, pea, rice,barley, wheat, sorghum, and maize (9, 128). Only GI, ELF3, ELF4, and LUX have been establishedto function in the circadian clocks in some plants, and the functions of the PRR genes seem tobe restricted to flowering time determination. None of these crop clock ortholog genes has yetbeen shown to play a role in regulating plant defense. Although the molecular mechanisms ofthe clock genes remain to be determined in non-Arabidopsis plants, at least two studies suggestthat the circadian clock of some crop plants enhances plant fitness and performance (43, 98).In particular, the circadian clock has played a significant role in tomato domestication becausetomato has been selected for lagging phase and lengthened period, presumably as an adaptation tothe longer and seasonally variable photoperiods encountered in the northern latitudes of Europeand North America (98). Additional studies in more crop species and functional characterizationof Arabidopsis clock ortholog genes in crop plants are necessary to establish and substantiate ageneral role of the circadian clock in enhancing fitness in crop plants, especially under biotic stressconditions.

CONCLUDING REMARKS

The circadian clock is clearly an integral part of the plant innate immune system and is criticalfor multiple layers of defense responses and broad-spectrum resistance against various pathogensand pests. Timed defense to anticipate attacks from pathogens and pests and to gate immuneresponses to individual invasions at a specific time of day could be an adaptation of plants gainedthrough coevolution with their pathogens and pests. We are still at the beginning of understand-ing the role the circadian clock plays in defense regulation. Much work remains to be done toelucidate the underlying molecular mechanisms in clock-defense cross talk, including but not lim-ited to high-resolution time-series experiments with biotic challenges, systems biology to modellarge-scale data sets related to circadian and defense conditions, and identification and detailedcharacterization of biochemical functions of some genes regulating the clock-defense cross talk.Knowledge obtained from such studies and the uncovering of genes acting at the converging pointof regulating the circadian clock and defense could be applied to improve disease resistance andproductivity in economically important crop plants.

SUMMARY POINTS

1. The circadian clock regulates plant defense against a broad spectrum of pathogens andpests.

2. The circadian clock affects both preformed and induced defense. This review focuses oncircadian regulation of stomatal defense, PTI, ETI, defense gene expression, and defensesignaling pathways mediated by SA, JA, and ROS.

3. Pathogen infection can reciprocally affect clock activity of the host through mechanismsthat are not yet well understood.

4. Some pathogens and pests have their own circadian clocks, which could be important fortheir interactions with the hosts.


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5. Timed defense means that plants incorporate external and internal time cues to anticipatelikely attacks from invaders at different times of day and ready defense responses for rapiddeployment to individual invaders at a specific time of day.

6. Successful manipulation of timed defense could be an important strategy to improvedisease resistance and productivity of economically important crop plants.

FUTURE ISSUES

1. The circadian clock affects multiple aspects of defense responses under challenged ornonchallenged conditions, but most mechanistic details remain incompletely elucidated.

2. The extent to which the plant innate immune response feeds back to modulate circadianclock function remains unclear, and the pathways by which this feedback is exerted needto be established.

3. The circadian clocks of pathogens and pests affect their virulence, as has been establishedin B. cinerea and T. ni, but the mechanistic understanding of this regulation remainslimited.

4. It will be important to understand the temporal coordination between pathogens andpests and their hosts, using their circadian clocks, and how such coordination contributesto the outcome of the interactions at the organismal level.

5. The circadian clock increases fitness by temporally partitioning potentially conflictingbiological processes to distinct times of day. In considering biotic challenge, this is usuallysimplified as a conflict between growth and defense, but this needs to be refined to identifymore precisely the conflicts between biological processes and defense responses.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

We thank Matt Fabian at UMBC for assistance with the figures. This work is supported by grantsfrom the National Science Foundation (IOS-1456140 to H.L. and C.R.M. and IOS-1025965 toC.R.M.) and the Next-Generation BioGreen21 Program, Rural Development Administration,Republic of Korea (SSAC PJ01106904 to C.R.M.).

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PY55_FrontMatter ARI 15 July 2017 11:31

Annual Review ofPhytopathology

Volume 55, 2017Contents

A Career on Both Sides of the Atlantic: Memoirs of a MolecularPlant PathologistNickolas J. Panopoulos � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Fusarium oxysporum and the Fusarium Wilt SyndromeThomas R. Gordon � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �23

The Evidential Basis of Decision Making in Plant Disease ManagementGareth Hughes � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �41

Ecology and Genomic Insights into Plant-Pathogenic andPlant-Nonpathogenic EndophytesGunter Brader, Stephane Compant, Kathryn Vescio, Birgit Mitter,

Friederike Trognitz, Li-Jun Ma, and Angela Sessitsch � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �61

Silicon’s Role in Abiotic and Biotic Plant StressesDaniel Debona, Fabrıcio A. Rodrigues, and Lawrence E. Datnoff � � � � � � � � � � � � � � � � � � � � � � � � � �85

From Chaos to Harmony: Responses and Signaling upon MicrobialPattern RecognitionXiao Yu, Baomin Feng, Ping He, and Libo Shan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 109

Exploiting Genetic Information to Trace Plant Virus Dispersalin LandscapesCoralie Picard, Sylvie Dallot, Kirstyn Brunker, Karine Berthier,

Philippe Roumagnac, Samuel Soubeyrand, Emmanuel Jacquot,and Gael Thebaud � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 139

Toxin-Antitoxin Systems: Implications for Plant DiseaseT. Shidore and L.R. Triplett � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 161

Targeting Fungicide Inputs According to NeedLise N. Jørgensen, F. van den Bosch, R.P. Oliver, T.M. Heick, and N.D. Paveley � � � � � 181

What Do We Know About NOD-Like Receptors In Plant Immunity?Xiaoxiao Zhang, Peter N. Dodds, and Maud Bernoux � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 205

Cucumber green mottle mosaic virus: Rapidly Increasing GlobalDistribution, Etiology, Epidemiology, and ManagementAviv Dombrovsky, Lucy T.T. Tran-Nguyen, and Roger A.C. Jones � � � � � � � � � � � � � � � � � � � � � 231

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Function, Discovery, and Exploitation of Plant Pattern RecognitionReceptors for Broad-Spectrum Disease ResistanceFreddy Boutrot and Cyril Zipfel � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 257

Tick Tock: Circadian Regulation of Plant Innate ImmunityHua Lu, C. Robertson McClung, and Chong Zhang � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 287

Tritrophic Interactions: Microbe-Mediated Plant Effectson Insect HerbivoresIkkei Shikano, Cristina Rosa, Ching-Wen Tan, and Gary W. Felton � � � � � � � � � � � � � � � � � � � 313

Genome Evolution of Plant-Parasitic NematodesTaisei Kikuchi, Sebastian Eves-van den Akker, and John T. Jones � � � � � � � � � � � � � � � � � � � � � � 333

Iron and ImmunityEline H. Verbon, Pauline L. Trapet, Ioannis A. Stringlis, Sophie Kruijs,

Peter A.H.M. Bakker, and Corne M.J. Pieterse � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 355

The Scientific, Economic, and Social Impacts of the New ZealandOutbreak of Bacterial Canker of Kiwifruit (Pseudomonas syringaepv. actinidiae)Joel L. Vanneste � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 377

Evolution of Hormone Signaling Networks in Plant DefenseMatthias L. Berens, Hannah M. Berry, Akira Mine, Cristiana T. Argueso,

and Kenichi Tsuda � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 401

Adaptation to the Host Environment by Plant-Pathogenic FungiH. Charlotte van der Does and Martijn Rep � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 427

The Candidatus Liberibacter–Host Interface: Insights intoPathogenesis Mechanisms and Disease ControlNian Wang, Elizabeth A. Pierson, Joao Carlos Setubal, Jin Xu,

Julien G. Levy, Yunzeng Zhang, Jinyun Li, Luiz Thiberio Rangel,and Joaquim Martins Jr. � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 451

Karyotype Variability in Plant-Pathogenic FungiRahim Mehrabi, Amir Mirzadi Gohari, and Gert H.J. Kema � � � � � � � � � � � � � � � � � � � � � � � � � � 483

Fatty Acid– and Lipid-Mediated Signaling in Plant DefenseGah-Hyun Lim, Richa Singhal, Aardra Kachroo, and Pradeep Kachroo � � � � � � � � � � � � � � � � 505

Adapted Biotroph Manipulation of Plant Cell PloidyMary C. Wildermuth, Michael A. Steinwand, Amanda G. McRae,

Johan Jaenisch, and Divya Chandran � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 537

Interplay Between Innate Immunity and the Plant MicrobiotaStephane Hacquard, Stijn Spaepen, Ruben Garrido-Oter, and Paul Schulze-Lefert � � � � 565

vi Contents

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Surveillance to Inform Control of Emerging Plant Diseases:An Epidemiological PerspectiveStephen Parnell, Frank van den Bosch, Tim Gottwald,

and Christopher A. Gilligan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 591

Errata

An online log of corrections to Annual Review of Phytopathology articles may be found athttp://www.annualreviews.org/errata/phyto

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