Growth versus immunity : a redirection of the cell cycle?

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Eichmann, Ruth and Schäfer, Patrick. (2015) Growth versus immunity—a redirection of

the cell cycle? Current Opinion in Plant Biology, 26. pp. 106-112.

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Growth

versus

immunity

—

a

redirection

of

the

cell

cycle?

Ruth

Eichmann

and

Patrick

Scha¨fer

Diseasescausedbyplantpathogenssignificantlyreduce growthandyieldinagriculturalcropproduction.Raising immunityincropsisthereforeamajoraiminbreeding programs.However,effortstoenhanceimmunityare challengedbytheoccurrenceofgrowthinhibitiontriggered byimmunitythatcanbeasdetrimentalasdiseases.Inthis review,wewillproposemolecularmodels toexplainthe inhibitorygrowth-immunitycrosstalk.Wewillbrieflydiscuss whytheresourcereallocationmodelmightnotrepresent thedrivingforcefortheobservedgrowth-immunity trade-offs.Wesuggestamodelinwhichimmunityredirectsand initiateshormonesignallingactivitiesthat canimpairplant growthbyantagonisingcellcycle regulationandmeristem activities.

Addresses

1_{SchoolofLifeSciences,UniversityofWarwick,GibbetHill,CV47AL} Coventry,UK

2

WarwickIntegrativeSyntheticBiologyCentre,UniversityofWarwick, GibbetHill,CV47ALCoventry,UK

Correspondingauthor:Scha¨fer,Patrick([email protected])

Current Opinion in Plant Biology 2015,26:106–112

ThisreviewcomesfromathemedissueonBiotic interactions

EditedbyUta Paszkowski andD Barry Scott

http://dx.doi.org/10.1016/j.pbi.2015.06.006

1369-5266/# 2015TheAuthors.PublishedbyElsevierLtd.Thisisan openaccessarticleundertheCCBYlicense(http://creativecommons. org/licenses/by/4.0/).

Introduction

Undercurrentclimates,bioticstressisamajorthreat in cropproductionaccountingforupto20–40%annualcrop yieldreduction[1].Inadditionto moreelaborated agri-cultural crop management and phytomedical strategies, we need to generate crop cultivars with a higheryield underbioticstress.Plantshaveevolvedahighlyeffective multi-layered immune system to encounter pathogen attack. Immunity relies on the recognition of non-self moleculesofmicrobialoriginthataredefinedas microbe-associated molecular patterns (MAMPs) and include fungal chitin, bacterial peptidoglycans, flagellin (flg) or elongationfactorTu(EF-Tu).MAMPsarerecognisedby plasmamembrane-localisedpatternrecognitionreceptors (PRRs)therebyactivatingabroadrepertoireofimmune responsesknownaspattern-triggeredimmunity(PTI)to

stopinvaders [2,3].Inresponseto PTI,pathogenshave evolved counter defence strategies that are based on secreted effector proteins, whose action in the plant apoplast and cytosol enables the suppression of PTI andrelease ofnutrients [4,5].The detectionof effector actionbyplantresistance(R)proteinsthatbelongtothe classof nucleotide-binding site leucine-rich repeat pro-teins (NLRs) activates effector-triggered immunity (ETI),whichischaracterisedbyhigherimmuneresponse kineticsthanPTIand involvescelldeath[6–8].

Based onthis concept andassuming asufficiently high selectionpressure,onewouldexpectthatplants accumu-late a highly diverse receptor arsenal to launch innate immune strategies that are almost unsurmountable by pathogens. In clear contrast, plants display ahigh vari-ability in the degree of immunity [9] suggesting the existenceof adownside ofimmunity.Infact,immunity is associated with fitness costs, and a hyper-active im-munesystemcandepleteanybenefitsintheabsenceof pathogens [10,11]. These fitness costs that range from growthinhibitiontolethalityareobservedatthelevelof PTIandETI[9,12,13] andcanaffectplant growthand yieldto anextentequivalenttothat causedbydiseases [14–16].Therefore,breedingforenhancedimmunityand growthincropsmustbebalancedespeciallyasweknow that growth signalling suppresses immunity [17,18]. Thisreviewwillsummariseourcurrentunderstandingof growth-immunitytrade-offsandproposeamolecularbasis of immunity-triggered growth inhibition. Focussing on roots,wediscussthefunctionofhormonesintheregulation ofthecellcycleasdrivingforceofgrowth,andhighlight recentfindingsontheinterplayofcellcycleandimmunity.

The

growth-immunity

trade-offs

causes10%yieldreduction[15].Thenegativepotential ofthegrowth-immunitytrade-offisobviousfromgenetic studies. In Arabidopsis, constitutive immunity (non-le-thal autoimmunity) reduced growth and yieldby up to 90%[9,16].Moreover,naturalpopulationsofArabidopsis carrygeneticallyincompatibleallelesof the PTI-regula-torACCELERATEDCELLDEATH6(ACD6)whose combination resultsinF1 progenies withstrong growth inhibition duetoautoimmunity[9,26].

Is

immunity-triggered

growth

inhibition

a

default

response?

Considering thehigh energy demand of immunity and growth, the observed growth-immunity trade-off might reflect acompetitionfor availableenergy resources and nutrients that are too limited to be allocated to both processessimultaneously[10,11,15].Forinstance, immu-nitycanaffectwheatgrowthunderNdepletion[11].But under standard nutrient regimes, energy and nutrient availability appears not to be a limiting factor in crops [27] and a recent study did not observe a correlation betweenNorClimitationanddefence[28].Inaddition, PTI activation does not necessarily suppress growth. TreatmentwiththeMAMPchitinblockspathogen inva-sionbyactivatingimmuneresponseshighlysimilartoflg orEF-Tuwithoutaffectinggrowth[29,30].Moreover,the Arabidopsis ecotype C24 has elevated pathogen resis-tance due to immunity levelsthat are higher than that observed in the autoimmunity and dwarf mutant cpr6-1.However,C24wasnotimpairedinyield[16,31].These studiesindicatethatPTIactivationdoesnotnecessarily affect growthand thismight hold truefor ETI aswell. AlthoughresistanceconferredbytheNLRRPM1affects growthandyield[14],overexpressionofotherRproteins does not seem to be costly to the plant [10]. Taken together, the growth-immunity trade-off is most likely not attributable to resource reallocation. Instead it appearsasifthegrowth-immunitycrosstalkistheresult of a conflictive activation of pathways or sharing of signallingcomponentsbyimmuneandgrowthsignalling.

Hormones

—

mediators

of

growth

and

immune

signalling

Hormones translateinternal andexternalstimuliwithin andacrosscellstherebyprovidingplantswitha consider-able degree of plasticity to grow and survive under changingenvironments.Thiscomplexityrequiresatight regulationasindividualhormonesignallingpathwaysare intertwinedandanyregulatorydisorderwouldimpairthis network and thus disturbgrowth or immunity. Various studiesofthelastdecadehaverevisedourunderstanding ofthefunctionofhormonesingrowthandimmunity.The canonicalgrowthhormonesauxin,brassinosteroids(BR), gibberellins (GA), cytokinins (CY) and strigolactones (SL) werefoundto affectimmunesignalling,whilethe typical stress hormones salicylic acid (SA), jasmonates (JA), ethylene (ET) and abscisic acid (ABA) influence

growthanddevelopment[32–34].Thesestudiessuggest thatindividualhormonesmediatethemutuallyinhibitory growth-immunitycrosstalk.Thetransitionfromagrowth (non-stressed) to an active immunity modus and vice versarequiresahormone-orchestratedrewiringofgrowth andimmunesignalling.Thecontributionofhormonesin growth-immunity trade-offshasrecently beenreviewed [35,36].Here,webrieflysummarise examplesofspecific hormonesthatprovideadirectlinktoparticularaspectsof growthregulation.Recentstudieshighlightedthefunction oftheBRpathwayinsuppressingPTI.UponBR recogni-tion,BRASSINOSTEROID-INSENSITIVE1(BRI1) to-getherwithBRI1-ASSOCIATEDRECEPTORKINASE 1 (BAK1)initiatesasignallingcascadeinwhichthe suc-cessive phosphorylation of BOTRYTIS-INDUCED KI-NASE1(BIK1),BRASSINOSTEROID-SIGNALLING KINASE 1 (BSK1) and BRI1-SUPPRESSOR1 (BSU1) resultsintheinactivationofthenegativeregulator BRAS-SINOSTEROID-INSENSITIVE 2 (BIN2) and hence the activation of transcription factors (TFs) including

bHLH HOMOLOG OF BR ENHANCED

EXPRES-SION2 INTERACTING WITH INCREASED LEAF

INCLINATION1BINDINGbHLH1(HBI1)and BRAS-SINAZOLE-RESISTANT1(BZR1)[17,37,38].BRand especially the flg-induced PTI pathways share BAK1, BIK1 and BSK1 [37,39,40]. It is still not entirely clear howtheseproteinscanserveBRandPTIpathwaysatthe sametimeandiftheyparticipateinthegrowth-immunity crosstalk.Currently,theTFsBZR1andHBI1are consid-ered crucial regulatory nodes in thiscrosstalk. Both can transcriptionally activategrowth-relatedgenesbut nega-tivelyregulateimmuneresponsesandthussuppressPTI [17,18].ThesestudiesindicateaprominentroleofBR in growth-triggeredsuppressionofPTI. Butwe areonly just beginning to understand how PTI inhibitsgrowth. The BR-PTI crosstalk depends on GA signalling since inhibitionofGAsynthesisabolishesthe immunosuppres-siveBReffect.GAandBRco-treatmenthadanadditive effectonblockingflg-triggeredgrowthinhibition[18].In theabsenceofGA,DELLAproteinscaninteractwithand

inhibit the TFs PHYTOCHROME INTERACTING

FACTORs(PIFs)andBZR1andblockgrowthresponses. InthepresenceofGA,DELLAproteinsaredegradedand releasePIFsandBZR1topromotegrowth[41]and sup-pressPTI(seeabove).Thisisinaccordancewithresults that showed that flg-mediated stabilisation of DELLA proteins contributed to PTI-triggered growth inhibition [42]. In addition to GA, auxin affects PTI. Navarro

et al. [43] showed that PTI induced miR393to silence theauxinreceptorsTIR1,AFB2andAFB3andenhanced resistance against the bacterial pathogen Pseudomonas syringae.Althoughthisstudyprovidedaclearconnection between PTIandthegrowthhormoneauxin, itwasnot shown whether auxin receptorsilencing correlated with growth inhibition. That impaired auxin signalling can contribute to the growth-immunity trade-off might be indicated by the dwarfed phenotype of non-lethal

autoimmunity mutants (e.g. cpr5, cpr6 and snc1). This dwarfismwasexplainedbyelevatedSAcontents,which mightstabiliseAUX/IAArepressorsandsuppressed auxin-regulatedgenes[44].JAmightrepresentanotherhubinthe growth-immunity crosstalk. JA treatment suppressed growthandwasshowntoinhibitauxindistributioninroots [45].Moreover,JAZIMDOMAIN(JAZ)proteins,which are suppressors of JA signalling, bind to DELLAs and disabletheirrepressiveinteractionwithgrowthpromoting TFs. JA treatment, in turn, induces JAZ degradation therebyreleasingthegrowthinhibitoryactivityof DEL-LAs[46,47,48].

Whilethesestudieshaveadvancedourunderstandingof thegrowthandimmunity-relatedhormoneinteractions,it is still mostly unclear how this redirection of hormone activities translates into cellular processes regulating plantgrowth.

Hormones

regulate

the

cell

cycle

Growth depends on cell proliferation and expansion, which is regulated by the cell cycle machinery. The mitoticcellcycle(MCC)controlscellnumberattheroot

stem cell niche and meristematic zone, whereas the endocycleenhancescellploidylevelsassociatedwithcell expansionat the elongationzone [49,50].The MCC is definedby fourphases: Gap1 phase (G1), followedby DNAsynthesis(S)andGap2phase(G2)andterminating incellcycleexitaftermitosis(M)(Figure1a).Cellcycle progression depends on coordinated G1-S and G2-M transitions with CYCLIN-DEPENDENT-KINASES (CDKs)incomplexwithCYCLINS(CYCs)asthemain regulators in thesetransitions. MCC entryis associated withthe activationof CDKA;1in complexwith CYCD andCYCA3as wellas theCDKB1-CYCB/CYCA2 com-plextophosphorylatetherepressor RETINOBLASTO-MA-RELATED1(RBR1) [51,52]. Thisessentialstep inG1-Stransitionallowsheterodimerisationof the tran-scriptionfactorsE2FaandE2FbwithDIMERISATION PARTNERa (DPa) to induce genes mediating DNA synthesis [53,54]. At the same time, SCFSKP2a might degrade the repressor dimer E2Fc-DPb [55]. For the subsequent G2-M transition, CDKA;1-CYCD3/CYCB1 andCDKB1-CYCA3/CYCBcomplexesactivate transcrip-tionfactors(e.g. MYB3R)to inducegenes participating inmitosisandcytokinesis[56].

Figure 1

DNA synthesis genes

E2Fc

DPbE2FbDPa

RBR1KRPs E2Fa DPa DELLAs CDKA;1 CDKA;1 MYB3Rs CDKB1/2 UVI4/ PYM GIG1/ OSD1 G1-S G2-M CYCA/D DKB1/2CYCA/B

DKA 1CYCB/D

GA CK Endoc yc le EDZ TZ MZ EDZ TZ MZ S G DNA synthesis genes E2Fc

DPbE2FbDPa

RBR1KRPs SIM/SMR APC/C

E2Fa DPa DELLAs CDKA;1 _CDKA;1 MYB3Rs Mitosis genes CDKB1/2 UVI4/ PYM GIG1/ OSD1 G1-S G2-M CYCA/D CYCA/B C/C CCS52 C/C CDC20 CYCB/D GA BR Auxin

Mitotic Cell Cyc

le S G2 G1 M DNA synthesis genes E2Fc DPbE2FbDPa

RBR1 KRPs

E2Fa DPa

DELLAs SIM/SMRAPC/C

CDC20 CCS52 CDKA;1 _CDKA;1 MYB3Rs CDKB1/2 UVI4/ PYM GIG1/ OSD1 G1-S G2-M CYCA/D DKB1/2CYCA/B

DKA 1CYCB/D

GA JA JA CK Endoc yc le S G DNA synthesis genes E2Fc DPbE2FbDPa

RBR1KRPs SIM/SMRAPC/C

E2Fa DPa DELLAs CDKA;1 CDKA;1 MYB3Rs Mitosis genes CDKB1/2 UVI4/ PYM GIG1/ OSD1 G1-S G2-M CYCA/D DKB1/2 CYCA/B C/C CCS52 C/C CDC20

DKA 1CYCB/D

GA BR SA Auxin

Mitotic Cell Cyc

le S G2 G1 M (a) (c) (b) (d)

Current Opinion in Plant Biology

SIM/SMRAPC/C

CDC20 CCS52

In contrast to the MCC, the endocycle does not enter mitosis and consists of a G and S phase resulting in repeated DNA synthesis cycles without cell division (Figure1b).Theestablishmentoftheendocycledepends onKIP-RELATEDPROTEINs(KRPs)andSIAMESE (SIM)/SIM-RELATED(SMR)toinhibitCDKA/B com-plex formationand,hence,G2-Mtransition[57,58]. Ad-ditionally, the E3 ligase ANAPHASE-PROMOTING COMPLEX/CYCLOSOME (APC/C) interacts with co-activators CELL CYCLE SWITCH 52 (CCS52) and CELLDIVISIONCYCLE20[CDC20]todegradeCYCBs and CYCA2sand establish the endocycle[59,60]. Endo-cycle onset isantagonised by the interactionof UV-IN-SENSITIVE4 (UVI4)/POLYCOME (PYM) and GIGAS CELL1(GIG1)/OMISSIONOFSECONDDIVISION1 (OSD1)withCCS52AandCDC20[61,62].

Auxin, BR, CK and GAplay central roles in cellcycle regulation(Figure1a,b).Auxin,BRandGApromotethe initiation and progressionof celldivision.The reduced meristemsizesobservedwhenBRandGAactivitiesare disturbed, correlate with reduced CYCB1;1 expression and,forBRonly,enhancedKRP2expression[63,64]

]aswellasDELLA-mediatedstabilisationofKRP2and induction of KRP2,SIM and SMRs [65]. Auxin induces

CYCA2;3 and CYCB1;1 and elevates CDKB2 gene and proteinlevelsto promoteMCC[66,67].Asauxinlevels decreasetowardsthetransitionzone,CKlevelsincrease to abort cell division and initiate endocycle entry and, hence,celldifferentiation.Takahashietal.[68b] identi-fiedCK-responsiveARABIDOPSISRESPONSE REG-ULATOR2 (ARR2) binding to CCS52A to mediate endocycleentry.Tosummarise,anydisturbanceor redi-rectioninhormonesignallingcanhavesignificantimpact on root growth and development and might explain immunity-triggeredinhibition ofrootgrowth.

The

redirection

of

the

cell

cycle

machinery

by

immunity

Althoughourknowledgeisstillfragmentaryitisobvious thatimmunitycansignificantlyaffecthormone-cellcycle networks(Figure1c,d).Forinstance,SA-mediated inhi-bition of growth might be directly associated with its suppressiveactivityonauxinsignalling[44].Inleaves,JA arrests growthby inhibiting MCCand endocycle[68a]. Interestingly,thereducedrootmeristemactivityafterJA treatment was found to bebased onthesuppression of genes participating in mitosis (e.g. CDKA;1, CYCB1;1), and this effectmightbe directlyconnectedto DELLA stabilisation [48,69]. Furthermore, the JA-regulatory TFMYC2bindstothePLETHORA1(PLT1)andPLT2

promoters to suppresstheirtranscription[69].In con-certwithauxin,PLTsdeterminerootgrowthand devel-opmentbyregulatingcelldivision,stemcellmaintenance and therootzonation (in themeristem,elongation, dif-ferentiation zone)[70].Thereduced meristemsize and disturbed zonationpatternupon JAtreatmentmight be

partially explained by antagonising auxin and PLT1/2 activities.

Asimmuneresponsesinvolvehormones,suchasJA,SA, GA and auxin, roots translate biotic stress into altered growth and development. Several studies identified a directconnection betweenimmunityand thecellcycle machinery: In Arabidopsis,overexpression of UVI4 and

OSD1 or loss of the atypical DP-E2F-LIKE1 (DEL1/

E2Fe) resulted in dwarfed phenotypes and enhanced resistance against P. syringae DC3000 and the powdery mildew fungus Golovinomyces orontii, respectively [71]. Interestingly, in addition to being a negative regulator ofCCS52a2,DEL1wasfoundtonegativelyregulatethe SA transporter ENHANCED DISEASE SUSCEPTI-BILITY5(EDS5)[72].TheenhancedSAaccumulation andslightdwarfismindel1-1waseliminatedbydeleting theSA synthesis geneISOCHORISMATE SYNTHASE1

(ICS1). Consistent with this, silencing of SA signalling genePHYTOALEXIN-DEFICIENT 4 (PAD4) abolished stuntedgrowthinUVI4andOSD1over-expressors[73]. Further, Bao et al. [73] revealed that enhanced resis-tance in OSD1-over-expressing lineswas dependent on CYCB1;1andtheRproteinSUPPRESSOROFNPR1-1, CONSTITUTIVE 1(SNC1),providingalinkbetween cell cycleregulation and ETI. The connection of ETI and the cell cycle was further substantiated by Wang

etal.[74].Bysearchingforsuppressorsofthe constitu-tiveimmunitymutantcpr5,Wangetal.identifiedSIMand

SMR1bothofthesegenesarerequiredforETI,dwarfism and elevated SA in cpr5. Based ontheir studies,CPR5 interactswithandnegativelyregulatesSIMandSMR1at the nuclear membrane. Upon onset of ETI through pathogen effector recognition by NLRs, SIM and SMR1arereleased tosupportRBR1 hyperphosphoryla-tion and subsequent over-activation of E2Fs to induce ETI-relatedcelldeathandimmunity[74]. SIM/SMR1-dependentRBR1hyperphosphorylationandE2Fs over-expressionwasunexpectedbecausethecellcycledefault functionsofSIMandSMR1aretoinhibitCDKsinorder to prevent RBR1 phosphorylation and E2F activation. Moreover, the higher disease susceptibility of sim smr

double mutants indicated thesignificance of their non-canonicalactivityinETI.Itwillbeimportanttodecipher thosemechanismsregulatingthepleiotropicfunctionof theseproteinsincellcycleandETI.Fromthesestudiesit maybededucedthatanybioticstresscouldredirectcell cycle function from growth into immunity, and that hormones(e.g.SA)arecentrallyinvolvedinthisswitch.

Conclusions

A hyperactive immune system can be deleterious to plants and impair breeding efforts to enhance stress resistanceincrops.Thisismostobviousfrom autoimmu-nitymutantsandgeneticallyincompatiblecombinations ofallelicvariantsofpositivePTIregulators(e.g. ACCEL-ERATEDCELLDEATH6)resultinginhighlyresistant

butstuntedplants[9,12,26].Thestudiesreviewedhere indicatethathormonestakeacentralroleinthe underly-ingconflictbetweengrowthandimmunesignalling.Ina multicellularplant, hormone-based communication ele-vatestheefficiencyandplasticityoforganssuchasroots byallocatingtaskstocelltypeswithdifferentfunctional properties.Thispartitioningoffunctionsrequiresatight coordinationbetweenthedifferentcelltypes.Under non-stressconditions,hormonescoordinatecellproliferation, elongationand differentiationto supportgrowth. Biotic stress redirects hormone activities towards immunity. What appears to be an inseparable hormone-regulated immunityorgrowthfate,canbeunlinked.Forexample, chitintriggersimmunitywithoutaffectinggrowth. More-over,werecentlyidentifiedtheabilityofarootcolonising endophyte to separate immune and growth signalling upon flg treatment [75]. In order to understand the molecularbasisof growth under immunity, we need to disassemble underlying hormone signalling networks. Rootcelltype-specificstudieshaveadvancedour knowl-edge of root development and revealed the cell type-specificregulationofmeristemsizeandzonationpattern by hormones [63,76,77]. Cell cycle regulators further showed a cell type-specific distribution, which might explaintheexpansionofCYCsinplants[78].Therefore, efforts to genetically decipher the growth-immunity crosstalk require analyses at cell type resolution. Such studies will provide information of the spatio-temporal contextofimmuneandgrowthpathwaysandtheir regu-lation through hormones. The recent re-evaluation of PLT and auxin functions in root development as well asthefunctionofABAandJAinintegratingsaltstressare indicativeofcelltype-specifichormoneactivitiesin reg-ulatingcomplexrootresponses[70,79].

Acknowledgements

WethankAlexJonesforcriticalcommentsonthemanuscript.Thiswork wassupportedbygrantsoftheDeutscheForschungsgemeinschaft(DFG), bytheUniversityofWarwickandacollaborativegrant(BB/M017982/1)for theWarwickIntegrativeSyntheticBiologyCentrebytheEngineeringand PhysicalSciencesResearchCouncil(EPSRC)andBiotechnologyand BiologicalSciencesResearchCouncil(BBSRC).

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