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Plant Science 212 (2013) 102– 107

Contents lists available at ScienceDirect

Plant Science

jo u r n al homep age: www.elsev ier .com/ locate /p lantsc i

eview

eview of stress specific organelles-to-nucleus metabolic signalolecules in plants

anmei Xiao1, Jinzheng Wang1, Katayoon Dehesh ∗

epartment of Plant Biology, University of California Davis, Davis, CA 95616, USA

r t i c l e i n f o

rticle history:eceived 2 July 2013eceived in revised form 12 August 2013ccepted 14 August 2013vailable online 27 August 2013

a b s t r a c t

Plants, as sessile organisms, have evolved an exquisitely tuned response network to survive environmen-tal perturbations. Organelles-to-nucleus signaling, termed retrograde signaling, plays a key role in stressresponses by communicating subcellular perturbations to the nucleus, thereby coordinating expressionof stress specific nuclear genes essential for adaptive responses to hostile environment. Recently, several

eywords:etrograde signalingEP pathway

eactive oxygen specieshloroplast

stress specific retrograde signals have been identified; most notable amongst them are reactive oxygenspecies, tetrapyrroles, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate (MEcPP), unsaturated fatty acids,nitric oxide (NO), 3′-phosphoadenosine 5′-phosphate (PAP), and �-cyclocitral (�-CC). It is expected thatthis trend will continue to provide fundamental insight into the integrative network of sensory systemscentral to the adaptive responses of plants to the prevailing environment. This review focuses on therecent advancements in the field.

© 2013 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022. Reactive oxygen species and redox mediated retrograde signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033. 2-C-methyl-d-erythritol 2,4-cyclodiphosphate (MEcPP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034. Unsaturated fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045. Nitric oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046. Phosphonucleotide 3′-phosphoadenosine 5′-phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1057. Hierarchy of retrograde signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1058. Conclusion and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

. Introduction

Information flow between organelles and the nucleus ischieved through complex and highly synchronized anterogradenucleus-to-organelle) and retrograde (organelle-to-nucleus)ignaling pathways. Retrograde signaling is a communication

complex and intricate regulatory network to coordinate cellularactivities and modify their energy production and metabolismin accordance with environmental changes to improve theirchance of survival under unfavorable conditions. Mitochondriaand chloroplasts, the main metabolic hubs, function as stresssensors that perceive stress and produce retrograde signals that

athway from organelles to the nucleus and is central to regulationnd coordination of numerous processes in living organisms,ncluding developmental progression, responses to biotic and abi-tic challenges, protein trafficking and remodeling of chromatintructure. Plants, because of their sessile nature, have evolved a

∗ Corresponding author. Tel.: +1 530 752 8187.E-mail address: kdehesh@ucdavis.edu (K. Dehesh).

1 These authors contributed equally to the manuscript.

168-9452/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.plantsci.2013.08.003

coordinate nuclear-encoded network of adaptive responses.Mitochondria and chloroplasts are considered semi-

autonomous organelles as the vast majority of their proteinsare encoded by nuclear genome [1,2]. Almost every functionalaspect of mitochondria and chloroplasts are tightly controlled bynuclear gene expression. In return, mitochondria and chloroplasts

also send signals back to regulate nuclear gene expression tocoordinate their developmental and functional status [3–5]. Thus,interorganellar signaling cascades are necessary to coordinatesubcellular proteome and balance protein stoichiometry. To date,

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owever, our understanding of chloroplast retrograde signalings further advanced than mitochondria-to-nucleus signaling. Soar, the best described examples of interorganellar communi-ation are the chloroplast-to-nucleus signaling pathways thatontrol photosynthesis-associated nuclear genes (PhANGs) duringhloroplasts biogenesis and function. Specifically, in responseo stresses such as high light or disruption of the carotenoidiosynthesis, chloroplasts initiate signaling cascades that result ineduced expression of PhANGs; a process well described by studieserformed on the genome uncoupled (gun) mutants [6–8]. Thesetudies showed that during photo-oxidative stress induced by theisruption of carotenoid synthesis the expression of nuclear genesncoding PhANGs are altered through the function of intermediatesf the tetrapyrrole pathway. These potential retrograde signalsre mediated in part through the transcription factor ABI4 [6,7].dditional studies using the green alga Chlamydomonas reinhardtii

end support to the putative roles of several tetrapyrrole pathwayntermediates, such as Mg-Protoporphyrin IX (Mg-ProtoIX), hemend billins, which function as plastids-to-nucleus retrogradeignals regulating expression of the PhANGs during chloroplastiogenesis, development and function [9,10].

In the past few years, in addition to reactive oxygen speciesROS), a number of metabolites of diverse origins were iden-ified and/or proposed as stress-specific organelles-to-nucleusetrograde signals including (1) methylerythritol phosphateMEP) intermediate 2-C-methyl-d-erythritol 2,4-cyclodiphosphateMEcPP) [11,12]; (2) unsaturated fatty acids [13–15]; (3) nitricxide (NO); and (4) 3′-phosphoadenosine 5′-phosphate (PAP)16,17]. Here we briefly review the current state of the availablenformation on these stress-specific retrograde signaling candi-ates.

. Reactive oxygen species and redox mediated retrogradeignaling

Reactive oxygen species (ROS) include hydrogen peroxide,uperoxide radicals, singlet oxygen, and hydroxyl radicals [18–22].hese chemically reactive molecules were initially recognized asoxic by-products of central metabolism in plant cell, that areemoved through antioxidative enzymes and antioxidants [18].owever, it is now apparent that ROS play a signaling role con-

rolling a myriad of processes including responses to biotic andbiotic stresses [19–22]. Because of the tight link between ROS andetabolism, almost any perturbation in cellular homeostasis could

ead to a change in the steady-state level of ROS in a particular com-artment(s), thereby affecting the redox status of plant cells. Plantsroduce significant amounts of ROS during electron transport andetabolism in mitochondria and chloroplasts, and subsequently

se antioxidants or scavenging systems to maintain their cellularOS and redox homeostasis. The ROS burst, or stress-mediated ele-ation of ROS levels, initiates signaling pathway(s) to reprogramuclear gene expression encoding chloroplast and mitochondrion

ocalized proteins. Bioinformatics analyses of transcriptomics, pro-eomics and metabolomics data sets have revealed ROS-mediatedeneral, as well as source and/or species-specific responses [23,24].his information has raised an intriguing question of how the sameignal, which is produced in different organelles, convey the infor-ation and lead to signaling cascades that trigger source-specific

uclear responses. It is postulated that, signal specificity is medi-ted through interaction of ROS with locally produced secondary

essengers. In the case of mitochondria, it is proposed that oxi-

ized peptides derived from proteolytic breakdown of oxidativelyamaged proteins mediate mitochondrial ROS specific responses25]. In the case of chloroplast ROS specific signaling, �-cyclocitral

212 (2013) 102– 107 103

(�-CC), an oxidative product of carotenoid, is reported to mediatesinglet oxygen signaling [26].

3. 2-C-methyl-d-erythritol 2,4-cyclodiphosphate (MEcPP)

The MEP pathway is an essential metabolic pathway present inplant plastids, apicomplexan protozoa and eubacteria. It is respon-sible for the biosynthesis of isopentenyl diphosphate (IPP) anddimethylallyl diphosphate (DMAPP), the building blocks of all iso-prenoids [27,28]. Any deficiencies in the MEP pathway result indefects in chloroplast biogenesis and development. Null mutantsin this pathway are lethal [11], due to disruption of the synthe-sis of essential isoprenoids such as carotenoids, prenyl chains ofchlorophylls and quinones, cytokinins, gibberellins and abscisicacid (ABA).

Genetic studies have established that the MEP pathway is notsolely a biochemical route essential for providing substrates forplastidial isoprenoids synthesis, but it also functions as a stresssensor that communicates environmental perturbations sensed byplastids back to the nucleus [11]. The MEP pathway also plays arole in plant development as demonstrated by studies in Nico-tiana benthamiana [29]. The virus-induced gene silencing of CMK, agene encoding 4-diphosphocytidyl-2-C-methyl-d-erythritol (DPC-ME) kinase, the fourth enzyme of the MEP pathway, resulted inincreased cell numbers and reduced cell size in all leaf layers, aunique phenotype not observed in mutants of the other MEP path-way genes [29]. This suggests that the accumulation of the CMKsubstrate DPC-ME might act as a signal regulating leaf cell numberand cell size. However, a direct evidence for signaling function ofDPC-ME is yet to be provided.

The enzyme 4-hydroxy-3-methylbut-2-enyl diphosphate syn-thase (HDS) catalyzing the sixth and the bottleneck step reactionin the MEP pathway, is responsible for conversion of MEcPP to(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). InArabidopsis, hds mutants with compromised HDS enzymatic activ-ities alter plant responses to biotic and abiotic stresses [11,12].The csb3 mutant, an allele of HDS, has constitutive expressionof Subtilisin-like protease P69C together with enhanced basal aswell as pathogen induced salicylic acid (SA) levels. Accordingly,csb3 mutants are more resistant to the bacterial pathogen Pseu-domonas syringae pv. tomato (Pst). These phenotypes in csb3 canbe reverted by the application of the fosmidomycin, an inhibitorof 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), theenzyme controlling the second step of the MEP pathway. This indi-cates that the phenotypes of csb3 mutant are controlled by theaccumulated intermediate metabolites produced in between stepscatalyzed by DXR and HDS enzymes [12].

Studies of a second allele of HDS, ceh1, established that theaccumulation of HDS substrate “MEcPP” in ceh1 mutants specifi-cally alters expression of selected stress responsive nuclear genesencoding plastidial proteins, such as hydroperoxide lyase (HPL) andisochorismate synthase 1 (ICS1). HPL is a stress-inducible nucleargene encoding a plastid-localized protein in the oxylipin path-way. HPL-derived metabolites, predominantly C6-aldehydes, areimplicated as intra- and inter-plant stress-responsive signalingmetabolites [30]. ICS1 is a stress-inducible nuclear gene encod-ing a key plastidial enzyme in the SA-biosynthetic pathway, whichis required for plant defense responses to biotic pathogens [31].Indeed the high level of SA led to notable enhanced resistanceof ceh1 to the biotrophic pathogen Pst. Increased expression ofHPL and ICS1 genes were, however, restricted to ceh1 mutant line

and not in any mutants of the other MEP pathway genes. Fur-ther genetic and metabolic analyses confirmed that the observedceh1 mutant phenotypes are caused by elevated levels of MEcPP.Accumulation of MEcPP was observed in plants challenged with

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igh light, hot temperature, or oxidative stress, further establishinghe physiological relevance of this metabolite in mediating stressesponses [32,33]. Moreover, both exogenous application of MEcPPnd stress-mediated induction of internal MEcPP levels by highight mimic the phenotype of ceh1 mutants as determined by con-titutive expression of an otherwise stress inducible gene, HPL. It isoteworthy that stress-mediated induction of MEcPP levels is not

imited to plants, but it is also found in bacterial cultures exposed toxidative stress [34], thus suggesting some functional conservationf a stress-signaling role of this metabolite. These results collec-ively established MEcPP as a stress-specific retrograde signaling

etabolite that communicates plastidial perturbations back tohe nucleus to regulate expression of selected stress-responsiveuclear genes. Interestingly, MEcPP also regulates gene expression

n the bacterium Chlamydia trachomatis by dissociating the histone-ike proteins from DNA [35,36]. These studies suggest that MEcPP

ay function as a chromatin remodeler to regulate gene expressionn plants.

. Unsaturated fatty acids

Fatty acids (FAs) are essential macromolecules produced pre-ominantly in plastids. FAs and FA -metabolites are not only majortructural and metabolic constituents of the cell, but also func-ion as modulators of a multitude of signal transduction pathwaysvoked by environmental and developmental stimuli. A growingody of evidence suggests that unsaturated FAs serve as criticalignaling molecules that modulate a variety of responses to bioticnd abiotic stresses [13,37]. Exogenous application and endoge-ous alteration of unsaturated FAs can significantly alter genexpression profile and metabolism to influence the outcome of abi-tic stress acclimation and plant–pathogen and plant–herbivorenteractions [13–15,37,38]. The level of polyunsaturated FAs in cel-ular membranes determines plant acclimation to temperature,alt, drought and heavy metal stresses [13,37]. Unsaturated FAslso play important roles in biotic stresses. For example, arachi-onic acid (AA) and eicosapentaenoic acid (EPA), which are notroduced in vascular plants, but are abundant in lipids of oomycetesuch as phytopathogenic Phytophthora species, are released intolant tissue in the early stages of infection, thereby potentiat-

ng elicitation of defense responses [39]. Transgenic Arabidopsislants producing AA and EPA, mimicking the pathogen releasef these compounds, showed altered resistance to biotic chal-engers resulting from AA’s action on salicylate and jasmonateJA) stress signaling networks, confirming AA signaling in variouslants [38]. Importantly, rapid activation of a general stress respon-ive cis-element known as rapid stress response element (RSRE) toxogenous application of a number of FAs including 18:2, 18:3, and0:4 suggests that some unsaturated FAs may function as a ret-ograde signal [38,40]. This exciting proposition is strengthenedy the key role of 18:1 levels in regulating JA-mediated defenseignaling [14,15,41,42]. That is, the Arabidopsis mutant suppres-or of SA insensitivity2 (ssi2), an allele encoding a stearyol-acylarrier protein desaturase (SACPD), have reduced levels of 18:1nd are constitutively activated in SA-mediated signaling, but arempaired in JA-mediated signaling. The corresponding biologicalonsequences are stunted phenotype and enhanced resistance ofsi2 lines to the oomycete pathogen Hyaloperonospora arabidopsidis,nd to the bacterial pathogen. Intriguingly, recovery of 18:1 levelsither by over expression of the other SACPD isoforms or by theecondary mutation in act1, restores the altered ssi2 morphological

nd defense-related phenotypes [41,42].

It is therefore tantalizing to suggest that some unsaturated FAsct as a retrograde signal, especially in light of rapid release of somensaturated FAs, including 18:2 and 18:3, from membranes by

212 (2013) 102– 107

phospholipase A enzymes in response to pathogen attack [43–45].However the exact signaling function of unsaturated FAs is yet tobe determined.

5. Nitric oxide

Nitric oxide (NO) plays pivotal roles in signal transduction inplants and animals, and is considered to be a potential retrogradesignaling molecule. In plants, the NO level is rapidly altered inresponse to biotic and abiotic stresses such as pathogen infection,drought, chilling, or salinity [46]. Biological roles of NO dependon when and where it is produced [47]. In animals, the localiza-tion and function of three main metabolic isozymes of nitric oxidesynthase (NOS) are well established [48]. However, the synthesisof NO in plants has remained debatable [49]. So far, the cyto-plasmic nitrate reductase is the best characterized enzyme whichcan produce NO in plants, albeit only ∼1% of the nitrate-reducingcapacity of this enzyme involved this process [50,51]. It is reportedthat chloroplasts possess NOS enzyme activity [52], suggestingthat endogenous NO can be produced in chloroplasts. Further evi-dence for plastidial NO production is provided by three mutantlines with altered levels of endogenous NO that are defective inchloroplast localized-proteins. Nitric oxide-associated 1 (NOA1),first recognized as a NOS enzyme, but later proven to be a GTPasein chloroplasts [49,50], produced less NO in response to stressesand ABA treatment [49,50]. The Arabidopsis mutant ssi2, the previ-ously discussed mutant with reduced 18:1 levels, accumulates highlevels of NO in chloroplasts, potentially through modification ofNOA1 activity [53]. Lastly, high NO levels were found in chlorophylla/b binding protein underexpressed 1 (cue1), a mutant that is defec-tive in the phosphoenolpyruvate/phosphate translocator protein ofchloroplast [54,55]. Although the localization of NO production isnot yet determined in cue1, all other mutants support the chloro-plast as a key site for NO production. Several studies have recentlyprovided genetic evidence for a significant role of NO in regulationof nuclear gene expression as determined by treatment of plantswith NO or when challenged with biotic or abiotic stimuli [56]. As areactive molecule, NO can regulate expression of stress responsivegenes either through modification of cysteine residues of proteins(S-nitrosylation) such as transcription factors and enzymes [57], orby direct or indirect interaction with biomolecules like fatty acids orhormones [58,59]. For example, S-nitrosoglutathione, which func-tions as an NO donor, facilitates oligomerization of nonexpressorof pathogenesis-related genes 1 (NPR1), a master regulator of sys-temic acquired resistance (SAR), through S-nitrosylation of cysteineresidues [60]. The oligomer-to-monomer switch of NPR1 is a criticalstep in inducing SAR, as nuclear translocation of the NPR1 monomeris required for resistance [60]. Moreover, DNA binding activity ofthe transcription factor TGA can be modulated by S-nitrosylationmodification, thereby changing the expression of pathogen resis-tance genes in nucleus [60,61]. The role of NO as a modulator of geneexpression is further strengthened by the report that NO accumu-lation in chloroplasts in ssi2 mutants elevates expression of nucleardefense genes [53]. It is also reported that the increase of ABAin response to stress promotes NO production, and consequentlyincreases antioxidant gene expression to protect cells [62].

In summary, stress-mediated plastidial induction of NO, fol-lowed by its diffusion into cytoplasm and/or nucleus, leads toactivation of other signaling molecules or modification of tran-scription factors, ultimately altering regulation of nuclear gene

expression. Based on these reports it is reasonable to surmise thatNO is a potential retrograde signaling molecule. However, despitenotable progress in this field, controversies surrounding the natureof NO synthesizing enzymes have yet to be resolved, and the signal

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ransduction mechanisms of NO between organelles and nucleusemain to be determined.

. Phosphonucleotide 3′-phosphoadenosine 5′-phosphate

PAP (3′-phosphoadenosine 5′-phosphate), a by-product of sul-ur assimilation, is present in organisms from all domains ofife. In plants, PAP is produced from 3′-phosphoadenosine 5′-hosphosulfate (PAPS) by the transfer of the sulfate group tocceptor molecules in various sulfation reactions including biosyn-hesis of thiols and glucosinolates. This process is catalyzed byytosolic sulfotransferases (ST) [63]. High levels of PAP are toxics they can inhibit both the activity of 5′ to 3′-exoribonucleasesXRNs), which alter RNA-processing [64], and the activity of polyADP-ribose) polymerase 1 (PARP-1), thereby affecting DNA repair65]. Emerging evidence suggests that PAP, which accumulatesn response to high light and drought stresses in plants, mayerve as a signaling molecule to regulate plant responses to cer-ain abiotic stresses [16,17,66–68]. For example, mutant plantshat accumulate high levels of PAP are more drought tolerant andhow constitutive or super-induction of expression of abiotic stressesponsive genes [16,17,66–68]. In Arabidopsis, SAL1, also known asIERY1 or FRY, encodes the major phosphatase that hydrolyzes theAP to AMP and Pi [17,69]. Mutants of SAL1 such as alx8, fry1, fou8,nd supo1 accumulate PAP to very high levels. These lines have ele-ated levels of foliar ABA and JA and exhibit constitutive inductionf high light, drought and salinity responsive nuclear genes, includ-ng APX2, DROUGHT RESPONSE BINDING 2A (DREB2A), RD29A andAT10 [16,17,66–68]. In Arabidopsis, APK1 and APK2 are the twoajor APS kinases that are responsible for the production of the

APS, the substrate for PAP synthesis in plants. The restoration ofhe sal1 phenotypes in apk1/apk2 double mutant further supportshe notion that PAP accumulation in sal1 mutants is responsibleor the stress response related phenotypes [16,67,70]. Transcrip-ome analysis of xrn and sal1 mutants suggested that PAP regulatesuclear gene expression at least in part by inhibiting nuclear XRNshat target certain stress-responsive genes [16].

While the studies on sal1 mutants indicate that PAP serves asignal molecule mediating abiotic stress responses, the proposalhat PAP is a chloroplast-to-nucleus signal should be reconsidered.his is because of the following reasons. First, PAP is exclusivelyroduced in cytosol and can be imported into chloroplast by theAP transporter PAPST [63,71]. Second, the localization of SAL1 istill a matter of debate, as it ubiquitously localized in chloroplast,itochondria, cytosol, and nucleus. Even though the full length

AL1-GFP used in one study [16] is convincingly and exclusivelyccumulated in chloroplasts and mitochondria, there is not yetvidence for the absence of native SAL1 in cytosol and nucleus.xistence of nuclear and cytoplasmic SAL1 could be mediatedhrough alternative splicing, specifically because SAL1 lacking thehloroplast transit peptide is localized both in cytosol and nucleus69,72]. Third, the chloroplast localized SAL1 only partially com-lements the phenotype of sal1 mutants, while the cytosolic anduclear localized truncated SAL1 protein completely recovers theal1 mutant phenotypes [16,72]. It is therefore likely that PAP is aytosolic signal modulating stress responses, while the chloroplastsnd/or mitochondria localized SAL1 acts as a buffer or modifier ofhe PAP pool that can indirectly affect PAP signaling function intress responses.

. Hierarchy of retrograde signals

We chose to begin this review with a discussion of ROS not onlyecause ROS are generally induced by stresses and trigger defenseesponses, but because of the inherent connection between ROS

Fig. 1. Schematic presentation of hierarchy of retrograde signals.

and production of currently known metabolic retrograde signalmolecules whose levels are directly or indirectly regulated by ROSlevels or by the redox state. As evidence for this regulation, considerthat unsaturated fatty acids and �-CC are both oxidation reactionproducts, levels of 18:1 can regulate NO production [53], accumula-tion of MEcPP and PAP are redox regulated [17,27,32,34,66,68,69],and the enzymes responsible for the conversion of MEcPP to down-stream products and degradation of PAP are sensitive to inhibitionby oxidative stresses (Fig. 1). In the case of MEcPP and PAP thismeans that stress-mediated elevation of ROS levels at the sites thathouse MEcPP and PAP most likely will induce accumulation of thesemetabolites.

Retrograde signaling is thus an intricate network instigated byROS and/or cellular redox state acting as sensor and initiator ofstress responses. Spatial and temporal changes of ROS levels andredox state modify highly conserved, but spatially and temporallyregulated, metabolic processes, thereby affecting the levels of spe-cific signal molecules. Each of these signal molecules regulates a setof distinct and overlapping genes. Precise modulation of the blendof these signals within the framework of species-specific signalingnetworks crafts the complexity and specificity of observed plantstress responses.

8. Conclusion and perspective

The past few years have seen an expansion of information onorganelles-to-nucleus retrograde signaling molecules, garneringoverdue recognition for the importance of these factors in con-trolling plant–environment interactions. However, the governingprinciples of perception and transduction of retrograde signals haveremained elusive. One could speculate a linear signaling transduc-tion mechanism, yet this integrative sensory cascade is ever morecomplicated. On the one hand, one retrograde signal might regulatedifferent genes of several pathways, and yet different retrogradesignals can regulate genes of similar pathway [73]. It is also essen-tial to delineate mode of transport of the signal, and to determinewhether a unidirectional proton symporter is responsible for theexport of the signaling molecule or that the signal may coopt NLS-containing proteins as carriers, or alternatively the transport occursthrough the use of noncanonical export–import machinery.

In the coming years, a combination of systems biology,metabolomic, genetic, biochemical and cell biological approacheswill pull back the veil currently obscuring the core mechanismsof these complex and critical integrative networks of sensory

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ystems central to the adaptive responses of plants to therevailing environment.

cknowledgments

This work is supported by the National Science Foundation grantOS-1036491 (K.D.). Jinzheng Wang was supported by the Min-stry of Science and Technology of China (grant 2013CB967300,007CB948201). We would like to thank Geoffrey Benn for hiselpful comments on the manuscript.

eferences

[1] D. Leister, Chloroplast research in the genomic age, Trends Genet. 19 (2003)47–56.

[2] G.E. Andersson, O. Karlberg, B. Canbäck, C.G. Kurland, On the origin of mitochon-dria: a genomics perspective, Philos. Trans. R. Soc. Lond. B: Biol. Sci. 358 (2003)165–179.

[3] S. Amirsadeghi, C.A. Robson, G.C. Vanlerberghe, The role of the mitochondrionin plant responses to biotic stress, Physiol. Plant. 129 (2007) 253–266.

[4] W. Chi, X. Sun, L. Zhang, Intracellular signaling from plastid to nucleus, Annu.Rev. Plant Biol. 64 (2013) 559–582.

[5] A.P. Fernandez, A. Strand, Retrograde signaling and plant stress: plastid signalsinitiate cellular stress responses, Curr. Opin. Plant Biol. 11 (2008) 509–513.

[6] S. Koussevitzky, A. Nott, T.C. Mockler, F. Hong, G. Sachetto-Martins, M. Surpin, J.Lim, R. Mittler, J. Chory, Signals from chloroplasts converge to regulate nucleargene expression, Science 316 (2007) 715–719.

[7] J.D. Woodson, J. Chory, Coordination of gene expression between organellarand nuclear genomes, Nat. Rev. Genet. 9 (2008) 383–395.

[8] J.D. Woodson, J.M. Perez-Ruiz, J. Chory, Heme synthesis by plastid fer-rochelatase I regulates nuclear gene expression in plants, Curr. Biol. 21 (2011)897–903.

[9] E.D. von Gromoff, A. Alawady, L. Meinecke, B. Grimm, C.F. Beck, Heme, a plastid-derived regulator of nuclear gene expression in Chlamydomonas, Plant Cell 20(2008) 552–567.

10] D. Duanmu, D. Casero, R.M. Dent, S. Gallaher, W. Yang, N.C. Rockwell, S.S. Martin,M. Pellegrini, K.K. Niyogi, S.S. Merchant, A.R. Grossman, J.C. Lagarias, Retrogradebilin signaling enables Chlamydomonas greening and phototrophic survival,Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 3621–3626.

11] Y. Xiao, T. Savchenko, E.E. Baidoo, W.E. Chehab, D.M. Hayden, V. Tolstikov, J.A.Corwin, D.J. Kliebenstein, J.D. Keasling, K. Dehesh, Retrograde signaling by theplastidial metabolite MEcPP regulates expression of nuclear stress-responsegenes, Cell 149 (2012) 1525–1535.

12] M.J. Gil, A. Coego, B. Mauch-Mani, L. Jorda, P. Vera, The Arabidopsis csb3 mutantreveals a regulatory link between salicylic acid-mediated disease resistanceand the methyl-erythritol 4-phosphate pathway, Plant J. 44 (2005) 155–166.

13] A. Kachroo, P. Kachroo, Fatty Acid-derived signals in plant defense, Annu. Rev.Phytopathol. 47 (2009) 153–176.

14] A. Kachroo, L. Lapchyk, H. Fukushige, D. Hildebrand, D. Klessig, P. Kachroo,Plastidial fatty acid signaling modulates salicylic acid- and jasmonic acid-mediated defense pathways in the Arabidopsis ssi2 mutant, Plant Cell 15 (2003)2952–2965.

15] J. Shah, P. Kachroo, A. Nandi, D.F. Klessig, A recessive mutation in the Ara-bidopsis SSI2 gene confers SA- and NPR1-independent expression of PR genesand resistance against bacterial and oomycete pathogens, Plant J. 25 (2001)563–574.

16] G.M. Estavillo, P.A. Crisp, W. Pornsiriwong, M. Wirtz, D. Collinge, C. Carrie, E.Giraud, J. Whelan, P. David, H. Javot, C. Brearley, R. Hell, E. Marin, B.J. Pogson, Evi-dence for a SAL1-PAP chloroplast retrograde pathway that functions in droughtand high light signaling in Arabidopsis, Plant Cell 23 (2011) 3992–4012.

17] P.B. Wilson, G.M. Estavillo, K.J. Field, W. Pornsiriwong, A.J. Carroll, K.A. Howell,N.S. Woo, J.A. Lake, S.M. Smith, A. Harvey Millar, S. von Caemmerer, B.J. Pogson,The nucleotidase/phosphatase SAL1 is a negative regulator of drought tolerancein Arabidopsis, Plant J. 58 (2009) 299–317.

18] J. Bailey-Serres, R. Mittler, The roles of reactive oxygen species in plant cells,Plant Physiol. 141 (2006) 311.

19] C.H. Foyer, G. Noctor, Redox signaling in plants, Antioxid. Redox Signal. 18(2013) 2087–2090.

20] T. Maruta, M. Noshi, A. Tanouchi, M. Tamoi, Y. Yabuta, K. Yoshimura, T. Ishikawa,S. Shigeoka, H2O2-triggered retrograde signaling from chloroplasts to nucleusplays specific role in response to stress, J. Biol. Chem. 287 (2012) 11717–11729.

21] R. Mittler, S. Vanderauwera, N. Suzuki, G. Miller, V.B. Tognetti, K. Vandepoele,M. Gollery, V. Shulaev, F. Van Breusegem, ROS signaling: the new wave? TrendsPlant Sci. 16 (2011) 300–309.

22] N. Suzuki, S. Koussevitzky, R. Mittler, G. Miller, ROS and redox signalling in theresponse of plants to abiotic stress, Plant Cell Environ. 35 (2012) 259–270.

23] I. Gadjev, S. Vanderauwera, T.S. Gechev, C. Laloi, I.N. Minkov, V. Shulaev, K.

Apel, D. Inze, R. Mittler, F. Van Breusegem, Transcriptomic footprints disclosespecificity of reactive oxygen species signaling in Arabidopsis, Plant Physiol. 141(2006) 436–445.

24] N.L. Ma, Z. Rahmat, S.S. Lam, A review of the “Omics” approach to biomarkersof oxidative stress in Oryza sativa, Int. J. Mol. Sci. 14 (2013) 7515–7541.

[

212 (2013) 102– 107

25] I.M. Moller, L.J. Sweetlove, ROS signalling – specificity is required, Trends PlantSci. 15 (2010) 370–374.

26] F. Ramel, S. Birtic, C. Ginies, L. Soubigou-Taconnat, C. Triantaphylidès, M.Havaux, Carotenoid oxidation products are stress signals that mediate generesponses to singlet oxygen in plants, in: Proc. Natl. Acad. Sci. U. S. A., 2012.

27] J.F. Hoeffler, A. Hemmerlin, C. Grosdemange-Billiard, T.J. Bach, M. Rohmer, Iso-prenoid biosynthesis in higher plants and in Escherichia coli: on the branchingin the methylerythritol phosphate pathway and the independent biosynthe-sis of isopentenyl diphosphate and dimethylallyl diphosphate, Biochem. J. 366(2002) 573–583.

28] E. Vranova, D. Coman, W. Gruissem, Network analysis of the MVA and MEPpathways for isoprenoid synthesis, Annu. Rev. Plant Biol. 64 (2013) 665–700.

29] C.S. Ahn, H.S. Pai, Physiological function of IspE, a plastid MEP pathway genefor isoprenoid biosynthesis, in organelle biogenesis and cell morphogenesis inNicotiana benthamiana, Plant Mol. Biol. 66 (2008) 503–517.

30] E.W. Chehab, R. Kaspi, T. Savchenko, H. Rowe, F. Negre-Zakharov, D. Klieben-stein, K. Dehesh, Distinct roles of jasmonates and aldehydes in plant-defenseresponses, PLoS One 3 (2008) e1904.

31] M.C. Wildermuth, J. Dewdney, G. Wu, F.M. Ausubel, Isochorismate synthaseis required to synthesize salicylic acid for plant defence, Nature 414 (2001)562–565.

32] Z. Li, T.D. Sharkey, Metabolic profiling of the methylerythritol phosphate path-way reveals the source of post-illumination isoprene burst from leaves, PlantCell Environ. 36 (2013) 429–437.

33] C. Rivasseau, M. Seemann, A.M. Boisson, P. Streb, E. Gout, R. Douce, M. Rohmer,R. Bligny, Accumulation of 2-C-methyl-d-erythritol 2,4-cyclodiphosphate inilluminated plant leaves at supraoptimal temperatures reveals a bottleneck ofthe prokaryotic methylerythritol 4-phosphate pathway of isoprenoid biosyn-thesis, Plant Cell Environ. 32 (2009) 82–92.

34] V.Y. Artsatbanov, G.N. Vostroknutova, M.O. Shleeva, A.V. Goncharenko, A.I.Zinin, D.N. Ostrovsky, A.S. Kapreliants, Influence of oxidative and nitrosativestress on accumulation of diphosphate intermediates of the non-mevalonatepathway of isoprenoid biosynthesis in corynebacteria and mycobacteria, Bio-chemistry (Mosc.) 77 (2012) 362–371.

35] N.A. Grieshaber, E.R. Fischer, D.J. Mead, C.A. Dooley, T. Hackstadt, Chlamydialhistone–DNA interactions are disrupted by a metabolite in the methylerythritolphosphate pathway of isoprenoid biosynthesis, Proc. Natl. Acad. Sci. U. S. A. 101(2004) 7451–7456.

36] N.A. Grieshaber, J.B. Sager, C.A. Dooley, S.F. Hayes, T. Hackstadt, Regulation ofthe Chlamydia trachomatis histone H1-like protein Hc2 is IspE dependent andIhtA independent, J. Bacteriol. 188 (2006) 5289–5292.

37] R.G. Upchurch, Fatty acid unsaturation, mobilization, and regulation in theresponse of plants to stress, Biotechnol. Lett. 30 (2008) 967–977.

38] T. Savchenko, J.W. Walley, E.W. Chehab, Y. Xiao, R. Kaspi, M.F. Pye, M.E.Mohamed, C.M. Lazarus, R.M. Bostock, K. Dehesh, Arachidonic acid: an evo-lutionarily conserved signaling molecule modulates plant stress signalingnetworks, Plant Cell 22 (2010) 3193–3205.

39] K.E. Ricker, R.M. Bostock, Evidence for release of the elicitor arachidonic acidand its metabolites from sporangia of Phytophthora infestans during infectionof potato, Physiol. Mol. Plant Pathol. 41 (1992) 61–72.

40] J.W. Walley, S. Coughlan, M.E. Hudson, M.F. Covington, R. Kaspi, G. Banu,S.L. Harmer, K. Dehesh, Mechanical stress induces biotic and abiotic stressresponses via a novel cis-element, PLoS Genet. 3 (2007) 1800–1812.

41] A. Kachroo, J. Shanklin, E. Whittle, L. Lapchyk, D. Hildebrand, P. Kachroo,The Arabidopsis stearoyl-acyl carrier protein-desaturase family and the con-tribution of leaf isoforms to oleic acid synthesis, Plant Mol. Biol. 63 (2007)257–271.

42] A. Kachroo, S.C. Venugopal, L. Lapchyk, D. Falcone, D. Hildebrand, P. Kachroo,Oleic acid levels regulated by glycerolipid metabolism modulate defense geneexpression in Arabidopsis, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 5152–5157.

43] J. Shah, Lipids, lipases, and lipid-modifying enzymes in plant disease resistance,Annu. Rev. Phytopathol. 43 (2005) 229–260.

44] P. Kachroo, J. Shanklin, J. Shah, E.J. Whittle, D.F. Klessig, A fatty acid desaturasemodulates the activation of defense signaling pathways in plants, Proc. Natl.Acad. Sci. U. S. A. 98 (2001) 9448–9453.

45] J.W. Walley, D.J. Kliebenstein, R.M. Bostock, K. Dehesh, Fatty acids and earlydetection of pathogens, Curr. Opin. Plant Biol. 16 (4) (2013) 520–526.

46] R. Wimalasekera, F. Tebartz, G.F. Scherer, Polyamines polyamine oxidases andnitric oxide in development, abiotic and biotic stresses, Plant Sci. 181 (2011)593–603.

47] C. Villanueva, C. Giulivi, Subcellular and cellular locations of nitric oxide syn-thase isoforms as determinants of health and disease, Free Rad. Biol. Med. 49(2010) 307–316.

48] C. Bogdan, Nitric oxide and the immune response, Nat. Immunol. 2 (2001)907–916.

49] E. Gas, U. Flores-Perez, S. Sauret-Gueto, M. Rodriguez-Concepcion, Hunting forplant nitric oxide synthase provides new evidence of a central role for plastidsin nitric oxide metabolism, Plant Cell 21 (2009) 18–23.

50] K.J. Gupta, A.R. Fernie, W.M. Kaiser, J.T. van Dongen, On the origins of nitricoxide, Trends Plant Sci. 16 (2011) 160–168.

51] P. Rockel, F. Strube, A. Rockel, J. Wildt, W.M. Kaiser, Regulation of nitric oxide

(NO) production by plant nitrate reductase in vivo and in vitro, J. Exp. Bot. 53(2002) 103–110.

52] S. Jasid, M. Simontacchi, C.G. Bartoli, S. Puntarulo, Chloroplasts as a nitric oxidecellular source. Effect of reactive nitrogen species on chloroplastic lipids andproteins, Plant Physiol. 142 (2006) 1246–1255.

ience

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

Y. Xiao et al. / Plant Sc

53] M.K. Mandal, A.C. Chandra-Shekara, R.D. Jeong, K. Yu, S. Zhu, B. Chanda, D.Navarre, A. Kachroo, P. Kachroo, Oleic acid-dependent modulation of NITRICOXIDE ASSOCIATED1 protein levels regulates nitric oxide-mediated defensesignaling in Arabidopsis, Plant Cell 24 (2012) 1654–1674.

54] S.J. Streatfield, A. Weber, E.A. Kinsman, R.E. Hausler, J. Li, D. Post-Beittenmiller,W.M. Kaiser, K.A. Pyke, U.I. Flugge, J. Chory, The phosphoenolpyru-vate/phosphate translocator is required for phenolic metabolism, palisade celldevelopment, and plastid-dependent nuclear gene expression, Plant Cell 11(1999) 1609–1622.

55] Y. He, R.H. Tang, Y. Hao, R.D. Stevens, C.W. Cook, S.M. Ahn, L. Jing, Z. Yang,L. Chen, F. Guo, F. Fiorani, R.B. Jackson, N.M. Crawford, Z.M. Pei, Nitric oxiderepresses the Arabidopsis floral transition, Science 305 (2004) 1968–1971.

56] S. Grun, C. Lindermayr, S. Sell, J. Durner, Nitric oxide and gene regulation inplants, J. Exp. Bot. 57 (2006) 507–516.

57] J. Feng, C. Wang, Q. Chen, H. Chen, B. Ren, X. Li, J. Zuo, S-nitrosylation of phos-photransfer proteins represses cytokinin signaling, Nat. Commun. 4 (2013)1529.

58] B. Sanchez-Calvo, J.B. Barroso, F.J. Corpas, Hypothesis, Nitro-fatty acids play arole in plant metabolism, Plant Sci. 199-200 (2013) 1–6.

59] W.Z. Liu, D.D. Kong, X.X. Gu, H.B. Gao, J.Z. Wang, M. Xia, Q. Gao, L.L. Tian,Z.H. Xu, F. Bao, Y. Hu, N.S. Ye, Z.M. Pei, Y.K. He, Cytokinins can act as sup-pressors of nitric oxide in Arabidopsis, Proc. Natl. Acad. Sci. U. S. A. 110 (2013)1548–1553.

60] Z.Q. Fu, X. Dong, Systemic acquired resistance: turning local infection intoglobal defense, Annu. Rev. Plant Biol. 64 (2013) 839–863.

61] C. Lindermayr, S. Sell, B. Muller, D. Leister, J. Durner, Redox regulation of theNPR1-TGA1 system of Arabidopsis thaliana by nitric oxide, Plant Cell 22 (2010)2894–2907.

62] S. Neill, R. Barros, J. Bright, R. Desikan, J. Hancock, J. Harrison, P. Morris, D.

Ribeiro, I. Wilson, Nitric oxide, stomatal closure, and abiotic stress, J. Exp. Bot.59 (2008) 165–176.

63] M. Klein, J. Papenbrock, The multi-protein family of Arabidopsis sulpho-transferases and their relatives in other plant species, J. Exp. Bot. 55 (2004)1809–1820.

[

212 (2013) 102– 107 107

64] B. Dichtl, A. Stevens, D. Tollervey, Lithium toxicity in yeast is due to the inhibi-tion of RNA processing enzymes, EMBO J. 16 (1997) 7184–7195.

65] E. Toledano, V. Ogryzko, A. Danchin, D. Ladant, U. Mechold, 3′-5′ phospho-adenosine phosphate is an inhibitor of PARP-1 and a potential mediator ofthe lithium-dependent inhibition of PARP-1 in vivo, Biochem. J. 443 (2012)485–490.

66] H. Chen, B. Zhang, L.M. Hicks, L. Xiong, A nucleotide metabolite controls stress-responsive gene expression and plant development, PLoS ONE 6 (2011) e26661.

67] V.M. Rodríguez, A. Chételat, P. Majcherczyk, E.E. Farmer, Chloroplasticphosphoadenosine phosphosulfate metabolism regulates basal levels of theprohormone jasmonic acid in Arabidopsis leaves, Plant Physiol. 152 (2010)1335–1345.

68] J.B. Rossel, P.B. Walter, L. Hendrickson, W.S. Chow, A. Poole, P.M. Mullineaux,B.J. Pogson, A mutation affecting ASCORBATE PEROXIDASE 2 gene expressionreveals a link between responses to high light and drought tolerance, Plant CellEnviron. 29 (2006) 269–281.

69] B.H. Kim, A.G. von Arnim, FIERY1 regulates light-mediated repression of cellelongation and flowering time via its 3′(2′),5′-bisphosphate nucleotidase activ-ity, Plant J. 58 (2009) 208–219.

70] S.G. Mugford, N. Yoshimoto, M. Reichelt, M. Wirtz, L. Hill, S.T. Mugford, Y.Nakazato, M. Noji, H. Takahashi, R. Kramell, T. Gigolashvili, U.I. Flugge, C.Wasternack, J. Gershenzon, R. Hell, K. Saito, S. Kopriva, Disruption of adenosine-5′-phosphosulfate kinase in Arabidopsis reduces levels of sulfated secondarymetabolites, Plant Cell 21 (2009) 910–927.

71] T. Gigolashvili, M. Geier, N. Ashykhmina, H. Frerigmann, S. Wulfert, S. Krueger,S.G. Mugford, S. Kopriva, I. Haferkamp, U.I. Flugge, The Arabidopsis thylakoidADP/ATP carrier TAAC has an additional role in supplying plastidic phospho-adenosine 5′-phosphosulfate to the cytosol, Plant Cell 24 (2012) 4187–4204.

72] H. Chen, L. Xiong, The bifunctional abiotic stress signalling regulator and

endogenous RNA silencing suppressor FIERY1 is required for lateral root for-mation, Plant Cell Environ. 33 (2010) 2180–2190.

73] G.M. Estavillo, K.X. Chan, S.Y. Phua, B.J. Pogson, Reconsidering the nature andmode of action of metabolite retrograde signals from the chloroplast, Front.Plant Sci. 3 (2012) 300.