Model of how plants sense zinc deficiency

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Model of how plants sense zinc deficiency Cite this: DOI: 10.1039/c3mt00070b

Ana G. L. Assunça ˜o,*a Daniel P. Persson,b Søren Husted,b Jan K. Schjørring,b Ross D. Alexanderc and Mark G. M. Aartsc Plants are capable of inducing a range of physico-chemical and microbial modifications of the rhizosphere which can mobilize mineral nutrients or prevent toxic elements from entering the roots. Understanding how plants sense and adapt to variations in nutrient availability is essential in order to develop plant-based solutions addressing nutrient-use-efficiency and adaptation to nutrient-limited or -toxic soils. Recently two transcription factors of the bZIP family (basic-region leucine zipper) have

Received 17th March 2013, Accepted 19th June 2013

been identified in Arabidopsis and shown to be pivotal in the adaptation response to zinc deficiency. They represent not only the first regulators of zinc homeostasis identified in plants, but also a very

DOI: 10.1039/c3mt00070b

promising starting-point that can provide new insights into the molecular basis of how plants sense and adapt to the stress of zinc deficiency. Considering the available information thus far we propose in

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this review a putative model of how plants sense zinc deficiency.

Regulation of adaptation to zinc deficiency The transcription factors bZIP19 and bZIP23 are two members of the Arabidopsis bZIP family. They were identified as essential regulators of the adaptation to zinc deficiency (Fig. 1). The target genes of these transcription factors (TFs) seem to be a small set of genes (16), with most of them already known to be involved in Zn homeostasis.1 Eight of these genes are members a

CIBIO, Research Center in Biodiversity and Genetic Resources, University of Porto, ˜o, Portugal. E-mail: [email protected] 4485-661 Vaira b Department of Plant and Environmental Sciences, Section for Plant and Soil Science, University of Copenhagen, DK-1871 Frederiksberg C, Denmark c Laboratory of Genetics, Wageningen University, 6708 PB Wageningen, The Netherlands

of the ZIP (Zrt/Irt-like proteins) family of cation transporters (ZIP1, 3, 4, 5, 9, 10, 12, IRT3). This is a family of efflux facilitators, which is found in all eukaryotic kingdoms (animals, plants, fungi and protists).2 In plants, ZIP family members have been shown to play a role in the transport of the essential micronutrients Zn, Fe and Mn, but also of the non-essential toxic metal Cd.3–7 ZIP members are likely candidates mediating root Zn uptake and transport and hence important players of the Zn homeostasis network. This network provides an adequate amount of Zn to all cell types, at all stages of development and under different environmental conditions.8 Within the set of bZIP19/23 target genes there are also the nicotianamine synthase genes NAS2 and NAS4 encoding enzymes that catalyse the synthesis of NA (nicotianamine).1 A correlation between

˜o is a research Ana Assunça scientist from the CIBIO research center at University of Porto, Portugal. Her research interests focus on plant adaptation to abiotic stress, in particular, unravelling the molecular network regulating the adaptation to micronutrient zinc deficiency, and understanding the mechanisms of adaptation to metal-enriched soils in metal hyperaccumulator species. ˜o Ana G. L. Assunça

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Daniel Pergament Persson is a post doc at the Plant Nutrition group at Faculty of Science, University of Copenhagen. His main area of research is speciation and localization analyses of Zn and Fe in cereal grains; mainly by the use of LC-ICP-MS and LA-ICP-MS techniques. His current project deals with isolation and identification of Zn-binding proteins in cereal endosperms. Daniel P. Persson

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Fig. 1 Scheme representing the response to zinc deficiency in Arabidopsis, mediated by the transcription factors bZIP19 and bZIP23. Zinc deficiency leads to the activation of bZIP9 and bZIP23 which activates the expression of ZIP and NAS genes. From Assunça˜o et al., 2010.69

tissue NA levels and NAS transcripts has been reported.9,10 NA is a non-proteinogenic amino acid present in plants which acts

Søren Husted is a professor of plant nutrition at University of Copenhagen, Department of Plant and Environmental Sciences, Faculty of Science. He has specialized in the functional role of trace elements in plants, primarily focusing on the role of Mn in photosynthesis and the chemical speciation of Fe and Zn in cereal grains. His research is very much technology driven and has a strong focus on developing Søren Husted new ICP-MS based analytical tools to provide more detailed information about the biological chemistry of trace elements in plants and in plant based foods.

as a low molecular mass metal chelator, binding several transition metals with very high affinity.11 NA is implicated in Fe, Cu, Zn and Mn homeostasis, cell-to-cell and long distance distribution of Fe and seems to enhance the symplastic mobility of Zn, thus being pivotal for Zn translocation within the plant.9,12,13 The presumed ZIP and NAS target genes of the bZIP19 and bZIP23 TFs are upregulated in response to zinc deficiency and contain a palindromic 10-bp motif (up to 3 copies) in their promoters. It has been shown that these bZIPs bind in vitro to the 10-bp cis element which has been named the ZDRE (zinc deficiency response element). The bZIP19 and bZIP23 double T-DNA insertion mutant line, m19m23, has strongly reduced expression of these genes, and shows a zinc hypersensitive phenotype when grown under zinc deficient conditions. Overexpressing bZIP19 or bZIP23 in the double mutant background completely complements the zinc hypersensitive phenotype.1 With these findings, a network of players involved in adaptation to zinc deficiency stress is emerging (Fig. 1). How this network allows plants to sense Zn deficiency and whether or not a Zn-deficiency sensing mechanism is linked to the bZIP19and bZIP23-based regulatory mechanism are still open questions.

Jan K. Schjøerring is a professor and head of the Plant and Soil Science Section at Faculty of Science, University of Copenhagen. His research focuses on transport and functional properties of mineral elements in plants.

Jan K. Schjørring

Ross Alexander is a postdoctoral research scientist from the Laboratory of Genetics, Wageningen, The Netherlands. His primary research goal is to better understand the molecular genetics of the Zn deficiency response in Arabidopsis, and more specifically to further explore the role of the two bZIP transcription factors bZIP19 and 23 in this process. Ross D. Alexander

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Mark Aarts is an associate professor at the Laboratory of Genetics of Wageningen University. He is heading a group with great interest in plant adaptation to resource limitations and excess Zn, Cd and Ni exposure, mainly using Arabidopsis thaliana and Noccaea caerulescens as model species.

Mark G. M. Aarts

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bZIP19 and bZIP23 transcription factors The bZIP-family is represented by many transcription factors, generally acting as dimers. Together with other well-known and large families of dimerizing TFs, such as the basic-region helixloop-helix (bHLH) and MADS box proteins, it is predicted to have emerged at the origin of eukaryotes, being present in plants, fungi and animals.14–16 The bZIP TFs are characterized by a 40- to 80-amino-acid-long conserved domain (bZIP domain) that is composed of two motifs: an alpha-helical basic region involved in DNA binding by recognition of core hexanucleotide DNA elements, and, at the C-terminal of this region, a coiled-coil leucine zipper domain that directs protein dimerization. These domains, involved in DNA-binding and dimerization activities, are highly conserved and shared among all members of the family.16–19 The Arabidopsis genome encodes 75 predicted bZIP TFs which have been divided into ten homologous groups, based on the sequence similarities of the bZIP domain, shared intron positions and of other conserved motifs. They are regulators of many central developmental and physiological processes including photomorphogenesis, leaf and seed formation, energy homeostasis, and abiotic and biotic stress responses, although many plant bZIPs are yet to be characterized.16,20,21 bZIP19 and bZIP23 belong to the bZIP group F together with a third member, bZIP24, which is a negative regulator in salt stress induced expression and acclimation responses.22 The predicted protein sequences of bZIP19 and bZIP23 indicate protein sizes of 28.7 and 27.3 kDa respectively. They share 69% of amino acid sequence identity with each other, and 28% and 32%, respectively, with bZIP24.1 In the analysis of evolutionary relationships in the plant bZIP family, the relationships between homologous and orthologous bZIP TFs were established and the ancestral origin and functions were inferred.16 In this analysis, a comparative approach between different available plant genomes allowed the definition of possible groups of orthologues. In rice, only one orthologue of AtbZIP19 and AtbZIP23 is found, the OsbZIP48. Interestingly, the existence of AtbZIP19/23 orthologues in the Bryophyte Physcomitrella patens (PpbZIP18 and PpbZIP19) suggests a conservation of the zinc deficiency response regulatory network throughout the plant kingdom.16,20 bZIP19 and bZIP23 are predicted to be gene pairs resulting from segmental duplications of the Arabidopsis genome. The putative bZIP19/23 orthologues are markedly different from bZIP24 orthologues in their first 50 N-terminal amino acids and in the region behind the bZIP domain.1,16 The functional core promoter that is specifically bound by the basic region of plant bZIP factors typically contains an ACGT core motif, as is found in the A-box (TACGTA), C-box (GACGTC), T-box (AACGTT) and G-box (CACGTG).20,23,24 However, the ZDRE cis element that is bound by bZIP19 and bZIP23 has a consensus sequence, RTGTCGACAY, with a TCGA core motif, which has not been reported before as a consensus bZIP binding site.1 The bZIP TFs have the ability to form homodimers and heterodimers, resulting in a range of potential dimers with a unique effect on transcription. Analysis of the dimerization

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potential of all bZIP factors encoded by the Arabidopsis genome indicates that bZIP19 and bZIP23 are predicted to form homodimers.14,25 Indeed bZIP19 or bZIP23 overexpression in the double mutant line background (m19m23) completely complements the zinc hypersensitive phenotype suggesting that bZIP19 and bZIP23 are redundant and thus function as homodimers. However, 4-week exposure of single bZIP19, but not bZIP23 T-DNA insertion mutants, revealed a mild Zn deficiency phenotype, suggesting that the presence of bZIP23 did not fully complement loss of bZIP19. Additionally, bZIP19 is also higher expressed than bZIP23.1 This apparent partial redundancy might be explained by insufficient local protein TF concentration/ abundance influencing dimer equilibrium.25,26 The regulation of adaptation to Zn deficiency in Arabidopsis is, at least partially, mediated by bZIP19 and bZIP23.1 The nature of the regulation of these TFs by the cellular Zn nutritional status, i.e. transcriptional, post-transcriptional, posttranslational, is not yet known. In the Fe deficiency regulatory mechanism, basic helix–loop–helix (bHLH) transcription factors, including Arabidopsis FIT,27–29 AtbHLH38, AtbHLH39,30,31 POPEYE,32 tomato FER33 and rice OsIRO2 and OsIRO3,34,35 play important roles in regulating Fe acquisition-related genes, like FRO2 and IRT1, in response to Fe deficiency. All these bHLH TF genes are induced under Fe deficiency, indicating the presence of other upstream factors acting as positive regulators.36 In the bZIP19- and bZIP23-based regulatory mechanism, preliminary results on a detailed analysis of the bZIP19 and bZIP23 transcriptional response to the Zn status indicate that expression levels are not significantly affected upon Zn deficiency. Their transcriptional target ZIP transporters, on the other hand, show a rapid induction (4–6 h) upon exposure to Zn limiting conditions thus suggesting a non-transcriptional-based regulation of bZIP19 and bZIP23 in response to the cellular Zn status (Alexander, R.D. and Aarts, M.G.M., unpublished data). Other TFs demonstrated to be involved in the Fe-deficiency response are the rice IDEF1 and IDEF2, which specifically bind to the IDE1 and IDE2 cis element (iron deficiency element), respectively.37,38 Their transcripts are constitutively expressed and the expression levels are not affected in response to the Fe status. They regulate Fe homeostasis and Fe acquisition-related genes. Interestingly it has been suggested that IDEF1 might be involved in sensing the cellular Fe nutritional status by directly binding to Fe and other divalent metals via its characteristic HisAsp repeat and Pro-rich regions.39 In the single celled green algae Chlamydomonas reinhardtii, the transcription factor CRR1 regulates Cu homeostasis and the response to copper deficiency.40,41 It is a SBP-domain TF, which is a highly conserved DNA-binding domain containing Zn-binding sites consisting of Cys and His residues.42 In CRR1, a Cys-rich C-terminal domain has been suggested to act as a sensor of the Zn status and function in Zn homeostasis regulation, additionally suggesting a molecular connection between Cu and Zn homeostasis.41 In Saccharomyces cerevisiae, the TF Zap1 zinc-responsive activator is the central player in the adaptation to Zn-limiting conditions. It is a seven (Cys2His2) zinc finger-containing TF and mediates the transcription of genes encoding Zn uptake

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Fig. 2 Alignment of the conserved CysHis-rich motif in the three bZIP proteins of the F-group of Arabidopsis bZIP transcription factors. His (H) and Cys (C) residues are represented in red and green, respectively.

and vacuolar transporters, including members of the ZIP family. It is active in zinc-limited cells and repressed in zincreplete cells and binds to a specific cis element, ZRE (zinc responsive element) found in the promoters of its target genes.43,44 In higher eukaryote animals, ranging from insects to mammals, the metal-responsive-element-binding transcription factor-1 (MTF-1), a six (Cys2His2) zinc finger-containing TF, is a key regulator of the Zn status. It responds to changes in intracellular Zn and upon metal-binding it is translocated to the nucleus controlling the expression of a number of genes, including members of the ZIP transport family, directly involved in the intracellular Zn sequestration and transport.45 This TF binds to metal response elements (MREs) located in the promoters of metal responsive genes. In these two different regulatory mechanisms there is evidence of a Zn-sensor function via a direct and reversible interaction of Zn with a subset of the TF zinc finger motifs.46–50 The defining characteristic of the F group of Arabidopsis bZIP TFs is the presence of a His-rich motif at the N-terminal of the basic region (Fig. 2). These are two boxes with conserved Cys and His residues.16,20 The conservation of these common CysHis-motifs in the F group bZIP proteins20 might suggest that they play a role in the transcription factor function. The three bZIPs are involved in metal ion stress response, although bZIP24, which is a regulator of adaptation to salt stress,22 is more distant from the other two, based on sequence similarity including differences in their CysHis-motifs (Fig. 2). It is tempting to hypothesize a role for the bZIP19- and bZIP23CysHis-motif as a Zn-sensor. This Zn-binding sensor function could act as a post-translational regulation mechanism of the bZIP19 and bZIP23 transcription factors.

Model of a putative zinc-sensor function for bZIP19 and bZIP23 Zinc is an essential nutrient for all organisms due to its function in proteins as a structural and catalytic cofactor, with the fraction of Zn-binding proteins of proteome estimated to range between 4% to 10%.51,52 Zinc requirements in bacteria and eukaryotic cells are in the low millimolar range, however cytosolic free Zn2+ levels are estimated to be in the pico- or nanomolar range under steady state growth conditions, revealing an extraordinary intracellular Zn-binding capacity.7,53 Difficulties in monitoring the free Zn2+ concentration in biological systems are a limitation to understanding how cellular Zn-dependent processes compete for available zinc. Also the role of free Zn2+ (or rapidly exchangeable) in these processes is not fully understood.54–56

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Metallomics The CysHis-rich motif from bZIP19 and bZIP23, as mentioned above, can be hypothesized to act as a zinc-sensor, thereby playing a role in their Zn-dependent regulatory function. A putative Zn-sensor function of bZIP19/23 would require reversible Zn-binding. Cytosolic free Zn2+ may thereby, via binding to the CysHis-motif, act as a signal of the cell Zn status modulating bZIP19 and bZIP23 activity. Under normal Zn supply, binding of Zn to the motif would render the TF non-functional via an effect on the TF conformation, its DNA-binding activity, or movement to the nucleus. Such posttranslational regulation of bZIP transcription factors has been previously described.26 Upon Zn deficiency, the ‘‘release’’ of coordinated Zn from the CysHis-motif of bZIPs would allow the TF to become functional (Fig. 3). The expression level of bZIP19 and bZIP23 is low, with bZIP19 being relatively higher expressed compared to bZIP23.1 If acting as Zn-sensors, a reservoir of the bZIP19/23 TFs would be expected in the cytosol (or nucleus) with low protein abundance, being coordinated with Zn under Zn sufficient conditions, and being activated upon Zn deficiency (Fig. 3). In spite of the contribution of plant bZIP TFs to many transcriptional response pathways, little is known about their regulation. Post-translational mechanisms affecting DNA binding and transcriptional properties, protein stability, dimerization, interaction with other proteins and phosphorylation are known to regulate their activity and subcellular partitioning, though only few plant bZIP TFs have been analyzed in this respect.26 The degree of Zn specificity of the proposed model is intriguing considering the multi-ionic environment of the cell, where Zn exists together with other trace elements of which several might have stronger affinities to thiol and imidazole groups (e.g. Cu and Ni) of the conserved CysHis-motif in the bZIP19/23 TFs. In addition, the bZIP19/23 should not only be able to bind Zn with high specificity, but crucially, they must also be able to release Zn when the cytosolic levels fall below a certain threshold concentration. Thus the type of Zn binding in these TFs would be different from the Zn coordination environments found in e.g. enzymes where Zn is strongly bound to the catalytic site and dissociation is negligible. Several attempts have been made to predict the nature of Zn binding sites in proteins and smaller peptides,57 but generally due to the complexity of the kinetic and thermodynamic processes controlling metal ion insertions into proteins it is difficult to predict whether Zn, Fe, Cu or any other cation from the first row transition elements will be given preference.58 Generally, very little is known about metal sensors in higher plants, but as the free Zn2+ activity in the cell is extremely low, it is likely that a series of ligand exchange reactions must take place53,59 if we envisage that Zn is specifically delivered to and released from the bZIP TFs. In bacterial metal sensors it has been observed that they are regulated by functional selectivity, where a protein might bind preferentially to a metal other than the regulated one, but without causing the appropriate conformational change required for elicitation of the regulatory function.60 The presumed bZIP19 and bZIP23 target genes, NAS2, 4, ZIP1, 3, 4, 5, 9, 10, 12 and IRT3, are activated under Zn deficient

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Fig. 3 Schematic model of a putative function as a zinc-sensor for bZIP19 and bZIP23 transcription factors (TFs). There is no distinction in this scheme between the bZIP19 and bZIP23. Under normal Zn supply (Zn-sufficient), binding of zinc to the motif renders the TF non-functional. Upon zinc deficiency, the release of coordinated Zn from the HisCys-motif of bZIPs allows the TF to be functional (Zn-deficient). Possibly a reservoir of bZIP19 and bZZIP23 exists in the cytosol where the Zn-sensor activity and TF activation take place. The activation of the TF in the nucleus cannot be excluded. The bZIP domain of the TF is represented in blue and contains the basic-region and leucine zipper domains. The HisCys-motifs are represented in grey.

conditions (Fig. 1).1 The involvement of several ZIP genes in the bZIP19/23-based Zn deficiency response might be due to different functions in the adaptation response and differential spatial and/or temporal expression. Information on the characterization of each of these ZIP genes is still poor, so their individual contribution is not yet known. In fact, insufficient information on the transporter functional characterization, membrane localization and expression patterns extends to most of the 15 ZIP members from Arabidopsis.61 However, of the bZIP19/bZIP23 target ZIP members, the IRT3 zinc transporter gene has been well studied62 and the ZIP1, 3, 4 and 12 have been shown to mediate zinc uptake.1,4,63 Recently, studies on the yet uncharacterized ZIP genes provided insight into what their possible roles in Zn transport and homeostasis are, suggesting different transporter localization and different contributions to Zn movement.63 Considering the NAS genes as bZIP19/bZIP23 targets, it might relate to the suggested role of NA in Zn translocation within the plant.12,13 An increase in NA under zinc deficiency might contribute to increasing the intracellular binding capacity for zinc and its translocation as a response to this stress. Additionally it can be speculated that an increase in the intracellular NA level has the effect of prolonging the sense of Zn deficiency and the corresponding bZIP19/23-based zinc deficiency response. A putative model of how plants sense zinc deficiency at the cellular level is shown in Fig. 3. It remains to be revealed how Zn deficiency is transmitted and integrated into a response at the whole-plant level. Zn deficiency is likely to be first sensed in

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shoots where a putative systemic Zn-deficiency signal would originate and trigger Zn deficiency response in roots, via activation of bZIP9 and bZIP23.64 Zn is considered to have intermediate mobility in the phloem,65 and complexation with ligands such as NA, organic acids and amino acids has been suggested to play a role in Zn translocation and long distance transport.12,66–68 A key aspect is if Zn itself can serve as a source of information on the Zn-status of the shoot and transmit it to the roots. The conservation of the zinc deficiency response regulatory network in the plant kingdom provides an exciting opportunity to investigate the underlying mechanisms in species that have evolved as extremophiles adapted to high zinc exposure, and in species important for agriculture as a possible avenue to achieve plant-based solutions to alleviate zinc deficiency.

Acknowledgements We thank Pedro Borges for helping in designing the figures in this article.

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Metallomics