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Plant Signal Behav. 2010 June; 5(6): 663–667.
PMCID: PMC3001555

Regulatory networks of cadmium stress in plants

Abstract

During their life, plants have to cope with a variety of abiotic stresses. Cadmium is highly toxic to plants, water soluble and therefore promptly adsorbed in tissues and its presence greatly influences the entire plant metabolism. In this review, we focus on the signal pathways responsible for the sensing and transduction of the “metal signal” inside the cell, ultimately driving the activation of transcription factors and consequent expression of genes that enable plants to counteract the heavy metal stress.

Key words: cadmium detoxification, heavy metal stress, phytoremediation, signal transduction, transcription factors

In order to respond to stress signals, plant cells must be able to perceive these signals and convert them into appropriate responses, which in turn confer on plants the ability to tolerate unfavorable conditions. Plant tolerance mechanisms require a coordination of complex physiological and biochemical processes, including changes in global gene expression, protein modification and primary and secondary metabolite compositions.1 In the last decade functional genomics approaches have partially unraveled the complex mechanisms that drive from stress perception and transduction, through a cascade of signaling molecules, to the expression modulation of genes responsible for plant stress response.2 In addition, the elucidation of the function of newly identified stress-responsive non-coding RNA will facilitate understanding of the complex response to stress.3

Soil and water pollution by heavy metals is a serious environmental problem. Although heavy metals occur naturally in soil as rare elements, agricultural practices, refuse dumping, metallurgy and manufacturing all contribute to their spread in the environment. Among heavy metal pollutants, cadmium (Cd) is considered to be one of the most phytotoxic. Because of its high solubility in water, it is promptly taken up by plants and this represents the main entry pathway into the food chain, also causing serious problems to human health.4 Even at low concentrations, the uptake by roots and transport to the vegetative and reproductive organs has a negative effect on mineral nutrition and homeostasis in plant shoot and root growth and development.57

Evident symptoms of Cd toxicity are leaf rolling and chlorosis, water uptake imbalance and stomatal closure.8 Cd damages the photosynthetic apparatus and causes a decrease in chlorophyll and carotenoid content.9 Together, these Cd effects are responsible for lowering the photosynthetic quantum yield. In addition, Cd decreases carbon assimilation by inhibiting enzymes involved in CO2 fixation.10 In several plant species, Cd toxicity is manifested at cellular level as chromosomal aberrations and alteration of cell cycle and division.11 High mutation rate and malformed embryos have been observed in Arabidopsis plants exposed to Cd.12

Plant molecular response to Cd stress is characterized by the synthesis of stress-related proteins and signaling molecules. Phytosiderophores, nicotianamine and organic acids are a few examples of chelating compounds that are released by roots and might influence heavy metals uptake. Functional genomics technologies have recently increased our knowledge of the complex regulatory networks associated with Cd stress in plants. In this article we review recent progress on the molecular component of the Cd-induced signal transduction that triggers the activation of genes responsible for Cd uptake, transport and detoxification.

Cadmium Stress: From Sensing to Gene Activation

Signal transduction pathways.

In whole plants, roots are the primary site through which heavy metals gain access. Analysis of the Cd and Cu localization under an electron microscope, for instance, showed that the root cell wall, in comparison with the cytoplasm, contains the majority of heavy metals.13 Indeed, because of their negative charge, cell walls have a significant capacity for heavy metal binding and retention.14 Cell walls have acquired importance as active metabolic sites, where a variety of signaling molecules are generated in response to extra-cellular stimuli. The finding that proteins directed to the apoplastic space are synthesized in response to Cd and Ni exposure is noteworthy, pointing out an important role of the cell wall as a prime heavy metal-sensing site.15

Gene expression patterns change in response to toxic elements. After sensing the heavy metal, the plant cell activates specific genes to counteract the stress stimuli. A signal transduction cascade is therefore responsible for the differential gene regulation. In eukaryotes, mitogen-activated protein kinase (MAPK) pathways represent a signaling mechanism that consists of three sequentially activated protein kinases: MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK), and MAPK.16,17 MAPKKKs are Ser/Thr protein kinases that phosphorylate MAPKKs. Once phosphorylated, and therefore activated, MAPKKs are responsible for the phosphorylation of MAPKs on Thr and Tyr residues. This phosphorylation renders these enzymes active. MAPKs are able to phosphorylate numerous substrates in different cellular compartments, among which, transcription factors. In plants, the MAPK cascade is involved in response to a variety of environmental, hormonal and developmental stimuli.18 It has recently been shown that stress due to excessive Cd (and Cu) activates different kinase enzymes belonging to the MAPK family.19 The phosphorylation cascade is therefore thought to be involved in Cd signaling to the nucleus (Fig. 1A).

Figure 1
Representation of the transduction pathway involved in Cd signaling. (A) Once entered the plant cell Cd induces ROS, responsible for the activation of MAPK kinase cascade. This, together with the activation of Ca-calmodulin system and stress-related hormones, ...

Calcium ions and calmodulin are well-known second messengers of external stimuli, and the participation of this system in heavy metal signaling has also been hypothesized.20 Indeed, Ca concentration in cells greatly increases during Cd stress21 and it stimulates calmodulin-like proteins that interact with Ca ions. Changing their conformation in response to Ca binding, calmodulin proteins regulate a variety of mechanisms, including ion transport, gene regulation, metabolism and stress tolerance that coordinate, at least in part, the plant response to Cd.22 The Ca/calmodulin system is also involved in sensing other heavy metals, and in fact, transgenic plants expressing a tobacco calmodulin-like protein exhibit increased Ni tolerance and Pb accumulation.23

Another mechanism that is thought to be involved in Cd sensing is the reduced glutathione-oxidized glutathione ratio (GSH/GSSG). Glutathione can control the differential expression of antioxidant enzymes, such as chalcone synthase, phenylalanine ammonia lyase, superoxide dismutase or glutathione reductase, usually induced by heavy metal stress.24 During Cd stress, a reduction in GSH/GSSG ratio has been observed in different plant species,24 with the consequent activation of the response genes.

Regulation in hormone synthesis has also been observed during heavy metal stress. Treatments with Cd or Cu, for instance, enhance jasmonic acid content in Arabidopsis, Oryza and bean.25 Ethylene synthesis is also increased upon treatment with Cd, Cu, Fe, Zn, and in the case of Cd and Cu, this increase is due to an upregulation of ACC synthase transcription and enhanced activity.25 Salicylic acid (SA) is another well-known hormone involved in stress signaling in plants and exposure to Cd has been shown to stimulate SA accumulation in roots.25 All these data together suggest that cross-talk exists between heavy metal signaling and biotic stress signaling. It has been shown that a mild exposure to heavy metals can induce greater plant resistance against viral and fungal infections without being connected to the direct toxic effect of the metal. Conversely, application of SA on barley seedlings before Cd treatment caused partial protection against the heavy metal toxicity.25

Hormone signaling is not the only example of redundancy between heavy metal and (a)biotic stress. The signal mediated by Reactive Oxygen Species (ROS) is also reported. In fact, heavy metal stress triggers the accumulation of ROS both directly, via Fenton or Haber-Weiss reaction and indirectly, unbalancing the activity of antioxidative enzymes, as in the case of Cd.24 H2O2 plays a role as signal molecule inducing defense mechanisms against both abiotic stresses, such as temperature and ozone,26 and pathogen attack.27 Based on the evidence that both heavy metal stress and ROS-mediated biotic stress induce phytoalexins biosynthesis, it has been hypothesized that heavy metal and biotic stress response share common signals.28 It remains anyway doubtful whether the effects of heavy metals on plants should be attributed to their direct effect on membranes, cellular enzymes and photosynthetic apparatus or to their indirect effect caused by the induction of some signaling pathways that are responsible for the so called heavy-metal stress response.

It is noteworthy that plant cells probably transduce heavy metal signaling in different ways for different heavy metals. The main differentiation is probably due to the fact that some metals do not have any known function and could induce deleterious effects even at low concentration. Conversely, other metal ions take part in the normal cell metabolism and are shown to be toxic only at high concentrations. A good example of this is the activation of the phosphorylation cascade of MAPK proteins induced by Cu and Cd. Cu stress rapidly activates SIMK, MMK2, MMK3 and SAMK kinases, and their activation is probably the consequence of oxidative stress generated by the metal ion.19 Conversely, activation of the above-cited MAPKs in response to Cd ions is rather slower than to Cu. This could be due to the fact that Cd stimulates an oxidative stress as a secondary effect, which is responsible for the MAPKs activation, delaying the phosphorylation cascade.19

Summarizing, heavy metal stress signals appear to be transduced through a variety of pathways that overlap and cross-talk. Activation of phosphorylation cascades, Ca-calmodulin system, ROS signaling and stress-related hormones eventually converge regulating transcription factors that are deputed to the activation of gene sets responsible for response to stress (Fig. 1A).

Modulation of transcription factors.

Transcriptomic changes upon Cd stress have been investigated in several plant species, including Arabidopsis,29,30 pea24 and barley.31 This analysis led to the identification of numerous transcription factors (TFs), involved in Cd plant response.3234

Cd-responsive TFs share the same signal transduction pathway with other stress-related TFs, and can therefore be activated by other abiotic stresses such as cold, dehydration, SA and H2O2.35 Moreover, the modulation of TFs belonging to several families demonstrates the complexity of the response of plants to Cd stress.32 TFs belonging to different families, such as WRKY,36 basic leucine Zipper (bZIP),37 ethylene-responsive factor (ERF)38 and myeloblastosis protein (MYB)34 play a significant role in controlling the expression of specific stress-related genes after Cd treatment.

Cd regulates the expression of ERF proteins (e.g., ERF1 and ERF2,30) belonging to the APETALA2 (AP2)/ethylene-responsive-element-binding protein (EREBP) family and is also able to bind to several pathogenesis-related promoters and dehydration responsive elements (DRE).35 An example of TF induced by Cd and binding to DRE motif is DREB2A: it can specifically interact with the promoter region of the Rd29A (desiccation responsive) gene, on the DRE motif, inducing the transcription of Rd29A after Cd-exposure.20

In addition, it was observed that MYB4 is highly expressed after Cd and Zn treatment in A. thaliana,34 while MYB43, MYB48 and MYB124 proteins are specifically induced by Cd in roots.30 Furthermore, the TFs MYB72 and bHLH100 (belonging to the helix-loop-helix TFs group) were studied for their implication in metal homeostasis because they showed an altered expression after Cd exposure.34 In Cd-treated Thlaspi caerulescens MYB28 and WRKY53 are strongly expressed,34,36 even if the latter has been supposed to be involved in the signal transduction pathway regulating the activity of other TFs.36

OBF5, belonging to the bZIP group, regulates the expression of glutathione S-transferase binding to its promoter region in a Cd-induced manner.20 TGA3 protein also has a putative role in modulating gene expression upon Cd-treatment,7 as well as in response to biotic stress.39 Recently, BjCdR15, orthologous to TGA3, has been identified in B. juncea after short Cd treatment; BjCdR15 influences the expression of several metal transporters, being therefore involved in long distance root-to-shoot Cd transport.7,32 In addition, its overexpression in A. thaliana and tobacco enhances Cd tolerance and accumulation in shoots.7

Finally, other TFs named metal-responsive TFs (MTFs),40 control the expression of metallothioneins by binding metal-regulatory elements (MREs) in their promoter region.41 MTF-1, for instance, was first identified as a Zn dependent MRE-binding factor42 essential for Zn and Cd dependent induction of the murine MT-I and MT-II genes.43

Activation of metal transporters.

Once Cd has entered the cells, plants use various strategies to cope with its toxicity. One such strategy consists of transporting Cd out of the cell or sequestering it into the vacuole, thereby removing it from the cytosol. Members of different transporter families contribute to Cd resistance. The ABC transporter AtPDR8 has been shown to mediate Cd extrusion out of the plasma membrane of root epidermal cells.44 Detoxification of Cd is also achieved by members of the ZIP (ZRT, IRT-like protein) family. They are plasma-membrane proteins induced in roots and shoots of Arabidopsis in response to Zn-limiting conditions, and being involved in the xylem uploading process, are potentially implicated in Cd root-to-shoot transport.45 IRT1 is essential for root iron uptake in response to iron deficiency but it also accepts Cd as a substrate.46 HMA4, a member of the P-type metal ATPase, functions as Zn/Cd transporter and by loading Cd into the xylem, it increases translocation to the shoot where Cd might have less damaging effects.47,48 Another family of metal transporters implicated in the mobilization of Cd is the NRAMP (natural resistance-associated macrophage protein). Indeed, expression of AtNRAMP1, AtNRAMP3 and AtNRAMP4 in yeast showed that these proteins are able to transport Cd.49 Recently, it was suggested that AtNRAMP6 functions inside the cell either by mobilizing Cd from its storage compartment or by taking up Cd into a cellular compartment where it is toxic.50 Finally, transporters of the CDF (cation diffusion facilitator) family appear to mediate the cytoplasmic efflux and vacuolar sequestration of divalent metal cations such as Zn, Cd, Co, Ni or Mn.45

Biosynthesis of chelating compounds.

In the cell, Cd is chelated by thiol-containing ligands such as glutathione (GSH) and its derivative phytochelatins (PCs),51 to allow the transport of Cd-complexes into the vacuole or in the apoplast by ATP-dependent membrane pumps.52 GSH is required for PCs synthesis. This process is catalyzed by the cytosolic PCs synthetase (PCS). It has been shown that PCS is constitutively expressed, but post-translationally activated by heavy metals.53 A recent study confirms that PCS is regulated by a Cd-dependent phosphorylation on a Thr residue next to the catalytic site, and it could therefore function as a “Cd sensor”.54 PCs have the general structure (γ-Glu-Cys)n-X (where n is a variable number from 2 to 11 and X an amino acid such as Gly, β-Ala, Ser, Glu or Gln)53 and Cd ions are bound to the thiolic groups of Cys. Cd-PCs complexes are transported into the vacuoles where they pack to form high-molecular-weight complexes8,51 (Fig. 1B). PCs also play a role in long-distance Cd transport from root to shoot: this would contribute towards keeping Cd accumulation low in the root, causing extra Cd transport to the shoot.55

Genes encoding PCS have been cloned from different organisms, for example, OsPCS1, TaPCS1, AtPCS1 and CePCS1 from rice, wheat, Arabidopsis and Caenorhabditis elegans respectively,8,56,57 and BjPCS1 from the metal-tolerant plant Brassica juncea.58 Experimental data confirmed that accumulation and tolerance to Cd is increased in transgenic plants overexpressing PCS.59 In B. juncea, enhanced tolerance to Cd, As and Zn was associated to the overexpression of AtPCS.60 However, an excessive expression of AtPCS caused hypersensitivity to Cd in Arabidopsis plants.61

Finally, metallothioneins (MTs) are low-molecular-weight Cysrich peptides also able to bind metal ions, such as Cd. Differently from PCs, MTs are products of mRNA translation, induced in response to heavy metal stress.53 Binding to Cd, MTs also contribute to detoxifying the cytosolic environment from Cd toxicity (Fig. 1B). Indeed, it has been reported that overexpression of mouse MT in tobacco plants enhances Cd tolerance in vitro,62 whereas the Arabidopsis MT2a and MT3 increased Cd tolerance when expressed in Vicia faba.63 Moreover, B. juncea MT2 confers increased tolerance to Cd and Cu in transgenic A. thaliana.64 In a recent study on hybrid Populus, it was shown that high levels of MT2b correlated with Cd and Zn concentrations, demonstrating that increased MT2b expression is one of the plant responses to chronic metal exposure.65

Conclusions and Perspectives

Heavy metal pollution is a significant environmental problem that is nowadays being evaluated as a major threat to humans. Researchers are concerned in developing new technologies for low cost and environmentally friendly land reclamation techniques. Increasing our knowledge about the mechanisms that enable plants to cope with heavy metal stress would help in creating new tools applicable in phytoremediation, which is any technology that uses plants to reclaim polluted soils and waters. It is therefore of primary importance to further dissect the processes of heavy metal detoxification and signaling pathways in plants, to identify useful targets for biotechnological applications to increase plant fitness in heavy metal polluted sites.

Footnotes

References

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