Oxidative stress in cyanobacteria - Wiley Online Library

REVIEW ARTICLE

Oxidative stress in cyanobacteria Amel Latifi, Marion Ruiz & Cheng-Cai Zhang ´ Aix-Marseille Universite´ and Laboratoire de Chimie Bacterienne, CNRS-UPR9043, Marseille, France

Correspondence: Amel Latifi, Aix-Marseille Universite´ and Laboratoire de Chimie ´ Bacterienne, CNRS-UPR9043, 31 chemin Joseph Aiguier, 13402 Marseille, Cedex 20, France. Tel.: 10033 4 91 16 41 88; fax: 10033 4 91 71 89 14; e-mail: [email protected] Received 7 May 2008; revised 14 August 2008; accepted 18 August 2008. First published online 25 September 2008.

Abstract Reactive oxygen species (ROS) are byproducts of aerobic metabolism and potent agents that cause oxidative damage. In oxygenic photosynthetic organisms such as cyanobacteria, ROS are inevitably generated by photosynthetic electron transport, especially when the intensity of light-driven electron transport outpaces the rate of electron consumption during CO2 fixation. Because cyanobacteria in their natural habitat are often exposed to changing external conditions, such as drastic fluctuations of light intensities, their ability to perceive ROS and to rapidly initiate antioxidant defences is crucial for their survival. This review summarizes recent findings and outlines important perspectives in this field.

DOI:10.1111/j.1574-6976.2008.00134.x Editor: Ferran Garcia-Pichel Keywords cyanobacteria; photosynthesis; reactive oxygen species; antioxidants; transcriptional regulation.

Introduction Life originally began on Earth under a reducing atmosphere (Dietrich et al., 2006). The atmosphere became oxidant as oxygen-producing photosynthesis evolved after the proliferation of cyanobacteria between 3.2 and 2.4 billion years ago (Brocks et al., 1999). Oxygen accumulation allowed the development of aerobic organisms that used oxygen as a powerful electron acceptor. At the same time, these organisms had to cope with the damaging effects of oxygen on the metabolic networks that had originally evolved in an anoxic environment. This is because reactive oxygen species (ROS) are unavoidably generated as intermediates of O2 reduction, or by its energization. The chemistry of oxygen species is well documented (for a review, see Imlay, 2003). ROS, including singlet oxygen (1O2), the superoxide anion (O 2 ), hydrogen peroxide (H2O2) and the hydroxyl radical (OH ) are powerful oxidizing agents. Singlet oxygen (1O2) is produced by energy input to oxygen, it is highly reactive, has a short half life in cells (Gorman & Rodgers, 1992) and reacts with target molecules (proteins, pigments, and lipids) in the immediate neighbourhood. The three oxygen reduction-intermediates (O 2 , H2O2, and OH ) have different intrinsic features, and therefore possess different reactivities, toxicity levels and targets. Both O 2 and OH have an 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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unpaired electron that renders them highly reactive with biomolecules (Fig. 1). Because O 2 is negatively charged, it does not diffuse through membranes. It oxidizes the [4Fe–4S]21 clusters to [3Fe–4S]11 releasing iron (Fe21). The hydroxyl radical is so reactive that reaction rates become diffusion limited. Even if H2O2 is less reactive it can be reduced to hydroxyl radical via the Fenton reaction (Fe211 H2O2 ! OH1FeO211H1 ! Fe311OH1OH ) and thus causes highly damaging effects. Even though DNA is not the direct target of H2O2 and O 2 in contrast to OH , they are nevertheless considered as potential mutagens because they can engender the release of the Fenton-active ferrous iron, thus leading to the production of a hydroxyl radical which can cause extensive lesions on DNA (reviewed by Imlay, 2003). Living organisms have developed various defences to protect themselves against ROS damage (for a review, see Imlay, 2003). While some of these defences are enzymatic [catalases, superoxide dismutases (SOD) and peroxidases], others are nonenzymatic (glutathione, vitamin A, C, E, carotenoids, etc.). When the balance between oxidant levels and antioxidant production is lost, the organisms have to face an oxidative stress that generates a variety of damage ranging from, for example, cell death in bacteria to serious pathologies in higher organisms. FEMS Microbiol Rev 33 (2009) 258–278

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Oxidative stress in cyanobacteria

UV-B

H2O

DNA Proteins Lipids

Catalases peroxidases

RUBISCO MAAs

H2O2

[FeS]

H2O Fe++

SODs

OH−

NADPH

O2−

[FeS] cysteine methionine

Flavoproteins O

hυ

NADP+ + H+

UV-B

2H+

MAAs hυ

Fdx

Fdx

FNR

Stroma Cyt b6f PQ

e−

PSII

PSI PQH2 e−

Lumen

e−

e−

3 P680 * PC H2 O

½ O2 + 2H+

2H+

3O2 ½ O2*

PC

DNA Proteins Lipids

Fig. 1. ROS production and targets. The unreactive di-radical O2 leads to the formation of chemically reactive species (ROS): In PSII, singlet oxygen (1O2) is produced by energy input to oxygen from photosensitized chlorophyll. In PSI, univalent reduction of O2 using electrons from PSII generates superoxide anion radicals (O 2 ). The O2 is disproportionated to H2O2 and O2 by SOD, and the H2O2 is reduced to water by catalases and peroxidases. In cyanobacteria, the reduction of O2 by A-type flavoproteins leads to water (see text for details). The reduction of H2O2 by metal catalysed Fenton chemistry generates the highly toxic hydrogen radical OH . Because of their intrinsic chemical properties, ROS react with different biological targets (boxes). Possible ROS production by O2 reaction with iron-containing components of the photosynthetic pathway is not presented in this figure. The effect of UV-B irradiance is shown. The possible role of mycosporine-like amino acids (MAAs) as UV-B sunscreens and as antioxidant molecules is discussed in the text.

Cyanobacteria are widespread in a variety of ecological niches and exist in different forms ranging from unicellular to highly sophisticated filamentous ones (for a review, see Stanier & Cohen-Bazire, 1977). The phototrophic nature of these organisms means that they not only need to manage the oxidative stress generated by oxygen reduction in the same way as heterotrophic organisms, but also that produced during photosynthetic electron transport. The fact that cyanobacteria constantly produce oxygen under illumination makes it crucial for them to prevent electron escape from normal electron transfer pathways to oxygen, thus avoiding oxidative stress as much as possible. While several reviews have addressed the oxidative stress responses in heterotrophic bacteria and plants, an overview of this field FEMS Microbiol Rev 33 (2009) 258–278

is still missing in the case of cyanobacteria, with the exception of a recent review that covers photoinhibition (Nishiyama et al., 2006). The aim of this manuscript is to review our current knowledge about how cyanobacteria generate, perceive, and defend themselves against ROS, and to discuss the perspectives in this field. Although the data are still limited, we have placed a particular effort on incorporating responses to ROS at cellular levels with the ecology of these organisms.

Sources of oxidative stress in cyanobacteria In all aerobically living organisms, respiration is thought to be a source of ROS produced inside the cells. Molecular 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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oxygen diffuses passively into the cell and is reduced to superoxide anion and H2O2 via the oxidation of flavoproteins, such as the NADH dehydrogenase II (NdhII) in Escherichia coli (for reviews, see Imlay, 2003; Giorgio et al., 2007). In addition to ROS produced by the respiratory machinery, photosynthetic organisms are challenged by ROS generated by the photosynthetic electron transport chain (Fig. 1). Light is essential for photosynthesis, but at the same time can also be a source of major stress. Singlet oxygen (1O2) is produced by an energy input to oxygen from photosensitized chlorophyll. It is thought to inhibit the repair of photosystem II (PSII) inactivated by light. The production of 1O2 and its impact on photoinhibition increases when the redox potential of the QA quinone decreases (Fufezan et al., 2007). If light intensity is higher than that normally managed by the capacity of the photosynthetic electron flow, not only does 1O2 production increase but other ROS can be formed, leading to the inactivation of the photosystems. This is because in these cases, oxygen rather than ferredoxin can be used as an electron acceptor, which generates a superoxide anion as a primary product. This reaction on the donor side of the photosystem I (PSI) was called the Mehler reaction as it was first described in chloroplasts by Mehler (1951). Since this pioneering work, it has been assumed that the reduction of oxygen by the PSI electron flow occurs in all oxygenic phototrophs. However, to what extent the Mehler reaction takes place in cyanobacteria is somewhat controversial. Compared to algae and higher plants, cyanobacteria undergo a high degree of O2 reduction by consuming 50% of the photosynthetic electrons instead of only 15% for plants (Badger et al., 2000). However, H2O2 production in Synechocystis PCC 6803 corresponds to 1% of the maximum rate of photosynthetic electron transport in vivo (Tichy & Vermaas, 1999). The discrepancy between the data cited above could be at least partly explained either by the fact that a strong reduction of H2O2 took place under the experimental conditions tested, or that the superoxide anion is not the main product of oxygen photoreduction, thus questioning the occurrence of the Mehler reaction in cyanobacteria. Indeed, Kaplan and colleagues suggested that the Mehler reaction in Synechocystis PCC 6803 does not produce ROS and that A-type flavoproteins directly reduce O2 to water, a role similar to their function in obligate anaerobes (Helman et al., 2003, 2005). One of the flavoproteins from Synechocystis PCC 6803 has indeed been shown to reduce O2 directly to water in vitro (Vicente et al., 2002). However, photosynthetic production of H2O2 has been recorded in Anacystis nidulans (Patterson & Myers, 1973). Clearly, further studies are needed to establish the extent of the Mehler reaction in cyanobacteria and to assess the role of A-type flavoproteins in the O2 metabolic pathway in cyanobacterial strains other than Synechocystis PCC 6803. 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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Characteristic oxidative damage in phototrophs Because the general mechanisms whereby ROS damage biomolecules inside the cell have been well documented (for a review, see Imlay, 2003), we attempt here to focus on the damage specific to cyanobacterial cells. Exposure of PSIIcontaining photosynthetic organisms to strong light severely inactivates this photosystem. This phenomenon has been called ‘photoinhibition’. PSII photoinhibition has been shown to occur in two steps: damage of the oxygen-evolving complex by strong blue light and UV with release of magnesium ions, and secondly, degradation of the D1 protein which, together with the D2 protein, constitutes the reaction centre P680. Photosynthetic organisms are able to overcome photodamage by the rapid and efficient repair of PSII (Ohnishi et al., 2005; reviewed by Nishiyama et al., 2006). Until recently, singlet oxygen was considered as being the principle cause of photodamage (Vass et al., 1992). However, studies that could separate repair from damage obviously demonstrated that photoinhibition is exclusively a light-dependent process and that the target of ROS is the de novo synthesis of D1 at the repair step. 1O2 and H2O2 have been shown to inhibit the translational elongation of psbA mRNA (Nishiyama et al., 2001, 2004). These studies also suggested that 1O2 and H2O2 could target a common step in the translation process. The mechanism whereby ROS inhibit the translation elongation has been assessed using an in vitro translation system from Synechocystis PCC 6803 (Kojima et al., 2007). While the addition of H2O2 inhibited the synthesis of the D1 protein, an exogenous supply of a reduced form of elongation factor G (EF-G) was able to restore the translation activity, so did the overexpression of EF-G in vivo (Kojima et al., 2007). The conclusion of this study is that EF-G is the target of ROS and that the redox state of this elongation factor may be the control point between the photosystem activity and D1 synthesis. This study unambiguously demonstrates that ROS do not damage D1 but inhibit rather its de novo synthesis (Kojima et al., 2007). The inhibition of EF-G is probably a general process that not only affects the translation of D1, but also other proteins because ROS inhibit the synthesis of the majority of the thylakoidal proteins. A key element in the response of some cyanobacteria to photoinhibition is a transient exchange in the constitutive form of D1 by alternate and more resistant isoforms of this protein. The cyanobacterium Synechococcus sp. PCC 7942 for example contains three psbA genes encoding two different forms of DI (Golden et al., 1986). psbA1 encodes the constitutive form D1 : 1, whereas psbAII and psbAII genes encode an alternate form D1 : 2 that differs from D1 : 1 at 25 residues. The D1 : 2 form transiently replaces D1 : 1 upon shifts to high light, allowing the bacteria to overcome FEMS Microbiol Rev 33 (2009) 258–278

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photoinhibitory damage to PSII (Schaefer & Golden, 1989). The D1 : 2 isoform has a 25% higher quantum yield and is more resistant to photoinhibition (Campbell et al., 1995). The exchange of the D1 isoform incorporated in PSII has been demonstrated in numerous cyanobacteria strains and under a lot of environmental stress such as UV-B irradiance (for a review, see Bouchard et al., 2006). The effects of UV irradiance on cyanobacteria are discussed below. Another possible target of ROS inside the photosynthetic apparatus is phycobilisomes. Phycobilisomes are involved in the capture of light in cyanobacteria. They are large extrinsic complexes attached to the outer surface of thylakoid membrane and composed of a core from which six rods radiate. The major core protein is allophycocyanin, while the rods contain phycocyanin and in some species both phycoerythrin and phycocyanin (for a review, see MacColl, 1998). A study that analysed in vivo, and under darkness, the structure and function of the phycobilisomes in Synechocystis PCC 6803 showed that H2O2 induced the interruption of an energy transfer between the core and the terminal emitter of phycobilisomes, which strongly suggests that the phycobilisomes core was disassembled under these oxidant conditions (Liu et al., 2005).

Defences against oxidative stress Energy dissipation Mechanisms for coping with oxidative stress are crucial for all organisms. cyanobacteria have developed numerous strategies in order to avoid the production of ROS or to scavenge them once produced. Energy dissipation presented in this paragraph as well as the UV-sunscreens discussed below can be considered as preventative mechanisms, whereas the enzymatic and nonenzymatic defences treated below embody the responses developed when an oxidant threat is perceived by the bacteria. Optimal photosynthetic efficiency is obtained when all the energy absorbed can be used for CO2 assimilation. The photosynthetic apparatus must then deal with several environmental changes such as the availability of carbon dioxide and marked variations in the quality and quantity of light. There are several protection pathways in the photosynthetic apparatus against intense light, well described in plants and recently reviewed by Szabo´ et al. (2005). One of those mechanisms is the nonphotochemical quenching (NPQ) of the excitation energy via the lightharvesting complex of photosystem II (LHCII). This process is triggered by the acidification of the thylakoid lumen resulting in the modification of the carotenoid viollaxanthin to zeaxanthin, which is a better energy-accepting carotenoid. The NPQ mechanism also involves the LHCII component PsbS protein, which is sensitive to low pH and is able in FEMS Microbiol Rev 33 (2009) 258–278

its protonated form to bind to zeaxanthin. The zeaxanthinbound PsbS is suggested as the site of the quenching. During this process conformational changes also occur in LHCII and allow the interaction between chlorophylls and carotenoids and the transfer of electrons from chlorophyll to zeaxanthin. The thermal dissipation then results in a decrease of PSII-related fluorescence emission, known as highenergy quenching (qE) (reviewed by Szabo´ et al., 2005). Because cyanobacteria do not possess LHCII, it has for a long while been assumed that they lacked such a photoprotective mechanism. However, recent studies have reported that under nutrient-replete conditions they do have at least two mechanisms for dissipating excess energy (Fig. 2). The first mechanism is characterized by blue lightinduced NPQ involving carotenoids (El Bissati et al., 2000; Rakhimberdieva et al., 2004). The observation that a phycobilisome-deficient mutant as well as a mutant lacking the phycobilisomes core were unable to induce quenching led to the assumption that the blue light-induced NPQ mechanism was associated with phycobilosomes. A more complete understanding of this mechanism was achieved when recent studies reported that the orange carotenoid protein (OCP), a soluble carotenoid-containing protein widely distributed among cyanobacteria species (reviewed by Kerfeld, 2004), was required for NPQ induction in Synechocystis PCC 6803 and mediated photoprotective energy dissipation through interaction with the phycobilisomes core (Wilson et al., 2006; reviewed by Kirilovsky, 2007). The second energy-dissipation mechanism described in cyanobacteria is related to the high light-inducible proteins (HLIPs), also designated small CAB-like proteins (SCPs) encoded by the hli genes. These proteins show similarity to the light-harvesting chlorophyll a/b-binding proteins of plants. It has been suggested that they could be involved in the regulation of tetrapyrrole biosynthesis in response to the cellular demand of chlorophyll (Xu et al., 2004). In Synechocystis PCC 6803, the expression of four hli genes was induced under high-light stress, low temperature and nutrient starvation. The quadruple hli mutant was unable to sustain photosynthetic activity and growth under high light, suggesting that HLIPs may play a critical role in photoprotection (He et al., 2001). They do so possibly by dissipating the excess energy absorbed (Havaux et al., 2003). The association of these proteins with photosystem II has been demonstrated recently in Synechocystis PCC 6803 (Yao et al., 2007). A third mechanism of energy dissipation is carried out by the CP43 0 protein and is induced when cyanobacteria are challenged by iron starvation (Fig. 2).

Nonenzymatic antioxidants The accumulation of ROS can be largely prevented by nonenzymatic antioxidants among which a-tocopherol and 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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(a) Blue light and high blue light

OCP PSII

PSII

Unquenched

Quenched

(b) High light

HLIPs

PSII

PSII

Unquenched

Quenched

(c) Iron starvation and oxidative stress Energy dissipation −Iron/ROS PSI

PSI CP43’

carotenoids are the most important in phototrophs. cyanobacteria possess a wide variety of carotenoids like myxoxanthophyll, b-carotene, and its derivatives (zeaxanthin, echinenone). These pigments dissipate energy from photosensitized chlorophyll or from 1O2, and several studies emphasized their antioxidative properties (for reviews, see Young & Frank, 1996; Edge et al., 1997). Zeaxanthin has been shown to be particularly important for photoacclimation during UV-B stress in Synechococcus PCC 7942 (Gotz et al., 1999), and the photosynthetic activity in a mutant of Synechocystis PCC 6803 deficient in zeaxanthin synthesis became more sensitive to high light and oxidative-stress treatment than the wild type (Schäfer et al., 2005). A study that investigated the acclimation of the carotenoid composition in four freshwater cyanobacteria in response to high irradiances indicated that the nature of the carotenoid overproduced in response to this stress varies from one cyanobacterium to another. However, for the four strains studied, the highest induction observed was in the level of the carotenoid-glycosyl myxoxanthophyll (Schagerl & Müller, 2006). Moreover, myxoxanthophyll has been shown to be the most effective carotenoid in protection against 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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Fig. 2. Photoprotective mechanisms against oxidative stress. Photosynthetic organisms prevent ROS production by absorbing excess excitation energy. In cyanobacteria at least three mechanisms are involved in light-induced energy dissipation as heat. (a) The OCP. (b) The small CAB or HLIPs proteins. The localization of these proteins around PSII is a hypothetical schematic representation. Their possible implication in photoprotection of the photosynthetic apparatus is discussed in the text. (c) The iron stress-induced protein IsiA (see text for details).

peroxidation in Synechocystis PCC 6803 (Steiger et al., 1999). The high degree of unsaturated bonds and the glycosidic nature of this carotenoid must be the reason for its antioxidant effectiveness, but to our knowledge genetic evidence of the photoprotective role of myxoxanthophyll in cyanobacteria is still missing. a-Tocopherol (vitamin E) is a lipid-soluble organic molecule exclusively synthesized by oxygenic phototrophs, including all green algae, plants and some cyanobacteria. Tocopherols can undergo two oxidation reactions: they may be oxidized by ROS to a tocopheryl radical and convert singlet oxygen to hydroperoxide. Both reactions can be reversed by ascorbate, recycling tocopherol (Neely et al., 1988). In plants, tocopherol is involved in scavenging singlet oxygen in the PSII reaction centre and in the protection of membrane lipids against peroxidation (Trebst et al., 2002; Havaux et al., 2005a). Tocopherol-deficient mutants have been obtained in the cyanobacterium Synechocystis PCC 6803 and these mutants remained able to cope with both high-light stress and 1O2 accumulation, suggesting that tocopherols are not specifically involved in protecting photosystems against these ROS (Maeda et al., 2005). FEMS Microbiol Rev 33 (2009) 258–278

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Table 1. Enzymatic defences Catalytic centre

Substrate

cyanobacteria

Superoxide dismutase (SOD)

Fe, Mn, Ni, Cu/Zn

O 2

Synechococcus PCC 7942w Anabaena cylindricaz Anabaena PCC 7120w Nostoc communez

Catalases Monofunctional Bifunctional

Haem Haem

H2 O2 H2O2, ROOH (in vitro)

H2 O 2 H2O2, ROOH

Peroxiredoxins (Prx)

Mn Selenocysteine (Mammalian) Cysteine (plants) One or two cysteine(s)-SH

Rubrerythrin (Rbr) DNA-binding protein (Dps)

Fe(Cys)4 and His, Glu-ligated di-iron Fe

H2 O2 H2 O 2

Enzyme

Glutathione peroxidase (GPX)

H2O2, ROOH, peroxynitrite

Haem

Synechococcus PCC 7942z Anacystis nidulansz Synechocystis PCC 6803w Synechocystis PCC 6803w Synechocystis PCC 6803w Synechococcus PCC 7942w Anabaena PCC 7120w Anabaena PCC 7120w Thermosynechococcus elongatusz Anabaena PCC 7120z Synechococcus PCC 7942z

Cyanobacterial strains in which the enzyme has been studied. w Represent studies that also reported on the implication of the enzyme in the defence against oxidative stress in vivo (see text for the corresponding references). z Represents studies that analysed only the enzymatic activity of the protein.

However, a compensatory role for carotenoids in these tocopherol-deficient mutants cannot be ruled out and could explain the phenotype obtained. Indeed, the enhanced sensitivity of the mutants to a combination of treatments with both high light and polyunsaturated fatty acids is consistent with their role in protecting membranes from lipid peroxidation (Maeda et al., 2005). These results indicate that the antioxidant function of tocopherols is conserved among oxygen-evolving phototrophs.

Antioxidant enzymes The superoxide anion and H2O2 produced by the photosynthetic chain are mainly scavenged by cellular enzymes, which results in the photoreduction of oxygen to water. Oxygen is first derived from the photo-oxidation of water in PSII, and then reduced back to water in PSI using electrons generated in PSII, and the whole reaction occurs without a net change in O2 This process is called the water–water cycle and can be subdivided into the following sequences (for a review, see Asada, 1999): Reaction 1 : 2 H2 O ! 4e þ 4Hþ þ O2

Reaction 2 : 2 O2 þ 2e ! 2O2

Reaction 3 : 2 O2 þ 2Hþ ! H2 O2 þ O2 Reaction 4 : 2H2 O2 ! 2H2 O þ O2 Sum :

2H2 O þ O2 ! O2 þ 2H2 O

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Reaction 1 corresponds to photo-oxidation of water in PSII, and reaction 2 to the photoreduction of oxygen to a superoxide anion in PSI. Disproportionation of O 2 to H2O2 and oxygen (reaction 3) is catalysed by SOD, and the dismutation of H2O2 to oxygen and water (reaction 4) is catalysed by catalases and peroxidases. Below we describe some of the key players involved in ROS production and scavenging in these reactions (Table 1). SODs are ubiquitous metalloenzymes that exist in four forms depending upon the nature of their catalytic metals: FeSOD, MnSOD, Cu/ZnSOD and NiSOD (reviewed by Fridovich, 1997). Genome sequence analyses based on 64 cyanobacterial SODs indicated that the CuZn form of SOD is rare among cyanobacteria (Priya et al., 2007). The marine unicellular Prochlorococcus species only possess a NiSOD, whereas the other unicellular strains possess FeSOD and NiSOD or FeSOD and MnSODs. By comparison, filamentous, heterotrichous and heterocystous strains only have iron and manganese forms. FeSOD and MnSODs are highly similar; nevertheless, they can be discriminated on the basis of structural features such as the presence of the highly conserved and metal-specific residues that are different between the two forms and a transmembrane domain only present in the manganese form (Priya et al., 2007). Several studies have reported the implication of SODs in protective processes in cyanobacteria. In the unicellular cyanobacterium Synechococcus PCC 7942, a sodB mutant, impaired in the synthesis of iron SOD, was much more sensitive to oxygen and light than the wild-type strain, suggesting a 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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protective role of this SOD against damage to photosystems, particularly PSI (Herbert et al., 1992). In the heterocystous strain Anabaena cylindrica, SOD activity has been detected in both vegetative cells and heterocysts. It has been assumed that it could be involved in the protection of the protondonating systems of nitrogen fixation (Henry et al., 1978). In another heterocyst-forming strain Anabaena PCC 7120, a MnSOD is involved in acclimation of this strain to high light (Zhao et al., 2007a, b). In this study, a fully segregated mutant of the gene encoding this SOD was obtained and was more sensitive to photoinhibition than the wild type, as indicated by a weaker PSI and PSII activity under high light compared with the wild type grown under light conditions. Because the nitrogenase activity of this sod mutant under light stress was slightly weaker than the wild type, it was concluded that MnSOD is required for nitrogenase protection against ROS (Zhao et al., 2007a). Even though this conclusion should be taken with care (because the observed effect was weak and the mutant was still able to sustain growth under the light intensity used) this study can be regarded as a starting point for the important question of the protection of heterocysts against oxidative stress. Reaction 4 described above is catalysed by catalases and peroxidases. Catalases exclusively dismutate H2O2, whereas peroxidases use a broad range of peroxides (ROOH) as substrates (Chelikani et al., 2004). Catalases are one of the most-studied enzymes, and the availability of a huge number of their sequences has allowed a detailed understanding of their structure–function relationship. Based on sequence similarities as well as physical and chemical properties, they have been classified into three groups: monofunctional haem-containing catalases, bifunctional haem-containing catalase–peroxidases and nonhaem-manganese catalases (Za´ mocky´ & Koller, 1999; Chelikani et al., 2004). Both types of haem-catalases have a cyanide-sensitive catalytic activity but they exhibit significant differences in their sequences, structures and mechanisms. Bifunctional catalases are phylogenetically more related to plant ascorbate peroxidases and yeast cytochrome c peroxidases, defining one of the two major superfamilies of haem peroxidases (Passardi et al., 2007). Manganese-catalases are less widespread than the other two classes and are characterized by a lower catalytic activity. A search of catalase-orthologues in the cyanobacterial genomes available in the NCBI databank revealed their presence in 20 cyanobacterial genomes among those completely sequenced so far. A catalase–peroxidase activity was purified and characterized in Synechococcus PCC 7942 and A. nidulans (Mutsuda et al., 1996; Obinger et al., 1997). Several recent studies have helped in the understanding of the catalytic mechanism of the bifunctional catalase KatG from Synechocystis PCC 6803 (for a review, see Smulevich et al., 2006). The function of this catalase in vivo has been 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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studied by analyzing the phenotype of a katG mutant. The data obtained suggested the protective role of this enzyme against exogenous H2O2, and the involvement of other peroxidases in coping with ROS produced inside the cells (Tichy & Vermaas, 1999). As discussed below, the latter function may be carried out by peroxiredoxins. Ascorbate peroxidases play a crucial role in H2O2 detoxification in plants (reviewed by Asada, 1999). These enzymes reduce H2O2 to monodehydroascorbate and water using ascorbate as the specific electron donor. Monodehydroascorbate spontaneously generates ascorbate and dehydroascorbate. Dehydroascorbate reductase uses glutathione to reduce dehydroascorbate to ascorbate (reviewed by Shigeoka et al., 2002). Oxidized glutathione is then regenerated by NADPH-glutathione reductase. This emphasizes the role of the ascorbate–glutathione cycle in the response of plants to oxidative stress. In spite of a low level of ascorbate in cyanobacteria, ascorbate peroxidase-like activities have been reported for Nostoc muscorum PCC 7119 and for Synechococcus PCC 6311; and in Synechococcus PCC 7942 dehydroascorbate reductase and glutathione reductase were involved in the regeneration of ascorbate and glutathione, respectively (Tel-Or et al., 1985, 1986; Rozen et al., 1992). However, further biochemical characterization and overall genetic evidence is needed to prove the implication of these enzymes as antioxidants in cyanobacteria. Another interesting question is to understand how cyanobacteria strains that lack both catalases and ascorbate peroxidases deal with high concentrations of H2O2? What is the nature of the antioxidant enzymatic activity involved in these cases? While ascorbate peroxidase is the major H2O2 scavenging enzyme in plants, animals use glutathione peroxidase (GPX) as the principle enzyme for this function. Mammalian GPX-s can also reduce alkyl and lipid hydroperoxides, and are known as selenium-dependent peroxidases because of the use of selenocysteine as a conserved catalytic residue. Glutathione peroxidases reduce peroxides by oxidizing glutathione. Rereduction of the oxidized form of glutathione is then catalysed by glutathione reductase, using NADPH as an electron donor (reviewed by Ursini et al., 1995). Multiple GPX-s homologues have been identified in higher plants and have been shown to carry a cysteine residue instead of a selenocysteine one, which results in a lower activity compared with the mammalian GPX-s (Maiorino et al., 1995). In Synechocystis PCC 6803, two glutathione peroxidaselike proteins have been characterized. They both showed a NADPH-dependent activity and were essential for the protection of membranes against lipid peroxidation indicating that GPX-s enzymes act as important antioxidants against oxidative stress in this cyanobacterium (Gaber et al., 2004). Peroxiredoxins (Prx-s), also called alkylhydroperoxidases, were recently identified and defined as a new ubiquitous, FEMS Microbiol Rev 33 (2009) 258–278

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family of thiol-specific antioxidant proteins catalyzing the reduction of H2O2, alkyl hydroperoxides and peroxynitrite, using thioredoxin and other thiol-containing reducing agents as electron donors (reviewed by Wood et al., 2003). Peroxiredoxins are thought to play an important role in the reduction of endogenously generated ROS. In the first step of the ROS reduction by peroxiredoxins, an N-terminal cysteine residue is involved in which the thiol side chain is oxidized into sulphenic acid. This catalytic cysteine is called peroxidatic cysteine. In the second step, the sulphenic acid is rereduced to a thiol before the next catalytic cycle begins. Based on the number of conserved cysteines and their location, as well as the differences in the mechanism involved in sulphenic acid reduction, peroxiredoxins have been subdivided into three categories. The first category includes the 2-cysteine peroxiredoxins (2-Cys Prx-s), which form homodimers. The sulphenic acid of one subunit is resolved by a cysteine located on the carboxy terminal of the second subunit. The resulting disulphide bridge between these two subunits is reduced by electron donors such as thioredoxins and glutaredoxins (reviewed by Poole et al., 2000). The second category contains 1-Cys Prx-s, which do not possess a resolving cysteine. Their sulphenic acid is probably regenerated by a thiol-containing partner via a mechanism that has not yet been elucidated (Kang et al., 1998). The third category includes atypical 2-Cys Prx-s, which are monomeric enzymes in which both the peroxidatic and resolving cysteines are located on the same subunit. The mechanism whereby sulphenic acid is resolved is similar to that occurring in 2-Cys Prx-s (Seo et al., 2000). Genomic analysis and physiological studies have shown the existence of multigenic families of peroxiredoxins in plants (Rouhier & Jacquot, 2005) and cyanobacteria (Stork et al., 2005). In both types of organisms, all three classes of peroxiredoxins are present. Disruption of genes encoding for 2-Cys Prx-s in Synechocystis PCC 6803 and Synechococcus sp. PCC 7942 affected the tolerance of the resulting strains to oxidative stress (Yamamoto et al., 1999; Perelman et al., 2003). The type II Prx of Synechocystis PCC 6803 showed a strong glutathione-dependent peroxidase activity and was essential for growth, even under moderate light (Kobayashi et al., 2004; Hosoya-Matsuda et al., 2005). The atypical 2Cys Prx-s, showing sequence similarities with the E. coli bacterioferritin comigratory protein (BCP), have been classified into the subclass Prx Q (Dietz et al., 2006). In Anabaena PCC 7120 there are four Prx Q-s proteins which all contain a conserved GCT catalytic motif and show various transcriptional patterns. Analysis of the periplasmic proteins using Western blotting revealed that two of these Prx Q-s proteins are localized in the periplasmic space, thus suggesting a direct action on lipid hydroperoxides removal (Cha et al., 2007). However, we performed a sequence analysis of these proteins for signal peptide prediction using FEMS Microbiol Rev 33 (2009) 258–278

the SIGNALP software (DEAMBULUM server). The results predicted that only one of these four Prx Q-s proteins has a signal peptide, suggesting that it would be the only one susceptible to be translocated across the membrane. A mutant deficient in the synthesis of one of these Prx Q proteins (Prx Q-A) was much more sensitive to oxidative stress than the wild-type strain, supporting the crucial role of peroxiredoxins as antioxidant proteins (Latifi et al., 2007). Surprisingly, this mutant showed higher lipid peroxidation than the wild type despite the fact that the Prx Q-A protein is not located in the membranes. Other mutants in the genes encoding soluble antioxidant enzymes, such as catalases or SOD, also suffer lipid peroxidation suggesting that the response to oxidative stress might require a synergetic action of the whole antioxidant system and that the absence of only one element is sufficient to impair the global defensive capability of the organism. This hypothesis and the different strategies developed to specifically protect each compartment of the cell should be the subject of interest in future investigations. Another type of peroxidase exists predominantly in airsensitive bacteria (for a recent review see Kurtz, 2006). They are nonhaem, iron-containing enzymes with two distinctive domains: a rubredoxin domain that contains a Fe(Cys)4 centre and a di-iron domain where iron is ligated to His and Glu residues, like in haemerythrin. This class of peroxidases has been called rubrerythrin (Rbr) from the contraction of rubredoxin and haemerythrin. The most likely mechanism for rubrerythrin function is the catalysis (by the di-iron centre) of H2O2 reduction to water using electrons from NADPH or NADH. The role of the Fe(Cys)4 centre is to transfer electrons to the di-iron centre. Very recently a rubrerythrin-homologue (RbrA) was identified in the filamentous cyanobacterium Anabaena PCC 7120. The transcription of rbrA was shown to occur after nitrogen stepdown and mainly in heterocysts. RbrA protein has a strong peroxidase activity using electrons driven from NADPH by ferredoxin : NADP1oxidoreductase. Genetic evidence supports the role of this enzyme in the protection of nitrogenase against H2O2 (Zhao et al., 2007b). The DNA-binding protein from starved cells (Dps) was first identified as nonspecific DNA-binding polypeptides that accumulate in starved E. coli cells in order to protect ´ DNA from oxidative stress mediated by H2O2 (Almiron et al., 1992). After this pioneering work, Dps homologues were discovered in a wide variety of prokaryotic organisms and were shown to be involved in various stress responses (Nair & Finkel, 2004). The active form of these proteins is composed of 12 subunits assembled in hexameric rings to form a compact and highly stable cage-like structure surrounding the chromosome (Wolf et al., 1999). Dps is structurally related to the iron storage protein ferritin and is hence characterized by iron-binding and storage activities. 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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Owing to its ferroxidase activity, Dps consumes H2O2 in two steps: Fe(II) oxidation is accomplished by H2O2 rather than O2, as in ferritins; the oxidized Fe(III) is then mineralized and stored as insoluble Fe(III). The whole reaction can be summarized as follows: 2FeðIIÞ þ H2 O2 ! 2FeðIIIÞOOH þ 4Hþ By oxidizing and mineralizing iron, Dps contributes to the storage of the Fe(III) form in the enzyme core and to the quenching of H2O2, avoiding oxidative damage mediated by the Fenton reaction (Zhao et al., 2002). Dps homologues have been reported in several cyanobacterial species (Castruita et al., 2006; Shcolnick et al., 2007; Xiong et al., 2007). DpsA from Synechococcus PCC 7942 exhibits a COOH-terminal domain similar to the carboxy domain of bacterioferritin. Biochemical characterization of this protein showed that it was a hemic protein with a weak catalase activity (Peña & Bullerjahn, 1995). Localization of DpsA in the thylakoidal membrane of Synechococcus PCC 7942 raised the possibility that it might exist into two fractions: a chromosome-bound pool involved in DNA-protection and a soluble fraction required for the proper functioning of the photosynthetic apparatus (Durham & Bullerjahn, 2002). The Dps-Te protein from the thermophilic cyanobacterium Thermosynechococcus elongatus has an increased thermostability, and a DNA protection activity against ROS in spite of the absence of a DNA-binding domain and the lack of DNA-binding ability (Franceschini et al., 2006). The DPS–protein MrgA from Synechocystis PCC 6803 is involved in the internal transport of iron, highlighting the diversity of functions carried out by DPS proteins (Shcolnick et al., 2007).

The intrinsic ability of photosynthetic electron transport in oxidative-stress tolerance In addition to the panel of detoxifying enzymes described above, some components of the photosynthetic electron transport chain have been shown to be important for tolerating oxidative stress. Cytochrome oxidases are present in both photosynthetic and respiratory chains and are supposed to help in removing excess electrons (Schubert et al., 1995). The roles of two cytochrome oxidases have been studied in Synechococcus PCC 7002: CTAD I cytochrome oxidase was required for resistance to extreme high-light stress, and so was CTAD II; the CTAD II mutant resisted oxidative stress only by inducing the synthesis of a membrane-bound SOD (Nomura et al., 2006). Another way of avoiding excessive excitation of PSI, and hence oxidative stress, is the use of alternative electron transport pathways to get rid of the electrons in excess downstream PSI. One such mechanism has been described recently in the marine cyanobacterium Synechococcus WH8102, in which a plasto2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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quinol terminal oxidase (PTOX) was proposed as the most probable candidate of undergoing an alternative pathway for electron transfer to oxygen prior to PSI (Bailey et al., 2008). PTOX enzymes, also called IMMUTANS terminal oxidases in plants, are associated with the photosynthetic electron transport chain, and they catalyse the oxidation of plastoquinol with the concomitant reduction of O2 to H2O (Wu et al., 1999). The analysis of a metagenomic dataset from the Sargasso Sea revealed a wide distribution of PTOX enzymes especially among high-light-adapted marine cyanobacterial strains (McDonald & Vanlerberghe, 2005). This descriptive analysis of PTOX distribution could be regarded as a first step in the assessment of the role of the alternative electron transport in the defence of cyanobacteria against oxidative stress. Genetic studies of mutants deficient in the synthesis of these enzymes should be performed in order to clearly demonstrate the importance of alternative oxidases in the regulation of the photosynthetic activity in cyanobacteria. The stromal extrinsic PSI subunit PsaE, whose function remained a much debated question, was recently suggested as playing a regulatory role in preventing electron leakage from PSI to oxygen (the Mehler reaction), thereby avoiding photo-oxidative damage. The psaE null mutant was able to tolerate oxidative stress by inducing the synthesis of antioxidant enzymes such as SOD and catalase (Jeanjean et al., 2008).

Regulation of the response to oxidative stress The activation of various regulators in response to an increase in ROS concentrations can often modulate the transcription of a subset of genes, allowing an appropriate response to the stress sensed. The way bacteria respond to elevated concentrations of either superoxide or H2O2 is completely different, illustrating the ability of these simple organisms to sense and to discriminate between these two signals. The molecular mechanism of these sensing pathways has been extensively studied in E. coli (reviewed by Storz & Imlay, 1999). The response to an increase in superoxide production is orchestrated by the SoxRS couple. SoxR contains a [2Fe–2S] cluster and is active only in its oxidized state. Thus, SoxR serves as the redox sensor, which is activated by superoxide and subsequently activates SoxS production. SoxS then induces the expression of a dozen genes, known as the SoxRS regulon, including detoxification enzymes (SOD) and DNA repair proteins (reviewed by Storz & Imlay, 1999). H2O2 sensing in E. coli and many other Gram-negative bacteria is achieved by a LysR-type transcription factor, OxyR. While SoxR is a Fe–S-based sensing system, OxyR activation by peroxide is based on cysteine chemistry. Two particular cysteine residues (Cys 199 and Cys 208) react with FEMS Microbiol Rev 33 (2009) 258–278

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H2O2 to form an intramolecular disulphide bond, and the resulting oxidized form of the protein is active in transcriptional regulation. The OxyR regulon includes the hydroperoxidase I (KatG), the alkyl hydroperoxide reductase AhpCF, the glutathione reductase GorA, Dps, and the small regulatory RNA oxyS (reviewed by Storz & Imlay, 1999). Not all bacteria have an OxyR homologue. For example, the Fur-like peroxide-sensing repressor PerR, first identified in Bacillus subtilis, was shown to be conserved in other Gram-positive and Gram-negative bacteria lacking OxyR. The PerR regulon in B. subtilis includes genes encoding the Dps homologue MrgA, the catalase KatA, the alkyl hydroperoxide reductase AhpCF and enzymes of haem biosynthesis. PerR is a zinc-metalloprotein that can use either Fe21 or Mn21, ligated to two conserved His and Asp residues as corepressors. The PerR activity is regulated by metal-catalysed oxidation (MCO). The catalytic centre-bound Fe21 reacts with peroxide in a Fenton-type chemistry, oxidizing the regulatory His residues and generating 2-oxo-His. This leads to an irreversible inactivation of the repressor, a mechanism which is very different from the redox statebased activation of OxyR and SoxR regulators (reviewed by Lee & Helmann, 2006). A number of studies revealed that the induction of superoxide-detoxifying enzymes in response to stress also occurs in cyanobacteria. For example, the transcription of a MnSOD gene was upregulated by methyl viologen in both Anabaena PCC 71201 and Plectonema boryanum UTEX 485 (Campbell & Laudenbach, 1995; Li et al., 2002); the expression of the FeSOD-encoding gene in Synechocystis PCC 6803 was strongly induced by high light (Kim & Suh, 2005). Up to now, no SoxR/SoxS homologues have been reported in cyanobacteria and the regulator sustaining the superoxide response is still unclear in these phototrophs. However, a PerR orthologue has been identified in Synechocystis PCC 6803 using a microarray approach (Li et al., 2004). Transcription of the perR gene (slr1738) was induced by peroxide, and the inactivation of perR derepressed, even in the absence of peroxide, the expression of a set of genes including the dps-homologue mrgA and ahpC alkylhydroperoxidase. The PerR protein was able to bind to the promotor region of the perR gene itself, and that of sll1621 encoding peroxiredoxin AhpC (Kobayashi et al., 2004). Together with the observation that a perR mutant was much more resistant to H2O2 than the wild-type strain (Houot et al., 2007), these data highlight the possibility that PerR may function as a peroxide-sensing repressor in Synechocystis PCC 6803. However, a majority of the genes that responded to oxidative stress were not regulated by PerR. One may postulate that in contrast to its role in B. subtilis, PerR does not act as the master regulator of the peroxide response in cyanobacteria. In agreement with this speculation, another microarray-based study using the same strain revealed the FEMS Microbiol Rev 33 (2009) 258–278

involvement of His kinases (Hiks) in H2O2 sensing (Kanesaki et al., 2007). Hik33 was responsible for the regulation of many more genes than was PerR, although a set of genes were coregulated by both Hik33 and PerR. Again, a number of peroxide-induced genes were regulated neither by Hik33 nor by PerR, indicating yet other regulators involved. The same study reported the dual role of PerR acting both as a positive and a negative regulator, and also commented on the minor implication of another three Hiks (Hik16, 34 and 41) in peroxide sensing. Altogether, these studies have shown that the cyanobacterial response to H2O2 is achieved by the coordinated action of several regulators; some of which remain to be identified (Fig. 3).

Crosstalk between oxidative stress and other stresses Being the subject of increasing study and large bodies of experimental data, the part played by ROS in biological processes points to a strong crosstalk between ROS homeostasis and other cellular networks. We will focus below on the most important and the most-studied connections.

Redox control A growing number of enzymatic and regulatory activities involved in cell response to oxidative stress are strictly controlled by means of redox-based reactions. Reduction of intra- or intermolecular disulphides by thioredoxins (Trx) is a fundamental example of such a regulation. Thioredoxins are small ubiquitous proteins that fulfil numerous cellular functions and share a highly conserved active site (Cys–Gly–Pro–Cys). They are part of a redox regulatory system in which electrons are transferred from NADPH to thioredoxin reductase and finally to thioredoxins. Implication of thioredoxins in oxidative stress response has been reported in many organisms (reviewed by Holmgren, 1989; Zeller & Klug, 2006). Thioredoxins are highly represented in all cyanobacterial genomes (Florencio et al., 2006). They have been reported to act as redox partners of several peroxiredoxins. Furthermore, screening for thioredoxins target proteins in Synechocystis PCC 6803 identified the catalase–peroxidase KatG, the 1 Cys-Prx and the Type II Prx peroxiredoxins as thioredoxins-regulated proteins (Lindahl & Florencio, 2003; Pe´ rez-Pe´ rez et al., 2006). In addition to thioredoxins, regulation of the thiol-redox state in cytoplasm requires other small ubiquitous proteins called glutaredoxins (Grx-s; glutaredoxins are oxidized by substrates and reduced nonenzymatically by glutathione). In contrast to thioredoxins, which are reduced by thioredoxin reductase, no oxidoreductase exists that specifically reduces glutaredoxins. Instead, oxidized glutathione (GSSG) is regenerated by glutathione reductase and NADPH. Taken together these components compose the glutathione system 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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Heterotrophic bacteria

Cyanobacteria

OxyR

Escherichia coli

OxyR

H O

NO OxyR

Grx

Inactive

Active

Synechocystis sp. PCC 6803

Bacillus subtilis PerR

?

Fe H O

Repression

Depression

(Holmgren, 1989). A study that analysed the evolution of gluthatione in phototrophic microorganisms reported the presence of high levels of glutathione in the nine cyanobacterial strains studied (Fahey et al., 1987). In addition, based on the detection of significant amounts of glutathione in the purple nonsulphur bacteria that have an oxygen-dependent metabolism, the authors postulated that the glutathione metabolism evolved around the time that oxygen photosynthesis evolved. The main role of glutathione was then suggested to be the protection against oxygen toxicity. However, the direct targets of the glutathione system in cyanobacteria and the differences between cyanobacterial glutaredoxins and plant ones remained unknown for a long time. The observation that the disruption of a glutaredoxincoding gene in Synechocystis PCC 6803 increased the sensitivity of this mutant to peroxide treatment was in agreement with the hypothesis which stipulated the role of glutathione in the oxidative stress response (Li et al., 2007). In this study, the authors screened of glutaredoxin targets in this cyanobacterium and identified 42 proteins. Twenty-six were not identified as glutaredoxin targets in plants. As in the case of thioredoxins, many glutaredoxin-targets identified in Synechocystis were proteins related to oxidative stress response such as the thioredoxin reductase (TR), the catalaseperoxidase KatG and the type II peroxiredoxin (Li et al., 2007). These data confirm the importance of glutathione in the antioxidant system of cyanobacteria and will probably open multiple perspectives towards the understanding of glutathione function in these organisms. However, because in vivo studies are usually carried out either in grx or trx mutants, the possibility of compensatory effects between these two systems could hinder the actual meaning of the data. This should be kept in mind and genetic studies 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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Fig. 3. Oxidative stress regulation. Peroxide sensing in heterotrophic bacteria involves either OxyR or PerR. OxyR oxidation by H2O2 activates its DNA-binding activity while metalcatalysed oxidation inactivates PerR-DNA-binding activity. cyanobacteria do not possess OxyR orthologs. H2O2 sensing involves a PerR ortholog and three histidine kinases in Synechocystis PCC 6803. The square with a question mark depicts potential regulators that remain to be identified. No superoxide anion receptor has been identified yet in cyanobacteria.

should be strengthened by biochemical approaches as far as possible.

Iron Because H2O2 reacts with ferrous iron generating the highly reactive hydroxyl radical, the extent of oxidative damage depends on the tight control of iron homeostasis. In many bacteria, iron control is mediated by the global transcriptional regulator Fur. Fur was first identified in E. coli as an iron-responsive repressor of iron-transport proteins under iron-replete conditions. However, under iron sufficiency, Fur also functions as a positive regulator of genes encoding iron storage proteins and some iron-utilizing enzymes such as the SOD, SodB. This reciprocal coupling between the control of iron homeostasis and defence against ROS suggests that the lack of iron regulation might cause oxidative stress (for a review, see Lee & Helmann, 2007). Fur orthologues are present in all the cyanobacterial genomes completely sequenced so far and listed in the NCBI database. In Anabaena PCC 7120, the FurA regulator has recently been shown to control the transcription of the dps gene (Herna´ ndez et al., 2007). Even though the direct implication of Dps in DNA protection against ROS in this organism has not been demonstrated, it could be reasonable to postulate such a protective role by analogy to other cyanobacterial strains. This raises the possibility of a potential role of Fur in regulating oxidative-stress defence in cyanobacteria. However, the most straightforward evidence of the link between ROS and iron control was demonstrated by studies that analysed the adaptation of cyanobacteria to iron starvation. Many cyanobacteria cope with this stress by inducing the expression of the isi (iron-stress inducible) FEMS Microbiol Rev 33 (2009) 258–278

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genes isiA and isiB (reviewed by Singh & Sherman, 2007). The isiB gene encodes flavodoxin, which is an electron carrier and can substitute the iron-rich soluble protein ferredoxin. The isiA encodes CP43 0 , which is related to the so-called core complex antenna family of chlorophyll-binding proteins including CP43 and CP47 in the core of PSII (reviewed by Singh & Sherman, 2007). Multiple monomers of CP43 0 are arranged in ring structures in the periphery of PSI. Pigment storage, light harvesting for PSI and energy dissipation in PSII are suggested functions for CP43 0 under iron-deplete conditions. However, several studies showed that isiA and isiB are induced not only by iron deficiency but also by several other stresses including oxidative stress (Havaux et al., 2005b; reviewed by Kouril et al., 2005), suggesting that cells challenged by iron starvation could suffer from oxidative stress which would be the primary signal for the induction of the isiA expression. We have recently shown that when cells of Anabaena PCC 7120 were subjected to iron limitation, they indeed exhibited a 100fold increase in the amount of ROS compared to nonstarved cells and they also suffered from lipid peroxidation. Using a ROS-quenching molecule (tempol) that can enter the cell, we were able to dissociate the oxidative stress from iron deficiency, and thus to demonstrate that the CP43 0 protein was not produced in iron-starved cells that were not coping with oxidative stress. Our data conclusively showed that iron starvation creates oxidative stress against which the photosystems must be protected (Latifi et al., 2005) (Fig. 2). We have also shown that cells grown under iron-deplete conditions induce the expression of a gene encoding the peroxiredoxin PrxQ-A and that a mutant deficient in the synthesis of this peroxidase was not able to sustain growth under iron starvation. These data indicate that growth under limited iron requires antioxidant protection (Xu et al., 2003; Latifi et al., 2007).

Nitrogen An increasing amount of data points to a connection between iron and nitrogen regulatory networks in cyanobacteria. The expression of furA and several iron-responsive genes from Anabaena PCC 7120 is modulated by the master regulator of nitrogen metabolism NtcA (Cheng et al., 2006; ´ ´ et al., 2007). The transcription of nifHDK, Lopez-Gomoll on which normally only occurs in response to a combined nitrogen starvation in the nitrogen-fixing strain Anabaena PCC 7120, is induced in iron-starved cells despite the presence of combined nitrogen (Razquin et al., 1994). Even though this transcriptional induction is not coupled to heterocyst formation, it at least shows that iron and nitrogen networks share common pathways (Razquin et al., 1994). Another example is illustrated by the expression pattern of the two cotranscribed genes pkn41 and pkn42 encoding FEMS Microbiol Rev 33 (2009) 258–278

protein kinases (Cheng et al., 2006). These two genes are induced under iron-starvation conditions and this regulation is exerted by NtcA. Similarly, we have shown that the expression of the pkn22 operon, encoding the protein kinase Pkn22 and the peroxiredoxin PrxQ-A, described previously as regulated by oxidative stress and iron starvation, is also under the control of NtcA (unpublished data). Recently, a bio-informatical approach has predicted the presence of putative Fur-binding sites in the promoter regions of a significant number of NtcA-regulated genes, and likewise, the presence of NtcA-binding sites in front of Fur-controlled ´ ´ et al., 2007). Some of these binding genes (Lopez-Gomoll on sites have been confirmed experimentally in vitro by DNAbinding assays. These studies suggest a mutual regulation of fur and ntcA, providing one mechanism in the link between nitrogen, iron and oxidative stress. In addition, nitrogen limitation led to an increase in the synthesis of a 2-Cys Prx in Synechococcus PCC 7942 (Aldehni et al., 2003), and the removal of nitrate from the growth medium induces the expression of a prx gene encoding 2-Cys Prx in both Synechocystis PCC 6803 and Synechococcus PCC 7942 (Stork et al., 2005). Ferredoxin, reduced by PSI-generated electrons, serves as the electron donor for nitrate reduction. One can imagine that nitrate removal might lead to a transient accumulation of reduced ferredoxin that can transfer its electrons to oxygen, thus generating ROS.

Salinity The transcription of several genes encoding peroxiredoxins were induced in response to salt stress in Synechocystis PCC 6803 and Synechococcus PCC 7942 (Stork et al., 2005). Similarly, the expression of isiA and isiB was highly induced by NaCl treatment in Synechocystis PCC 6803 (Vinnemeier et al., 1998). A mutant of Synechococcus PCC 7942, characterized by an increased tolerance to salinity, showed a constitutive high-level expression of isiA (Bagchi et al., 2007). Furthermore, the overexpression of the catalase gene katE from E. coli in Synechococcus PCC 7942 improved its resistance to high salinity (Kaku et al., 2000). A recent study reported that the cyanobacterial regulatory noncoding RNA, yfr1, was required for growth under both oxidative stress and high-salinity conditions (Nakamura et al., 2007). All of these experimental results suggest that salt and oxidative stress might be connected. A strong proof in favour of this suggestion lies in the observation that high salinity induced the release of H2O2 from Microcystis aeruginosa cells (Ross et al., 2006) and that high NaCl concentrations break down the ROS scavenging activities resulting in oxidative injury in Anabaena doliolum (Singh & Kshatriya, 2002). It has been shown that cyanobacterial cells facing salt stress exhibit a high demand for ATP synthesis. Under these conditions the CO2 fixation rate may be decreased causing the 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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overreduction of the ferredoxin pool (Van Thor et al., 2000). This can partly explain why high salinity leads to oxidative stress in cyanobacteria. It is tempting to speculate here that any physiological condition that decreases the ATP to NADPH balance would result in ROS production, hence in oxidative stress. The observation that a Synechocystis mutant deficient in the synthesis of ferredoxin quinone reductase (FQR) was sensitive to high light is in agreement with this hypothesis (Yeremenko et al., 2005). Indeed, FQR benefits cyclic electron flow around PSI and drives ATP formation without the net production of reduced ferredoxin or NADPH, thus decreasing the electron leak to oxygen.

UV irradiation effects The requirement of cyanobacteria for solar radiation renders them vulnerable towards UV effects. While UV-B (wavelength 280–315 nm) acts directly on and thus damages DNA and proteins, UV-A (wavelength 315–400 nm) is thought to cause long-term photosensitized oxidation (for a recent review on UV impact on organisms, see Caldwell et al., 2007). UV-B can damage the photosynthetic apparatus, thus inhibiting photosynthesis (Fig. 1). The activity of ribulose-1,5-biphosphatase carboxylase-oxygenase (RUBISCO), involved in the Calvin cycle of CO2, was shown to be directly inhibited by UV-B in the N2-fixing cyanobacterium Anabaena BT2 (Kumar et al., 2003). The PSII complex is another direct target of UV-B because they alter the electron transport at both PSII donor and acceptor sides in Synechocystis PCC 6803 (Vass et al., 1999). UV-B have also been shown to damage the D1 protein and also to inhibit its synthesis, thus impairing the PSII repair process (Sass et al., 1997; Ivanov et al., 2000; Sicora et al., 2006). In addition, UV-B can indirectly cause oxidative stress by the production of ROS. Indeed, upon exposure to UV-B irradiation, the production of ROS and lipid peroxidation in Anabaena sp. increased for 5 days, then decreased to preirradiation levels (He et al., 2002). These effects correlate with the decrease of the chla content during the first few days followed by an increase back to the normal level. It was noted that both UVA and UV-B irradiance caused similar effects. Because oxidative effects observed with both UV-A and UV-B in this cyanobacterium were only obtained after a long period of exposure, it would be reasonable to assume that the oxidative stress caused by UV irradiation here is indirect, and the consequence of damage by UV on cellular activities. ROS production upon UV exposure was also reported in the case of Nostoc commun DRH1, a cyanobacterium highly resistant to desiccation (Shirkey et al., 2000). In this organism, the extracellular polysaccharide layer, glycan, which is thought to play an important protective role against desiccation, is a source of ROS production within minutes of UV-A or UV-B irradiation. SodF, a Fe-containing SOD, abundant after 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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long-term desiccation, may play a role in the defence against ROS produced after rehydration and UV exposure (Shirkey et al., 2000). Whether the damage caused by UV stress is direct or indirect, cyanobacteria must effectively protect themselves against their harmful effects. Among the strategies used by organisms to counteract UV damage, the synthesis of UVabsorbing compounds, that serve as passive preventative mechanisms, is widespread in microorganisms, plants and animals (for a recent review, see Cockell & Knowland, 1999). In microorganisms, these UV screening compounds include mycosporines and mycosporine-like amino acids (MAAs), scytonemin, and several absorbing substances of unknown chemical structure (reviewed by Cockell & Knowland, 1999). Mycosporines are small water-soluble molecules, having absorption maxima between 310 and 365 nm, and composed of either a cyclohexenone or cyclohexenimine chromophore carrying nitrogen or imino alcohol substituents. When substituted with amino acids residues, they are called MAAs (reviewed by Garcia-Pichel & Castenholz, 1993; Rˇezanka et al., 2004). Scientists interested in this field can also refer to the database on photoprotective compounds in cyanobacteria, phytoplankton and macroalgae developed by Gröniger et al. (2000) (http://www.biologie. uni-erlangen.de/botanik1/index.html). A correlation between the MAAs content, and UV-B irradiance has been reported in numerous cyanobacteria (Garcia-Pichel & Castenholz, 1993). Induction of the MAA, shinorine in response to UVB has been shown in three heterocystous N2-fixing cyanobacteria (Sinha et al., 2001), and also in the cyanobacterium Chlorogleopsis PCC 6912 (Portwich & Garcia-Pichel, 1999). The strong effect of UV-B on the induction of MAAs synthesis, as well as the presence of a special photoreceptor required for the induction of MAAs synthesis (Portwich & Garcia-Pichel, 2000), are considered as strong indications in favour of MAAs’ function as UV-B sunscreens. However, to our knowledge this protective role in vivo remains to be proven. A variety of other functions have been ascribed to MAAs such as their possible role in osmotic and dessication stress (for a recent review, see Oren & Gunde-Cimerman, 2007). Mycrosporine glycine has been shown to effectively protect a variety of biological systems against photosensitization damage by quenching singlet oxygen (Suh et al., 2003). In this study, 1O2 was generated by illumination of methylene blue or eosine Y, and its effect on mitochondrial electron transport, lipid peroxidation, hemolysis of erythrocytes and growth inhibition of E. coli has been investigated in the absence or the presence of exogenously added mycrosporine glycine. In all cases, addition of mycrosporine glycine resulted in a decrease in the level of 1O2 produced and in protection of the biological system analysed (Suh et al., 2003). It was concluded that some MAAs have, in addition to their role as UV-absorbing molecules, FEMS Microbiol Rev 33 (2009) 258–278

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an antioxidant activity. However, as the capacity of this MAA to quench singlet oxygen was tested in vitro, the MAAs’ function as ROS scavengers in bacteria is still questionable. Scytonemin is a yellow–brown, lipid-soluble dimeric pigment with a molecular mass of 544 Da and a structure based on indolic and phenolic subunits, with an in vivo maximum at 370 nm (Proteau et al., 1993). While MAAs are widespread among prokaryotic and eukaryotic microorganisms, scytonemin is specific to cyanobacteria. It is deposited in extracellular cyanobacterial sheaths, and absorbs the UVA irradiation before it reaches the cell. Scytonemin has been shown to protect the photosynthetic machinery from UV-A damage in the terrestrial cyanobacterium Chlorogleopsis sp. (Garcia-Pichel et al., 1992). The observation that scytonemin synthesis was induced by UV-A irradiation, but not UV-B, is in agreement with its photoprotective role against UV-A (Garcia-Pichel et al., 1992). A scytonemin-deficient mutant of the cyanobacterium Nostoc punctiforme ATCC 29133 was obtained and showed a similar growth rate to the wild-type strain in response to an UV-A stress. Because the genome of this cyanobacterium does not contain orthologues of the scytonemin biosynthesis genes, the most credible explanation of the mutant-phenotype is the occurrence of other UV-A protective compounds that compensate for the absence of scytonemin (Soule et al., 2007).

Oxidative stress in the ecology of cyanobacteria As discussed above, high light irradiation, salt stress or certain nutrient limitation may destabilize the balance between oxidants and antioxidants in the cells, leading to oxidative stress. These environmental factors change daily or seasonally for cyanobacteria in their natural habitats. Several studies suggest that oxidative stress may be involved in the seasonal disappearance of cyanobacterial blooms. The occurrence of cyanobacterial blooms has been reported in many countries around the world, causing serious water pollution and economical problems (Dittmann & Wiegand, 2006). Cyanobacterial blooms are also recognized as potent health risks because many of the bloom-forming cyanobacterial strains produce a wide range of toxins, including neurotoxins, and hepatotoxins, such as microcystins. Most studies have focused on analyzing the bloom formation, but until recently little was known about the reason for the demise of these blooms, viral lysis having been cited as the most likely cause. An autocatalytic programmed cell death (PCD) has been shown to operate in the nitrogen-fixating cyanobacterium Trichodesmium spp. that forms extensive blooms in the tropical and subtropical oceans (BermanFrank et al., 2004). Well documented in higher eukaryotes, PCD is a genetically programmed suicide driven by a series FEMS Microbiol Rev 33 (2009) 258–278

of complex biochemical events and specialized cellular machinery (reviewed by Leist & Nicotera, 1997). Interestingly, in Trichodesmium spp., PCD was induced in response to high irradiance, iron starvation and oxidative stress and was postulated to be a major cause of bloom ending (Berman-Frank et al., 2004). Similarly, recent data on M. aeruginosa showed that H2O2 treatment induced PCD in this organism, associated with a significant release of toxins in the medium (Ross et al., 2006). Several genes encoding for caspases, enzymes involved in PCD in eukaryotes, are found in the recently sequenced genome of M. aeruginosa (Frangeul et al., 2008), and caspase activity as well as proteins reacting to human caspase-3 antibodies were also reported in Trichodesmium spp. (Berman-Frank et al., 2004). It is also worth noting that oxidative damage is the main mechanism whereby cyanotoxins induce apoptosis and hepatotoxicity in injured hosts (Ding & Nam Ong, 2003). In consequence, and regarding the importance of oxidative stress in many fields, it is reasonable to assume that it would continue to be the subject of increasing attention and intensive research efforts. Oxidant stress could eventually be considered as a possible strategy for bloom control and remediation. However, such initiatives should be approached with great caution when dealing with toxic cyanobacterial strains because they can engender other problems linked to the massive release of toxins into the environment. Another natural habitat which is interesting to investigate for oxidative stress is the microbial mats. They are dense, stratified biofilms where autotrophic and heterotrophic organisms cohabit and where cyanobacteria are often the dominant member of the photoautotrophic microorganisms. An in-depth treatment of the physiology of cyanobacteria in microbial mats is outside the scope of this review. Nevertheless, we would like to highlight how useful the elucidation of cyanobacteria response to oxidative stress in these ecosystems will be, and to underline at the same time how difficult this task is. At the photic zone of microbial mats, the oxygen levels produced by cyanobacteria may accumulate to levels as high as 600% of air saturation, possibly because of the high rate of oxygen emission and the low permeation of the polysaccharide matrix associated with the mats. Upon changes of the daily cycle of light, local oxygen concentrations vary dramatically (Revsbech et al., 1983; Revsbech & Ward, 1984). In addition the local gradient of light, nutrient, salinity and desiccation, as well as the activity of heterotrophic organisms, challenge cyanobacteria to adapt constantly (Ludwig et al., 2006; Abed et al., 2007; Polerecky et al., 2007; reviewed by Rothrock & GarciaPichel, 2005). An elevated level of O2 in the mats was suggested to increase the photorespiration and therefore to change the cellular redox state (Bateson & Ward, 1988; Epping et al., 1999). As discussed above, these conditions are sources of oxidative stress. However, adaptive responses 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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of microbial mat populations to a putative oxidant injury have not yet been thoroughly tackled. The responses of the thermophilic Synechococcus OS-B 0 isolated from the microbial mat of Octopus Spring (Yellowstone National Park) have been studied under laboratory conditions (Kilian et al., 2007). The data obtained indicated that some of the mechanisms developed by this cyanobacterium to cope with high-light stress were similar to those used by mesophilic well studied cyanobacteria. For example, the transcription of SOD and terminal oxidase encoding genes was induced and elevated level of carotenoids was measured. However, while the surfaces of microbial mats are subjected to very high irradiances, the axenic cultures of Synechococcus OS-B 0 were unable to resist continuous high light irradiances lower than those encountered in the mats (Kilian et al., 2007). Another investigation of a microbial mat from Solar Lake (Sinai Egypt) suggested that the cyanobacterium Microcoleus chthonoplastes might use vertical migrations down the mat as a defence mechanism to avoid the UV-B deleterious effect (Bebout & Garcia-Pichel, 1995). This conclusion was mainly based on the observation that UV-B exposure induced a colour change and significant reduction of gross photosynthesis in the surface layers of the mats. These changes were accompanied by an increase of gross photosynthesis at deeper layers of the mat (Bebout & Garcia-Pichel, 1995). Because these experiments were performed in the laboratory with experimental UV-B exposures, it is difficult to predict that bacterial motility, which is expected to have a great impact on the distribution of the microbial community, would be used as a defence mechanism in the mat. In conclusion, the studies cited above contributed to the understanding of the adaptation of cyanobacteria from microbial mats to an oxidative threat but also emphasized the point that data obtained under axenic or laboratory conditions hardly inform about what actually occurs inside the mats, where various oxic and anoxic organisms have metabolic activities strongly integrated and highly influenced by continuous changes in the biogeochemistry of their habitat. Consequently, the challenges in this field will be to assess the oxidative stress and the organisms’ responses in situ.

Concluding remarks The exciting field of oxidative stress in cyanobacteria is only just burgeoning. Much of what we know about the generation of ROS within the photosynthetic pathway comes from studies on plants, but cyanobacteria as a unique model for photosynthetic research should allow us to contribute to a better understanding of the oxidative stress in photosynthetic organisms in general in the future. Even if some perspectives were given at the end of the sections covered above, we focus below on what we consider to be major 2008 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved

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challenges in this field for up and coming research. Although much attention has been focused on photosynthetic electron transport as the major source of ROS production, little is known about the contribution of the respiratory chain in ROS production. Because different ROS are generated simultaneously in cells, it is not easy to determine the specific response for each reactive form. Future efforts should be dedicated towards elucidating the biological effects and the specific targets of each ROS species in cyanobacteria and the specific physiological responses that they arouse. Significant progress has already been made in the identification of ROS-scavenging enzymes in the last few years, although much more effort should be made in order to better elucidate the role of these enzymes in vivo and to determine in which cellular compartment they act and in what range of oxidants they are able to detoxify. Recent work has established the involvement of PerR and Hik33 in the response to peroxide stress but at the same time has also highlighted the implication of other unknown regulators in this mechanism, illustrating the extraordinary complexity of the underlying regulatory networks. Moreover, the genetic control of the response to superoxide anion and to singlet oxygen has not been elucidated yet. In our opinion, identification of these regulators and understanding of their molecular mechanisms should be given great importance during the coming years as this will clarify our view about how cyanobacteria sense and then respond to ROS, and how they incorporate this response into their global regulatory network. The need to effectively coordinate ROS response with redox conditions of the cells may have led to the emergence of antioxidant proteins whose functions involve redox-reactive cysteine residues. The elucidation of the relationship between thioredoxins/glutaredoxins and proteins involved in sensing and responding to oxidative stress is still at an early phase and presents a challenging physiological puzzle for future investigations in cyanobacteria. What also remains completely unexplored is how these phototrophs manage to repair oxidized biomolecules. Identification of DNA and protein repair mechanisms will be the future challenge for our understanding of how cyanobacteria respond to oxidative damage. Moreover, studies about ROS could well be important for the understanding of the contribution of ROS to the toxicity and physiology of some strains during the bloom cycle, and for the potential use of the ROS-quenching molecules produced by cyanobacteria as potential antioxidants.

Acknowledgements We would like to thank Robert Jeanjean, Hans Matthijs and Michel Havaux for their helpful discussions and comments. We apologize to those people whose work was not cited in this review because of synthesis concerns. The work in FEMS Microbiol Rev 33 (2009) 258–278

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our laboratory was supported by the Centre National de la Recherche Scientifique (CNRS) and Agence Française de Sécurité Sanitaire de l’Environnement et du Travail (AFSSET).

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