Can a Disulfide Bond Oxidize Again

Regulation of intracellular signalling through cysteine oxidation past reactive oxygen species

Hiroaki Miki,

Department of Cellular Regulation, Inquiry Constitute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Nihon

*Hiroaki Miki, Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka Academy, Suita, Osaka 565-0871, Japan. Tel: +81 6 6879 8293, Fax:

+81 6 6879 8295

, email: hmiki@biken.osaka-u.ac.jp

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Yosuke Funato

Department of Cellular Regulation, Enquiry Found for Microbial Diseases, Osaka Academy, 3-one Yamadaoka, Suita, Osaka 565-0871, Nihon

Search for other works past this author on:

Received:

28 December 2011

Accustomed:

20 January 2012

Published:

27 Jan 2012

Abstract

Reactive oxygen species (ROS) have been regarded as harmful molecules that damage diverse molecules inside cells by oxidation and are responsible for ageing and various man diseases. Even so, recent studies take revealed an opposite aspect of ROS that these are actively generated in cells and mediate physiological intracellular signalling as second messengers. Several proteins have been shown to part as effectors for ROS, which are sensitively and reversibly oxidized past ROS. Such ROS-effector proteins commonly possess a highly reactive cysteine (Cys) residue, of which oxidation changes the protein function, thus enabling betoken transmission to downstream targets. Among the ROS effectors, protein tyrosine phosphatase (PTP), thioredoxin (TRX) and peroxiredoxin (PRX) family unit proteins possess special domains/motifs to maintain the reactivity of Cys and utilize them to reply to ROS. Progressively advancing identification of ROS-effector proteins reveals the pleiotropic functions of ROS in physiological and pathological cell biology.

Reactive oxygen species (ROS) have long been regarded as harmful molecules generated every bit by-products of respiration causing oxidative damages to diverse cellular components. The accumulation of such damages is idea to be responsible for ageing and multiple disorders, such as cancers, neurodegenerative diseases and diabetes mellitus (1). Still, accumulating evidences from recent studies take shed low-cal on a novel aspect of ROS; i.e. ROS mediate physiological intracellular signalling. There are multiple types of ROS-generating enzymes, such equally nicotinamide adenine dinucleotide phosphate (NADPH), oxidase (Nox) and Dual oxidase (Duox), which are activated by physiological stimuli and produce ROS to cause advisable jail cell responses (two). Contrary to the great advances in understanding the ROS-generation mechanism, the molecular signalling events downstream of ROS are poorly understood. This review article describes the importance of ROS-effector proteins, which are sensitively and reversibly oxidized past ROS, in ROS-mediated signalling.

ROS every bit Second Messengers

Stimulation of culture cells with very high level of hydrogen peroxide (H_twoO_ii) results in cell decease. In contrast, it has been known that moderate amount of H_twoO_ii can augment cell proliferation and that the level of intracellular H₂O₂ is consistently elevated in various cancer prison cell lines (three). Therefore, at appropriate level, ROS have been suggested to function as signalling molecules that positively touch on cell proliferation. In 1990, Shibanuma et al. reported the importance of H₂O₂ in the proliferation response to platelet-derived growth factor (PDGF) in culture cells (four). They clearly demonstrated that the level of H₂O_two increased in response to PDGF stimulation. Furthermore, the addition of H_iiO₂ to the civilisation medium by itself stimulated phosphorylation of proteins, which was inhibited by catalase, an H₂O₂-degrading enzyme. A like finding using endothelial cells was also reported by Sundaresan et al. (5). Some other important discovery was reported in 1999 with the identification of the ROS-generating enzyme Mox1 (at present known as Nox1) (6). Suh et al. isolated the novel cDNA encoding Mox1, which was similar to NADPH oxidase, the superoxide (O₂ ⁻-generating enzyme involved in killing of pathogenic leaner by neutrophils. In a striking contrast, Mox1 was expressed predominantly in colon but rarely in leukocytes. Unexpectedly, suppression of Mox1 expression by antisense oligonucleotides resulted in the reduction not only of the ROS level, simply besides of the proliferation rate, thus suggesting the growth-promoting office of Mox1 and O_two ⁻. On the footing of these seminal findings, it became evident that ROS not merely damage cells, but also play a second messenger role and regulate cell proliferation.

Target Proteins for ROS

ROS induce oxidation. Because the importance of switchability between ON and OFF states in intracellular signalling, proteins that tin be sensitively and reversibly oxidized by ROS are candidates for mediating the signalling part of ROS. Among the xx amino acids that comprise proteins, cysteine (Cys) is of particular involvement, because the thiol moiety (–SH) in the side chain of Cys is very sensitive to oxidation and tin can course disulfide bonds with another thiol moiety. Information technology is well known that disulfide bonds tin can exist reduced dorsum to the gratuitous thiol moiety under physiological intracellular weather. Therefore, the Cys residues that be on the protein surface are considered to exist the physiological targets for ROS. This oxidative reaction has been thought to occur non-specifically, merely recent studies revealed the presence of highly reactive Cys selectively oxidized by ROS.

Protein Tyrosine Phosphatase

Protein tyrosine phosphatases (PTPs) are enzymes that catalyse the chemical reaction to dephosphorylate phosphotyrosine in proteins. Among all PTPs, one Cys balance is conserved in the catalytic centre and functions as a transient acceptor for the phosphate during reaction. The thiol moiety (–SH) of this Cys is kept chemically active, which makes information technology prone to oxidation past ROS. Therefore, PTPs are generally sensitive to oxidation and indeed, several PTPs take been shown to be negatively regulated past oxidation of their catalytic Cys (7, eight). This is consistent with the abovementioned concomitant increment of H₂O₂ and tyrosine phosphorylation in endothelial cells stimulated with PDGF (5). Thus, the inactivation of PTPs by ROS seems to cooperate with the activation of tyrosine kinases to efficiently induce tyrosine phosphorylation by growth factors.

Equally shown in Fig. 1, the thiol moiety (–SH) is oxidized to go the sulfenyl moiety (–SOH), which is known to exist reduced to the thiol moiety by various antioxidants that exist in cells. Notwithstanding, the sulfenyl moiety (–SOH) can exist further oxidized to the sulfinyl moiety (–And so₂H) and sulfonyl moiety (–So₃H). These highly peroxidized moieties cannot exist reduced under the normal intracellular status. There are several molecular mechanisms to avoid such peroxidation, which accounts for the reversible regulation of the part of PTPs by the redox reaction.

Fig. i

Cys oxidation by ROS. The thiol moiety is oxidized to go the sulfenyl moiety (–SOH). The sulfenyl moiety can form disulfide bond with some other thiol moiety. The sulfenyl moiety and disulfide bond tin exist reduced by various antioxidants in cells, such equally TRX. The sulfenyl moiety can also become the sulfinyl (–So₂H) and sulfonyl moiety (–Then₃H) upon further oxidation, which cannot be reduced under the normal intracellular environment.

Fig. 1

Cys oxidation by ROS. The thiol moiety is oxidized to become the sulfenyl moiety (–SOH). The sulfenyl moiety can form disulfide bond with another thiol moiety. The sulfenyl moiety and disulfide bond can be reduced past diverse antioxidants in cells, such as TRX. The sulfenyl moiety can likewise become the sulfinyl (–SO₂H) and sulfonyl moiety (–And so₃H) upon further oxidation, which cannot exist reduced under the normal intracellular environment.

Disulfide (–SS–) bond germination

Phosphatase and tensin homologue deleted from chromosome ten (PTEN), which is known to suppress human cancers, is a PTP domain-containing protein that catalyses the dephosphorylation of phosphotyrosine and phosphatidylinositol (3,iv,v)-trisphosphate (PIP₃) (9–11). When PTEN is subjected to oxidation, the catalytic Cys forms an intramolecular disulfide bond with some other Cys (12, 13) and protects itself from farther irreversible oxidation. The disulfide bond tin be reduced nether normal intracellular conditions with the aid of reducing enzymes, such every bit thioredoxin (TRX). The oxidation of PTEN inactivates its phosphatase action and presumably contributes to broaden the signal intensity relayed by phosphorylation. Therefore, such disulfide bond formation in PTEN is an intricate mechanism to allow the reversible redox regulation of the phosphatase activeness.

Sulfenylamide (–SN–) bail germination

Protein-tyrosine phosphatase 1B (PTP1B) is a PTP domain-containing protein involved in the regulation of insulin signalling and has been shown to be regulated by oxidation (14). In 2003, ii dorsum-to-dorsum papers were published in Nature, reporting on a novel construction of PTP1B that is completely dissimilar from any known oxidized forms of proteins (15, 16). X-ray crystallographic analyses revealed that the oxidized Cys in the catalytic centre forms the sulfenylamide (–SN–) bond with nitrogen atom in the main chain in the polypeptide (Fig. ii). This sulfenylamide bond formation protects it from farther oxidation, as does the disulfide bond. In addition, the sulfenylamide bond can as well be reduced under normal intracellular condition and thus, enables reversible redox regulation.

Fig. 2

Sulfenylamide bond formation in PTP1B. The thiol moiety of Cys215 (shaded) becomes the sulfenyl moiety upon oxidation. And so, the sulfenyl moiety reacts with the nitrogen cantlet in the peptide bond of Ser216 and forms sulfenylamide bail. The sulfenylamide bond tin can be reduced to the thiol moiety in cells.

Fig. 2

Sulfenylamide bond germination in PTP1B. The thiol moiety of Cys215 (shaded) becomes the sulfenyl moiety upon oxidation. Then, the sulfenyl moiety reacts with the nitrogen atom in the peptide bond of Ser216 and forms sulfenylamide bond. The sulfenylamide bond tin be reduced to the thiol moiety in cells.

The same mechanisms via the germination of disulfide bonds and sulfenylamide bonds tin clearly explain the reversible redox regulation. Especially, the disulfide bond formation is observed in other several PTPs, such every bit phosphatase of regenerating liver (PRL) 3 (17). However, there are reports indicating the different mechanisms of redox regulation of PTPs. MAP kinase phosphatase (MKP) is a PTP domain-containing protein involved in stress signalling pathway by negatively regulating the activity of c-Jun N-terminal kinase (JNK). When cells are stimulated with tumour necrosis factor α (TNFα), ROS are actively generated and oxidizes MKP, which results in the inhibition of its phosphatase activity and contributes to sustained activation of JNK (eighteen). The catalytic centre Cys in MKP is shown to be of import for this redox regulation. Withal, in this example, oxidized MKP forms high molecular weight protein complexes including a sulfenyl moiety then targeted to degradation by proteasomes. And so far as we know, the detailed molecular nature of this high-weight complex of MKP remains uncharacterized. Besides, a report shows an unexpected mechanism of redox regulation in the case of another PTP domain-containing protein Sdp1; oxidized Sdp1 shows a stronger catalytic activity than its reduced form (nineteen). In this case, disulfide bond formation occurs in a pair of Cys, which exist almost the catalytic centre Cys. This disulfide bond formation induces a structural modify in Sdp1, which augments the recognition of its substrate. This appears to be an unusual instance and there has been no report indicating a like mechanism working in other PTPs, but information technology should be noted that oxidation of PTPs does not ever lead to inactivation of the phosphatase activeness.

TRX Family Proteins

TRX

TRX is highly conserved through development fifty-fifty from prokaryotes and catalyses the chemical reaction to reduce disulfide bonds in target proteins (20). TRX possesses a pair of redox-active Cys in its catalytic middle (TRX motif). TRX reduces its target proteins, such every bit peroxiredoxin (PRX), by transferring disulfide bonds to the Cys pair and becomes oxidized to class a disulfide bond in itself (Fig. three). Oxidized TRX is then reduced and recycled by the reducing enzyme TRX-reductase. Therefore, TRX can also exist reversibly oxidized and reduced as PTPs.

Fig. three

The TRX system and PRX. PRX possesses a reactive Cys, which can reduce H₂O₂ and, in turn, is oxidized to form a disulfide bond (intra- or intermolecular, which depends on PRX isoforms). TRX reduces its target oxidized proteins, such as PRX, and becomes oxidized to form a disulfide bond in itself. Oxidized TRX is reduced and reactivated by TRX-reductase. TRX-reductase is a dimeric poly peptide that contains selenocysteine and flavin adenine dinucleotide (FAD) and catalyses the electron transfer from NADPH to TRX.

Fig. 3

The TRX system and PRX. PRX possesses a reactive Cys, which can reduce H₂O_ii and, in turn, is oxidized to form a disulfide bond (intra- or intermolecular, which depends on PRX isoforms). TRX reduces its target oxidized proteins, such as PRX, and becomes oxidized to grade a disulfide bond in itself. Oxidized TRX is reduced and reactivated by TRX-reductase. TRX-reductase is a dimeric protein that contains selenocysteine and flavin adenine dinucleotide (FAD) and catalyses the electron transfer from NADPH to TRX.

TRX contributes to maintain the global redox environment in cells and protects cells from oxidative stress by reducing a number of intracellular oxidized proteins. In contrast, it has been reported that TRX besides participates in the regulation of a specific signalling pathway. Apoptosis signal-regulating kinase 1 (Ask1) is a poly peptide kinase that can induce apoptosis and is involved in ROS-induced cell death (21). Every bit stated to a higher place, stimulation of cells with TNFα results in ROS generation and prison cell death, and Ask1 plays a critical role in this ROS-mediated cell death. TRX normally binds to Ask1 and suppresses its kinase action (22). Still, when cells are stimulated with TNFα, TRX becomes oxidized and forms intramolecular disulfide bonds (Fig. 4). Oxidized TRX loses its ability to associate with Ask1. And so, Ask1 free from TRX can be activated and induce apoptosis. Collectively, information technology has get clear that TRX is involved in the regulation of Ask1 signalling past using its redox-sensitive nature.

Fig. iv

Redox-dependent activation of Ask1 and Dvl. Stimulation of cells with ROS induces the oxidation of TRX, which dissociates from Ask1. So, Ask1 free from TRX becomes activated and stimulates the downstream signalling, which results in apoptosis (left). Similar to the instance of the TRX/Ask1 complex, ROS besides induces the oxidization of NRX and dissociation from Dvl, which leads to the activation of Wnt signalling (right).

Fig. 4

Redox-dependent activation of Ask1 and Dvl. Stimulation of cells with ROS induces the oxidation of TRX, which dissociates from Ask1. And then, Ask1 free from TRX becomes activated and stimulates the downstream signalling, which results in apoptosis (left). Similar to the case of the TRX/Ask1 circuitous, ROS besides induces the oxidization of NRX and dissociation from Dvl, which leads to the activation of Wnt signalling (right).

Nucleoredoxin

Nucleoredoxin (NRX) was discovered as an oxidoreductase that contains a pair of redox-active Cys in its catalytic centre, equally does TRX. The original report indicated that NRX mainly localizes in the nucleus (23), merely it was later shown that NRX likewise exists in the cytoplasm (24). NRX was also identified every bit a major binding protein for dishevelled (Dvl), an essential mediator of Wnt signalling. NRX straight binds to Dvl and inhibits its function, and thus, NRX tin suppress the activeness of Wnt signalling. Moreover, it was reported that NRX stabilizes Dvl by inhibiting ubiquitination and degradation of Dvl (25). At present, NRX is regarded as a bifunctional molecule to retain a pool of inactive Dvl for robust activation of Wnt signalling upon stimulation.

Equally TRX, the NRX role is regulated by oxidation. Indeed, when the purified poly peptide complex of NRX and Dvl was incubated with H_twoO_two, it readily cancelled the interaction. In addition, stimulation of cells with H_twoO_ii abolished the endogenous protein complex and resulted in the activation of Wnt signalling in a fashion independent of extracellular Wnt ligands. These experimental results clearly signal the redox-responsive office of NRX on the regulation of Dvl activity (26), which is very like to the case of the TRX/Ask1 circuitous (Fig. 4). Therefore, it might be a general feature that TRX-family proteins regulate various intracellular signalling pathways in a redox-dependent mode by forming intramolecular disulfide bonds.

PRX Family Proteins

PRX is an H₂O₂-scavenging enzyme catalysing the reaction to reduce H₂O₂ to H₂O (27) (Fig. 3). PRX possesses a highly reactive Cys, which is oxidized to grade a disulfide bond coupled with the reduction of H_twoO₂. Oxidized PRX is then reduced and recycled by the TRX system. Therefore, PRX is as well considered to be a target for ROS. Indeed, it has been shown that Tpx1, the yeast homologue for PRX, mediates H₂O₂-induced activation of the p38/JNK homologue Sty1 (28). In this example, oxidized Tpx1 by H₂O₂ forms a transient intermolecular disulfide bond with Sty1, which stimulates activation of Sty1.

It was reported that PRX forms loftier molecular weight homo-oligomers when subjected to high levels of oxidative stress (29). These homo-oligomers are shown to take a chaperone-similar activity, which contributes to the protection of cells from oxidative stress. Therefore, the function of PRX appears to be dynamically regulated by the level of oxidative stress. In addition, the PRX homo-oligomers directly bind and activate mammalian Ste20-similar kinase 1 (MST1) (30). This activation leads to jail cell expiry and mediates apoptotic response to p53-activating anticancer drugs, such as cisplatin.

Other ROS Targets

PTPs and TRX and PRX family proteins unremarkably possess special poly peptide structures that maintain redox-active Cys, which sensitively responds to ROS. Even so, several exceptional cases are also reported. Morinaka et al. (31) performed an in vivo screen for proteins that contain disulfide bonds, by using the TRX mutant that specifically forms stable complex with proteins bearing disulfide bonds. They establish many proteins co-precipitated with the TRX mutant, and i of the major proteins was identified every bit collapsin response mediator protein (CRMP) 2, a protein that plays an essential role in repulsive axon guidance caused by Semaphorin (32). Stimulation of dorsal root ganglia neurons with Semaphorin resulted in the generation of H₂O_ii in the growth cones and induced oxidation of CRMP2. This oxidation occurs at Cys504 that exists in the carboxy-terminal tail region in CRMP2 and links two CRMP2 proteins. Homo-oligomerization of CRMP2 linked with the disulfide bond has been shown to be essential for Semaphorin response, but it remains unknown as to why CRMP2 is selectively oxidized by Semaphorin stimulation. CRMP2 does not possess some redox-sensitive special structural motif and Cys504 exists in the carboxy-terminally located region that is reported to exist unstructured (33, 34). It volition be an interesting issue to clarify what determines the sensitivity of CRMP2 Cys504 to H₂O₂.

Recently, Lyn, a Src family tyrosine kinase (SFK), was shown to directly respond to H_iiO_ii (35). In a previous report, live imaging analyses using GFP-HyPer, a GFP-based H_twoO₂-specific probe (36), in zebrafish showed that H₂O₂ functions equally a chemoattractant for recruiting leukocytes to wounded areas (37). Yoo et al. revealed that Lyn in leukocytes is activated past wound-derived H₂O₂ and triggers the chemotactic movement of leukocytes to the wounds (Fig. 5). In this process, Cys466 in Lyn seems to be the direct target of oxidation by H_iiO₂, because the mutation of Cys466 to alanine specifically abolishes H₂O₂-induced activation of Lyn. Details about this activation of Lyn via Cys466 oxidation nonetheless remain unknown; i.e. why is Cys466 sensitive to H_twoO₂? Does oxidized Cys466 form an intra- or intermolecular disulfide bond? Considering the cross-species conservation of Cys466 in SFKs, still, this oxidation-dependent activation machinery might be a general feature beyond SFKs.

Fig. 5

H₂O₂-mediated activation of Lyn at zebrafish wounds. Upon local injury of the tail fin of zebrafish, H_iiO₂ is produced at the wounded areas by ROS-generating enzyme Duox. H₂O_two diffused from the wounds penetrates into neutrophils and oxidizes Cys466 of Lyn. Oxidized Lyn becomes activated and induces the migration of the neutrophils to the wounds.

Fig. 5

H₂O₂-mediated activation of Lyn at zebrafish wounds. Upon local injury of the tail fin of zebrafish, H₂O_ii is produced at the wounded areas by ROS-generating enzyme Duox. H₂O₂ diffused from the wounds penetrates into neutrophils and oxidizes Cys466 of Lyn. Oxidized Lyn becomes activated and induces the migration of the neutrophils to the wounds.

Moreover, information technology has been reported that oxidation of specific Cys occurs in several other proteins and plays a disquisitional role in the regulation of their function, such as ataxia-telangiectasia mutated (ATM) (38) and pyruvate kinase M2 (PKM2) (39). Every bit in the cases of CRMP2 and Lyn, these studies do non analyze why the specific Cys is redox-sensitive, just suggest that there still remain a number of unidentified ROS-effector proteins.

Conclusion

In this review article, we take briefly explained the roles of the target proteins for ROS in intracellular signalling, with an emphasis on highly reactive Cys that direct senses and responds to ROS. Examples of such redox-responsive proteins have been increasingly accumulating. Amidst them, some proteins possess special structures, such as PTP, TRX and PRX domains/motifs, which contribute to go along the redox-active Cys, but others practise not. Information technology remains an open question every bit to what determines the chemic reactivity of Cys in such cases, which would be important to search for novel ROS-effector proteins and ultimately sympathize the whole image of redox signalling.

Funding

Research in our laboratory is supported by Funding Program for Next Generation Earth-Leading Researchers from Nippon Society for the Promotion of Science (JSPS) to H.M., Heady Leading-Edge Inquiry Projects from Osaka Academy to H.Yard. and Grants-in-Aid for Scientific Inquiry from JSPS and Ministry of Education, Culture, Sports, Science and Technology-Japan to Y.F.

Conflict of interest

None alleged.

Abbreviations

Abbreviations

• Ask1

  apoptosis signal-regulating kinase 1

• ATM

  ataxia-telangiectasia mutated

• CRMP

  collapsin response mediator protein

• Cys

• Duox

• Dvl

• FAD

  flavin adenine dinucleotide

• H₂O₂

• JNK

• MKP

• MST1

  mammalian Ste20-similar kinase one

• NADPH

  nicotinamide adenine dinucleotide phosphate

• Nox

• NRX

• O₂ ⁻

• PDGF

  platelet-derived growth factor

• PIP_iii

  phosphatidylinositol (3,4,five)-trisphosphate

• PKM2

• PRL

  phosphatase of regenerating liver

• PRX

• PTP

  poly peptide tyrosine phosphatase

• PTP1B

  protein tyrosine phosphatase 1B

• PTEN

  phosphatase and tensin homologue deleted from chromosome ten

• ROS

• SFK

  Src family unit tyrosine kinase

• TNFα

• TRX

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© The Authors 2012. Published by Oxford Academy Press on behalf of the Japanese Biochemical Society. All rights reserved

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Source: https://academic.oup.com/jb/article/151/3/255/797505

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