Resveratrol Exerts Antioxidant Effects by Activating SIRT2 To

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Resveratrol Exerts Antioxidant Effects by Activating Sirt2 to Deacetylate Prx1 Yanchao Pan, Hua Zhang, yueting zheng, juanzuo Zhou, Jing Yuan, Yang Yu, and Jiangyun Wang Biochemistry, Just Accepted Manuscript • DOI: 10.1021/acs.biochem.7b00859 • Publication Date (Web): 10 Nov 2017 Downloaded from http://pubs.acs.org on November 12, 2017

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Biochemistry

Resveratrol Exerts Antioxidant Effects by Activating SIRT2 to Deacetylate Prx1 Yanchao Pan,†,‡ Hua Zhang,‡ Yueting Zheng,‡ Juanzuo Zhou,‡ Jing Yuan,† Yang Yu,‡ and Jiangyun Wang*,‡ †

Diagnosis and Treatment of Infectious Diseases Research Laboratory, Shenzhen Third People’s Hospital, Shenzhen 518112, China

‡

Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China

Abstract: Resveratrol is a promising chemical agent that treats multiple aging-related diseases and improves healthspan. While reactive oxygen species (ROS) undoubtedly play ubiquitous roles in the aging process and resveratrol has been shown to be an effective antioxidant, the mechanism through which resveratrol acts against oxidative stress remains unknown. Here we show that resveratrol activates SIRT2 to deacetylate Prx1, leading to increased H2O2 reduction activity and decreased cellular H2O2 concentration. Knockdown of SIRT2 or Prx1 by RNA interference abrogates resveratrol’s ability to reduce H2O2 level in HepG2 cells. Using purified SIRT2 and a Prx1 mutant harbouring acetyllysine at the 27th position (Prx1-27AcK), we show that resveratrol enhances SIRT2’s activity to deacetylate Prx1-27AcK, resulting in significantly increased H2O2 reducing activity. Thus, SIRT2 and Prx1 are targets for modulating intracellular redox status in the therapeutic strategies for aging-related disorders.

Reactive oxygen species (ROS) arise as the by-products of aerobic respiration and growth-factor mediated cellular signalling.[1-3] There is strong evidence that ROS play important roles in aging,[1-3] and treatments that confer resistance to oxidative stress result in extended lifespan.[4-6] Therefore, there is intense interest in developing methods to counteract ROS to ameliorate aging-related disorders including cancer, diabetes and heart diseases.[7]

We first tested if resveratrol can react with H2O2 directly. To a PBS buffer (pH 7.4) containing 5 µM H2O2, resveratrol was added.

Figure 2. A) Resveratrol (Resv) does not react directly with H 2O2 in a test tube, but can lower H2O 2 concentration in HepG2 cells. B) Knockdown of Prx1 or SIRT2 by siRNA abrogates resveratrol’s ability to decrease H2O2 concentration in HepG2 cells. C) Resveratrol addition decreases AcK abundance in Prx1 in HepG2 cells. D) Knockdown of SIRT2 by siRNA abrogates resveratrol’s ability to decrease AcK abundance in Prx1 in HepG2 cells.

Resveratrol (trans-3,5,4’-trihydroxystilbene, Figure 1) is a polyphenolic compound found in plants such as grapes and mulberries.[8] About two decades ago, it was discovered that resveratrol has cancer chemopreventive and antioxidative activity.[9] Since then, resveratrol has been intensively studied for its roles in cancer prevention, cardioprotection and calorie restriction-like effects in animal models and human,[10-11] and tremendous progress has been made in developing new strategies to chemically synthesize resveratrol derivatives, with the aim to develop antiaging agents.[12-14] It is thought that the beneficial effects of resveratrol are related to its ability to act as antioxidant, and activate silent information regulator family members (SIRTs or Sirtuins), which are protein lysine deacetylases regulating metabolism, stress response and aging.[15-17] Despite the great progress, the mechanism through which resveratrol acts to decrease H2O2 concentration remains unknown.

Figure 1. Resveratrol enhances SIRT2’s activity to deacetylate the acetyllysine at the 27 th position of Prx1, resulting in enhanced H2O2 reducing activity.

Figure 3. A) SDS-PAGE analysis of myoglobin-4TAG mutant expression in the presence or absence of 2 mM AcK, using BL21(DE3) cells or cobB knockout cells. B) Western blot analysis of myoglobin-4TAG mutant expressed in either BL21(DE3) cells or cobB knockout cells. C) ESI-MS spectra of myoglobin-4TAG mutant, expressed in BL21(DE3) cells in the presence of AcKRS/tRNAPylCUA . D) ESI-MS spectra of myoglobin-4TAG mutant, expressed in cobB knockout cells, in the presence of AcKRS/tRNAPylCUA.

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Subsequently, 5 µM Peroxyfluor-1 (PF1) was added to culture medium, followed by incubation for 40 min. While PF1 exhibits strong H2O2 turn-on fluorescence (λex = 488 nm, λem = 520 nm), [1819] addition of resveratrol has no effect on fluorescence, indicating that resveratrol does not react with H2O2 directly. To determine resveratrol’s antioxidant activity in living cells, we cultured HepG2 cells in DMEM medium. When the cells reached 60% confluence, 0 to 100 µM resveratrol was added to culture medium. Twelve hours after resveratrol addition, 5 µM PF1 was added to culture medium, followed by incubation for 40 min. The H2O2 concentration in HepG2 cells was then analysed using fluorescence activated cell sorting (FACS) with a 488 nm laser. As Figure 2A and S1 show, resveratrol addition resulted in a dose-dependent decrease of H2O2 concentration in HepG2 cells, consistent with previous studies, which have shown that resveratrol has protective effects on hydrogen peroxide-induced apoptosis.[16]

Since resveratrol does not react with H2O2 directly, we surmised that it might act indirectly by enhancing the activity of H2O2 detoxifying enzymes. Because it is well-known that resveratrol can up-regulate lysine deacetylation activity of SIRT enzymes,[11, 15] we searched a human liver tissue protein lysine acetylation database[2021] for H2O2 reducing enzymes whose activity might be regulated by lysine acetylation. We found that peroxiredoxin1(Prx1), a highly abundant cytoplasmic enzyme whose main function is H2O2 reduction,[22] was known to be acetylated at the Lys27 position, but the function of Lys27 acetylation was not known. To determine if Prx1 plays a role to mediate the antioxidative activity of resveratrol, we used small interference RNA (siRNA) to knock-down the expression of Prx1 in HepG2 cells (Figures 2B and S2). We found that siRNA knockdown of Prx1 resulted in an increase of H2O2 concentration, consistent with Prx1’s function as a H2O2 detoxifying enzyme. While the addition of 100 µM resveratrol resulted in more than 50% decrease of H2O2 concentration in HepG2 cells, the same treatment caused less than 10% H2O2 concentration decrease in HepG2 cells where Prx1 expression was attenuated by siRNA. To further determine the function of Prx1 acetylation, we performed siRNA knockdown of SIRT2, a target be identified to bind and deacetylate Prx1.[15]. As Figure 2B shows, RNA interference against SIRT2 abrogates resveratrol’s ability to reduce H2O2 concentration in HepG2 cells. To determine if lysine acetylation plays a role in this signal-transduction pathway, we quantified AcK abundance in Prx1 in response to various concentration of resveratrol using an anti-AcK antibody in an immunoprecipitation assay. As Figure 2C and S3a show, Prx1 acetylation decreased in a dose-dependent manner when resveratrol was added to HepG2 cells. However, once SIRT2 was knocked down using siRNA against SIRT2, this effect was abrogated (Figure 2D and S3b). Altogether, these results suggest that in response to resveratrol, SIRT2 deacetylates and activates Prx1, leading to increased H2O2 reduction activity and decreased cellular H2O2 concentration.

To further confirm this model, we then used the genetic code expansion strategy to overexpress Prx1 mutant harbouring AcK in the 27th position in E. coli.[23-25] To determine if a previously reported AcK specific Nε-acetyllysyl-tRNAsynthetase(AcKRS)/tRNAPylCUA pair can be used for selective AcK incorporation,[24] we expressed a myoglobin-TAG4 mutant. While SDS-PAGE and western-blot analysis confirmed that the AcKRS/tRNAPylCUA pair can be used to incorporate AcK in response to TAG codon in the 4th position, ESI-MS showed that both lysine and AcK were incorporated in the 4th position. Because very little full-length myoglobin was obtained in the absence of AcK, we surmised that CobB, the only sirtuin homolog protein deacetylase found in E. coli,[26] might be responsible for deacetylation AcK after its genetic incorporation into proteins. To verify this hypothesis, we constructed cobB knockout BL21(DE3) strain.[27] As Figure 3A shows, while myoglobin-4AcK yield was similar in wild type and ∆cobB strain, the AcK signal was enhanced by about two-fold in the

∆cobB strain (Figure 3B). Importantly, no mass signal corresponding to Lys4 incorporated was detected if the expression was carried out in the ∆cobB strain (Figure 3D). These results indicate that CobB is indeed responsible for the non-specific deacetylation of AcK in E. coli, and cobB gene knockout can significantly enhance AcK incorporation selectivity.

Figure 4. A) Western blot analysis of SIRT2 deacetylation of Prx1-27AcK using an anti-AcK antibody, and its dependence on resveratrol. B) Comparison of Prx127AcK and wildtype Prx1 enzyme activity, monitored by NADPH absorbance at 340 nm. C) Mechanism of H 2O2 reduction by Prx1-Trx-TrxR-NADPH cascade. D) Structure of thioredoxin. E) Structure of Prx1.

Using the ∆cobB BL21(DE3) strain, we then expressed Prx127AcK and assessed AcK incorporation by MALDI-TOF mass spectrometry (Figure S4). As Figure 4A shows, a recombinant form of SIRT2 purified after expression in E. coli exhibits resveratrol dependent Prx1-27AcK deacetylase activity. Interestingly, in the presence of 40 µM or more resveratrol, Prx1-27AcK is completely deacetylated by SIRT2. By contrast, some AcK signal can still be detected in Prx1 when 40-100 µM of resveratrol was added to HepG2 cells. It is possible that in HepG2 cells, a lysine acetyltransferase can constitutively acetylate Prx1, resulting in incomplete Prx1 lysine deacetylation even after SIRT2 activation. We also tested Prx1-27AcK deacetylation in response to Sirt1, however, no signal was appeared even in the presence of 100 µM resveratrol (Figure S5).

To investigate whether Lys27 acetylation play a role in regulating the H2O2 reducing activity of Prx1, we directly compared the enzyme activity of Prx1-AcK27 and the wildtype Prx1 using purified enzymes. [2] In human cells, reduced Prx1 reacts with H2O2 through its thiol groups at Cys52/Cys173 residues, resulting in Cys52-Cys173 disulphide bond formation.[22] This disulphide bond is then reduced by thioredoxin (Trx). Oxidized thioredoxin is then reduced by thioredoxin reductase (TrxR), through NADPH consumption (Figure 4C).[22] To a Hepes buffer (pH 7.0) containing 5 µM Prx1-AcK27 or wildtype Prx1, and 1.5 µM thioredoxin (Trx), 1 µM thioredoxin reductase (TrxR) and 150 µM NADPH was added

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Biochemistry

130 µM H2O2. Since H2O2 reduction is coupled with NADPH oxidation, we monitored H2O2 reduction using NADPH absorption at 340 nm. As Figure 4B shows, the H2O2 reducing activity of Prx127AcK is four- fold less than wildtype Prx1. While Prx1 alone can react with H2O2 directly, the reduction of Cys52/Cys173 disulfide requires interaction with thioredoxin. It is possible that Lys27 acetylation can significantly affect Prx1-Trx binding by modulating the electrostatic interaction between Prx1 and Trx. To confirm this hypothesis, we performed surface plasmon resonance (SPR) experiments. As Figure S6 shows, Lys27 acetylation significantly decreases the interaction between Trx and Prx1. We surmise that Lys27 acetylation may affect Prx1-Trx binding by modulating the electrostatic interaction between Prx1 and Trx. Further investigations are being performed to delineate the mechanism.

In summary, we have demonstrated that resveratrol activates SIRT2 to deacetylate Prx1-27AcK, which significantly enhance its H2O2 reducing activity, using purified enzymes/substrates, and in HepG2 cells.[28]The key role of H2O2 in carcinogenesis is supported by the results that cancer cells usually have elevated level of H2O2, which may play a key role in malignant transformation, and explain many hallmarks of cancer such as DNA damage and genetic instability. [28] Conversely, an increase of H2O2 detoxifying enzyme activity can reduce cell proliferation, and inhibit cancer metastasis.[28]Our results indicate that small molecules targeting SIRT2 and Prx1 may modulate intracellular redox status in the therapeutic strategies for aging-related disorders. Key to our success is the discovery that the bacteria Sir2-like protein CobB acts as nonspecific deacetylase for genetically encoded AcK, and that cobB gene knockout results in significantly enhanced AcK incorporation selectivity. In previous studies, chemically synthesized peptides bearing AcK at specific positions have been used as sirtuin substrates, for mechanistic studies and high-through screening to obtain potent sirtuin inhibitors or activators. However, such peptide fragments cannot fully recapitulate the functional interaction between sirtuin and their protein substrates, and much controversies have been generated.[29-30] Using the genetic code expansion method and cobB knockout strain, full-length protein substrates selectively bearing AcK in specific positions can be conveniently prepared in milligram quantity. By using purified full-length protein substrates bearing AcK in specific positions, resveratrol derivatives and other compounds can be screened using fluorescent reporters [31] to identify more potent activators of sirtuin lysine deacetylases, which may exhibit enhanced anti-oxidative and life-span extension properties.[32]

ASSOCIATED CONTENT Supporting Information Supporting Figures S1-S6 and experimental Methods.

AUTHOR INFORMATION Corresponding Author [email protected]

Author Contributions This work was conceived by Jiangyun Wang. Yanchao Pan, Hua Zhang,Yueting Zheng, Juanzuo Zhou performed the experiments and collected data. Jing Yuan and Yang Yu revised the manuscript. All authors have given approval to the final version of the manuscript.

Funding Sources This work is supported by the Research Program of China (2011CBA00800), National Science Foundation of China (91313301, 21325211, 21502026) and Sanming Project of Medicine in Shenzhen.

Notes The authors declare no competing finacial interests.

ACKNOWLEDGMENT We thanks Yuanyuan Chen for technical help with Biacore experiments.

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Resveratrol antioxidant Yanchao Pan, Hua Zhang, Yueting Zheng, Juanzuo Zhou, Jing Yuan, Yang Yu, and Jiangyun Wang* __________ Page – Page Resveratrol Exerts Antioxidant Effects by Activating Sirt2 to Deacetylate Prx1 Resveratrol is a promising antioxidant that treats multiple aging-related diseases and improves healthspan. However, the mechanism through which resveratrol acts against oxidative stress remains unknown. Here we show that resveratrol activates Sirt2 to deacetylate peroxiredoxin 1 (Prx1) at the 27th position to enhance its H2O2 reducing activity, both in vitro and in vivo. Thus, Sirt2 and Prx1 are targets for modulating intracellular redox status in therapeutic strategies for aging-related disorders. .

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