Glutaredoxin 1 (Grx1) Protects Human Retinal Pigment Epithelial Cells From Oxidative Damage by Preventing AKT Glutathionylation

Liu, Xiaobin; Jann, Jamieson; Xavier, Christy; Wu, Hongli

doi:10.1167/iovs.14-15876

Cited by 45 publications

(46 citation statements)

References 31 publications

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“…Treatment of lung fibroblasts with Fas-ligand resulted in cell death when WT-Fas, but not C294A-Fas was expressed [ 17], suggesting that glutathionylation of Fas is a pre-requisite for cell death signal transduction. In addition, glutathionylation of the cell survival kinase Akt has been associated with decreased Akt activation and reduced cell viability in the human fetal retinal pigment epithelial cells when challenged with H 2 O 2 [ 40]. Conversely, overexpression of Grx1 resulted in decreased levels of Akt glutathionylation in response to H 2 O 2 and increased activation of Akt signaling [ 40].…”

Section: Discussionmentioning

confidence: 99%

“…Considering the context of Grx1 deficiency, it is important to note that Akt1 has been reported in other contexts to be regulated both directly [40] and likely indirectly [46] through reversible protein glutathionylation. Thus, treatment of human retinal pigment epithelial cells with H 2 O 2 resulted in Akt1 glutathionylation, impaired phosphorylation of Akt1, and cell death [40]. Over-expression of Grx1 resulted in decreased levels of glutathionylated Akt1, normalized phosphorylation/activation of Akt1, and increased cell viability when challenged with H 2 O 2 [40].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, treatment of human retinal pigment epithelial cells with H 2 O 2 resulted in Akt1 glutathionylation, impaired phosphorylation of Akt1, and cell death [40]. Over-expression of Grx1 resulted in decreased levels of glutathionylated Akt1, normalized phosphorylation/activation of Akt1, and increased cell viability when challenged with H 2 O 2 [40]. These data indicate that glutathionylation of Akt itself or of regulators of Akt may interfere with its cell-survival activity.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

et al. 2016

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Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH; and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in C. elegans, however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx−/− mice we provide evidence that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents; and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homolog in a C. elegans in vivo model of PD. Therefore; our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

et al. 2016

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“…The same group also found that Grx1 protected lens epithelial cells from oxidative stress by reactivating the oxidatively-inactivated glyceraldehyde 3-phosphate dehydrogenase (G3PD) through dethiolation [15]. Grx1 is also critical for protecting human RPE cells against oxidative stress, and our previous study has shown that Grx1 overexpression protected RPE cells from H 2 O 2 -induced apoptosis by stimulating AKT phosphorylation through prevention of AKT glutathionylation [16]. Considering Grx1’s protective abilities in RPE cells, Grx1 could be a potential pharmacological target for retinal degenerative diseases, like AMD.…”

Section: Introductionmentioning

confidence: 99%

Salvianolic Acid B (Sal B) Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Cell Death by Activating Glutaredoxin 1 (Grx1)

Liu

Xavier

Jann

et al. 2016

IJMS

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Protein glutathionylation, defined as the formation of protein mixed disulfides (PSSG) between cysteine residues and glutathione (GSH), can lead to cell death. Glutaredoxin 1 (Grx1) is a thiol repair enzyme which catalyzes the reduction of PSSG. Therefore, Grx1 exerts strong anti-apoptotic effects by improving the redox state, especially in times of oxidative stress. However, there is currently no compound that is identified as a Grx1 activator. In this study, we identified and characterized Salvianolic acid B (Sal B), a natural compound, as a Grx1 inducer, which potently protected retinal pigment epithelial (RPE) cells from oxidative injury. Our results showed that treatment with Sal B protected primary human RPE cells from H2O2-induced cell damage. Interestingly, we found Sal B pretreatment upregulated Grx1 expression in RPE cells in a time- and dose-dependent manner. Furthermore, NF-E2-related factor 2 (Nrf2), the key transcription factor that regulates the expression of Grx1, was activated in Sal B treated RPE cells. Further investigation showed that knockdown of Grx1 by small interfering RNA (siRNA) significantly reduced the protective effects of Sal B. We conclude that Sal B protects RPE cells against H2O2-induced cell injury through Grx1 induction by activating Nrf2 pathway, thus preventing lethal accumulation of PSSG and reversing oxidative damage.

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“…Recently, GRX-1 was reported to be able to control the glutathionylation of molecules implicated in LPS-or IL-1β-stimulated signaling pathways in a variety of cell types. GRX-1 suppresses oxidative stress-induced AKT glutathionylation and apoptosis in human retinal pigment epithelial cells [38]. It also regulates IL-1-mediated glutathionylation of TNF receptor-associated factor 6, an intermediate molecule involved in the IL-1R and TLR4 signaling pathways [39].…”

Section: Discussionmentioning

confidence: 99%

PEP-1-GRX-1 Modulates Matrix Metalloproteinase-13 and Nitric Oxide Expression of Human Articular Chondrocytes

Hwang¹,

Park²,

Kim³

et al. 2016

Cell Physiol Biochem

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Background: The protein transduction domain (PTD) enables therapeutic proteins to directly penetrate the membranes of cells and tissues, and has been increasingly utilized. Glutaredoxin-1 (GRX-1) is an endogenous antioxidant enzyme involved in the cellular redox homeostasis system. In this study, we investigated whether PEP-1-GRX-1, a fusion protein of GRX-1 and PEP-1 peptide, a PTD, could suppress catabolic responses in primary human articular chondrocytes and a mouse carrageenan-induced paw edema model. Methods: Human articular chondrocytes were isolated enzymatically from articular cartilage and cultured in a monolayer. The transduction efficiency of PEP-1-GRX-1 into articular chondrocytes was measured by western blot and immunohistochemistry. The effects of PEP-1-GRX-1 on matrix metalloproteinases (MMPs) and catabolic factor expression in interleukin (IL)-1β- and lipopolysaccharide (LPS)-treated chondrocytes were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and western blot. The effect of PEP-1-GRX1 on the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) signaling pathway were also analyzed by western blot. Finally, the inhibitory effect of PEP-1-GRX-1 on MMP-13 production was measured in vivo in a mouse carrageenan-induced paw edema model. Results: PEP-1-GRX-1 significantly penetrated into human chondrocytes and mouse cartilage, whereas GRX-1 did not. PEP-1-GRX-1 significantly suppressed MMP-13 expression and nitric oxide (NO) production in LPS-stimulated chondrocytes, and NO production in IL-1β-stimulated chondrocytes, compared with GRX-1. In addition, PEP-1-GRX-1 decreased IL-1β- and LPS-induced activation of MAPK and NF-κB. In the mouse model of carrageenan-induced paw edema, PEP-1-GRX-1 significantly suppressed carrageenan-induced MMP-13 production as well as paw edema. Conclusion: These results demonstrate that PEP-1-GRX-1 can be transduced efficiently in vitro and in vivo into human chondrocytes and mouse cartilage tissue and downregulate catabolic responses in chondrocytes by inhibiting the MAPK and NF-κB pathway. PEP-1-GRX-1 thus has the potential to reduce catabolic responses in chondrocytes and cartilage.

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Glutaredoxin 1 (Grx1) Protects Human Retinal Pigment Epithelial Cells From Oxidative Damage by Preventing AKT Glutathionylation

Cited by 45 publications

References 31 publications

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

Regulation of DJ-1 by Glutaredoxin 1 in Vivo: Implications for Parkinson’s Disease

Salvianolic Acid B (Sal B) Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Cell Death by Activating Glutaredoxin 1 (Grx1)

PEP-1-GRX-1 Modulates Matrix Metalloproteinase-13 and Nitric Oxide Expression of Human Articular Chondrocytes

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