<scp>SIRT</scp>5 promotes <scp>IDH</scp>2 desuccinylation and G6<scp>PD</scp> deglutarylation to enhance cellular antioxidant defense

Zhou, Lisha; Wang, Fang; Sun, Renqiang; Chen, Xiufei; Zhang, Mengli; Xu, Qi; Wang, Yi; Wang, Shiwen; Xiong, Yue; Guan, Kun Liang; Yang, Pengyuan; Yu, Hongxiu; Ye, Dan

doi:10.15252/embr.201541643

Cited by 220 publications

(171 citation statements)

References 43 publications

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“…It has been proven that G6PD acetylation on K 403 affects the formation of active dimers, which decreases G6PD activity (15). Conversely, 2 other studies have reported that glycosylation on Ser and sirtuin 5‐associated deglutarylation of G6PD increase G6PD activity (48, 49). In this study, we present a novel finding for the regulation of the G6PD protein.…”

Section: Discussionmentioning

confidence: 94%

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High glucose–induced ubiquitination of G6PD leads to the injury of podocytes

Wang

Yan

et al. 2019

The FASEB Journal

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Oxidative stress contributes substantially to podocyte injury, which plays an important role in the development of diabetic kidney disease. The mechanism of hyperglycemia‐induced oxidative stress in podocytes is not fully understood. Glucose‐6‐phosphate dehydrogenase (G6PD) is critical in maintaining NADPH, which is an important cofactor for the antioxidant system. Here, we hypothesized that high glucose induced ubiquitination and degradation of G6PD, which injured podocytes by reactive oxygen species (ROS) accumulation. We found that G6PD protein expression was decreased in kidneys of both diabetic patients and diabetic rodents. G6PD activity was also reduced in diabetic mice. Overexpressing G6PD reversed redox imbalance and podocyte apoptosis induced by high glucose and palmitate. Inhibition of G6PD with small interfering RNA induced podocyte apoptosis. In kidneys of G6PD‐deficient mice, podocyte apoptosis was significantly increased. Interestingly, high glucose had no effect on G6PD mRNA expression. Decreased G6PD protein expression was mediated by the ubiquitin proteasome pathway. We found that the von Hippel–Lindau (VHL) protein, an E3 ubiquitin ligase subunit, directly bound to G6PD and degraded G6PD through ubiquitylating G6PD on K366 and K403. In summary, our data suggest that high glucose induces ubiquitination of G6PD by VHL E3 ubiquitin ligase, which leads to ROS accumulation and podocyte injury.—Wang, M., Hu, J., Yan, L., Yang, Y., He, M., Wu, M., Li, Q., Gong, W., Yang, Y., Wang, Y., Handy, D. E., Lu, B., Hao, C., Wang, Q., Li, Y., Hu, R., Stanton, R. C., Zhang, Z. High glucose—induced ubiquitination of G6PD leads to the injury of podocytes. FASEB J. 33, 6296–6310 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 94%

“…G6PD is subject to complex regulation, and modifications of G6PD protein have been reported (15, 48, 49). It has been proven that G6PD acetylation on K 403 affects the formation of active dimers, which decreases G6PD activity (15).…”

Section: Discussionmentioning

confidence: 99%

High glucose–induced ubiquitination of G6PD leads to the injury of podocytes

Wang

Yan

et al. 2019

The FASEB Journal

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“…However, these sirtuins may contribute to ROS homeostasis based on their targets. For example, SIRT5 may act in parallel to SIRT3 via deacetylation of FOXO3A and desuccinylation of IDH2 [46,47]. Likewise, SIRT4 may affect ROS via pyruvate dehydrogenase complex (PDH), glutamate dehydrogenase (GDH) and fatty acid oxidation through malonyl-CoA decarboxylase (MCD) [48–50].…”

Section: Mitochondrial Sirtuins Protect Against Age-related Diseasesmentioning

confidence: 99%

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

Ven

Santos

Haigis

2017

Trends in Molecular Medicine

260

189

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Advancing age is the major risk factor for the development of chronic diseases and is accompanied with changes in metabolic processes and mitochondrial dysfunction. Mitochondrial sirtuins (SIRT3-5) are part of the sirtuin family of NAD+-dependent deacylases and ADP-ribosyl transferases. The dependence on NAD+ links sirtuin enzymatic activity to the metabolic state of the cell, poising them as stress sensors. Recent insights have revealed that SIRT3-5 orchestrate stress responses through coordinated regulation of substrate clusters rather than a few key metabolic enzymes. Additionally, mitochondrial sirtuin function has been implicated in the protection against age-related pathologies including neurodegeneration, cardiopathologies and insulin resistance. In this review, we highlight the molecular targets of SIRT3-5 and discuss their involvement in aging and age-related pathologies.

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“…It also functions in glycolysis and TCA cycle by controlling the PTM level of succinate dehydrogenase complex (GDH), pyruvate dehydrogenase complex (PDH), and GAPDH (29,30). In response to oxidative stress, SIRT5 desuccinylates superoxide dismutase [Cu-Zn] (SOD1), isocitrate dehydrogenase 2 (IDH2), and deglutarylates glucose-6-phosphate 1-dehydrogenase (G6PD) to maintain cellular redox homeostasis (31,32). SIRT5 may play a role in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

et al. 2018

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The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.Significance: These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. Cancer Res; 78(2); 372-86.Ó2017 AACR.

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SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense

Cited by 220 publications

References 43 publications

High glucose–induced ubiquitination of G6PD leads to the injury of podocytes

High glucose–induced ubiquitination of G6PD leads to the injury of podocytes

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

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