Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1

Bräutigam, Lars; Jensen, Lasse D.; Poschmann, Gereon; Nyström, Staffan; Bannenberg, Sarah; Dreij, Kristian; Lepka, Klaudia; Prozorovski, Timour; Montaño, Sergio; Aktaş, Orhan; Uhlén, Per; Stühler, Kai; Cao, Yihai; Holmgren, Arne; Berndt, Carsten

doi:10.1073/pnas.1313753110

Cited by 81 publications

(68 citation statements)

References 45 publications

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“…Activation of SirT1 improved NAFL and conversely hepatic SirT1 deficiency led to steatosis (56). Inhibition of SirT1 activity by reversible GSH adducts has recently been described by our group and was confirmed by other investigators (11,67,71,77). Because NAFL (58) is associated with oxidative stress, increased protein GSH adducts may play an important role in the pathogenesis of steatotic livers.…”

Section: Introductionsupporting

confidence: 57%

Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Шао

Han

Hou

et al. 2017

Antioxidants & Redox Signaling

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Aims: Nonalcoholic fatty liver (NAFL) is a common liver disease associated with metabolic syndrome, obesity, and diabetes that is rising in prevalence worldwide. Various molecular perturbations of key regulators and enzymes in hepatic lipid metabolism cause NAFL. However, redox regulation through glutathione (GSH) adducts in NAFL remains largely elusive. Glutaredoxin-1 (Glrx) is a small thioltransferase that removes protein GSH adducts without having direct antioxidant properties. The liver contains abundant Glrx but its metabolic function is unknown. Results: Here we report that normal diet-fed Glrx-deficient mice (Glrx -/-) spontaneously develop obesity, hyperlipidemia, and hepatic steatosis by 8 months of age. Adenoviral Glrx repletion in the liver of Glrx -/-mice corrected lipid metabolism. Glrx -/-mice exhibited decreased sirtuin-1 (SirT1) activity that leads to hyperacetylation and activation of SREBP-1 and upregulation of key hepatic enzymes involved in lipid synthesis. We found that GSH adducts inhibited SirT1 activity in Glrx -/-mice. Hepatic expression of nonoxidizable cysteine mutant SirT1 corrected hepatic lipids in Glrx -/-mice. Wild-type mice fed high-fat diet develop metabolic syndrome, diabetes, and NAFL within several months. Glrx deficiency accelerated high-fat-induced NAFL and progression to steatohepatitis, manifested by hepatic damage and inflammation. Innovation: These data suggest an essential role of hepatic Glrx in regulating SirT1, which controls protein glutathione adducts in the pathogenesis of hepatic steatosis. Conclusion: We provide a novel redox-dependent mechanism for regulation of hepatic lipid metabolism, and propose that upregulation of hepatic Glrx may be a beneficial strategy for NAFL. Antioxid. Redox Signal. 27, 313-327.

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Section: Introductionsupporting

confidence: 57%

Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Шао

Han

Hou

et al. 2017

Antioxidants & Redox Signaling

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“…Finally, HDAC8 was demonstrated to be modified by NO in vitro (Feng et al, 2011). Interestingly, the catalytic activity of SIRTUIN1 is regulated by reversible S-glutathionylation, which guides vascular development in zebrafish (Bräutigam et al, 2013). HDACs generally operate in large multiprotein complexes, which can affect their activity, subcellular localization, or the genes to which they are targeted (Sengupta and Seto, 2004).…”

Section: Redox Regulation Of Hdacsmentioning

confidence: 99%

Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases

et al. 2016

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Histone acetylation, which is an important mechanism to regulate gene expression, is controlled by the opposing action of histone acetyltransferases and histone deacetylases (HDACs). In animals, several HDACs are subjected to regulation by nitric oxide (NO); in plants, however, it is unknown whether NO affects histone acetylation. We found that treatment with the physiological NO donor S-nitrosoglutathione (GSNO) increased the abundance of several histone acetylation marks in Arabidopsis (Arabidopsis thaliana), which was strongly diminished in the presence of the NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. This increase was likely triggered by NO-dependent inhibition of HDAC activity, since GSNO and S-nitroso-N-acetyl-DL-penicillamine significantly and reversibly reduced total HDAC activity in vitro (in nuclear extracts) and in vivo (in protoplasts). Next, genome-wide H3K9/14ac profiles in Arabidopsis seedlings were generated by chromatin immunoprecipitation sequencing, and changes induced by GSNO, GSNO/2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide or trichostatin A (an HDAC inhibitor) were quantified, thereby identifying genes that display putative NO-regulated histone acetylation. Functional classification of these genes revealed that many of them are involved in the plant defense response and the abiotic stress response. Furthermore, salicylic acid, which is the major plant defense hormone against biotrophic pathogens, inhibited HDAC activity and increased histone acetylation by inducing endogenous NO production. These data suggest that NO affects histone acetylation by targeting and inhibiting HDAC complexes, resulting in the hyperacetylation of specific genes. This mechanism might operate in the plant stress response by facilitating the stress-induced transcription of genes.

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“…A conserved cysteine in the catalytic domain of Sirt1 serves as a substrate for glutaredoxin 2. Glutaredoxin 2 deglutathionylates the cysteinyl residue and thereby orchestrates Sirt1-dependent vascular development in zebrafish embryos (Bräutigam et al, 2013). A morpholino-based glutaredoxin 2 knock-down lead to delayed and disordered vascular development in zebrafish indicating the physiological relevance of Sirt1 post-translational (redox-)regulation.…”

Section: Nuclear Functions Of Gapdhmentioning

confidence: 99%

Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub?

Hildebrandt¹,

Knuesting²,

Berndt³

et al. 2015

Biological Chemistry

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131

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Cytosolic glyceraldehyde 3-phosphate dehydrogenase (GAPDH, E.C. 1.2.1.12) is present in all organisms and catalyzes the oxidation of triose phosphate during glycolysis. GAPDH is one of the most prominent cellular targets of oxidative modifications when reactive oxygen and nitrogen species are formed during metabolism and under stress conditions. GAPDH harbors a strictly conserved catalytic cysteine, which is susceptible to a variety of thiol modifications, including S-sulfenylation, S-glutathionylation, S-nitrosylation, and S-sulfhydration. Upon reversible oxidative thiol modification of GAPDH, glycolysis is inhibited leading to a diversion of metabolic flux through the pentose-phosphate cycle to increase NADPH production. Furthermore, oxidized GAPDH may adopt new functions in different cellular compartments including the nucleus, as well as in new microcompartments associated with the cytoskeleton, mitochondria and plasma membrane. This review focuses on the recently discovered mechanism underlying the eminent reactivity between GAPDH and hydrogen peroxide and the subsequent redox-dependent moonlighting functions discriminating between the induction either of adaptive responses and adjustment of metabolism or of cell death in yeast, plants, and mammals. In light of the summarized results, cytosolic GAPDH might function as a sensor for redox signals and an information hub to transduce these signals for appropriate responses.

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Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1

Cited by 81 publications

References 45 publications

Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases

Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub?

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