SIRT1 is a redox‐sensitive deacetylase that is post‐translationally modified by oxidants and carbonyl stress

Caito, Samuel; Saravanan, R.; Cook, Suzanne; Chung, Sangwoon; Yao, Hongwei; Friedman, Alan E.; Brookes, Paul S.; Rahman, Irfan

doi:10.1096/fj.09-151308

Cited by 262 publications

(244 citation statements)

References 75 publications

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“…Indeed, there are studies indicating that the cysteine residues in SIRT1 are vulnerable to oxidative and nitrosative stress, which lead to impaired sirtuin activity (Caito et al. 2010; Zee et al. 2010; Shao et al.…”

Section: Discussionmentioning

confidence: 99%

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

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Despite the fact that skeletal muscle insulin resistance is the hallmark of type‐2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose‐induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type‐2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased β‐hydroxyacyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase activities, despite reduced mitochondrial mass. Long‐chain acyl‐CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long‐chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type‐2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.

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Section: Discussionmentioning

confidence: 99%

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

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“…1A). Previous studies have shown that oxidative stress reduces the protein expression of SIRT1 (26,27). To determine whether SIRT1 interacted with TyrRS as its deacetylase, we coexpressed TyrRS with either SIRT1 or SIRT2 in HEK293T cells and then measured the acetylation level of TyrRS.…”

Section: Significancementioning

confidence: 99%

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Cao

Xiao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Tyrosyl-tRNA synthetase (TyrRS) is well known for its essential aminoacylation function in protein synthesis. Recently, TyrRS has been shown to translocate to the nucleus and protect against DNA damage due to oxidative stress. However, the mechanism of TyrRS nuclear localization has not yet been determined. Herein, we report that TyrRS becomes highly acetylated in response to oxidative stress, which promotes nuclear translocation. Moreover, p300/ CBP-associated factor (PCAF), an acetyltransferase, and sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, regulate the nuclear localization of TyrRS in an acetylation-dependent manner. Oxidative stress increases the level of PCAF and decreases the level of SIRT1 and deacetylase activity, all of which promote the nuclear translocation of hyperacetylated TyrRS. Furthermore, TyrRS is primarily acetylated on the K244 residue near the nuclear localization signal (NLS), and acetylation inhibits the aminoacylation activity of TyrRS. Molecular dynamics simulations have shown that the in silico acetylation of K244 induces conformational changes in TyrRS near the NLS, which may promote the nuclear translocation of acetylated TyrRS. Herein, we show that the acetylated K244 residue of TyrRS protects against DNA damage in mammalian cells and zebrafish by activating DNA repair genes downstream of transcription factor E2F1. Our study reveals a previously unknown mechanism by which acetylation regulates an aminoacyl-tRNA synthetase, thus affecting the repair pathways for damaged DNA.

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“…Sirtuin-3 and Sirtuin-1 (SIRT3 and SIRT1) were reported to be covalently modified by 4-HNE (Caito et al, 2010;Fritz et al, 2011). This modification by 4-HNE can inhibit SIRT3 deacetylase activity (Fritz et al, 2011).…”

Section: -Hydroxynonenal Promotes the Growth And Invasion Of Breast mentioning

confidence: 99%

4-Hydroxynonenal Promotes Growth and Angiogenesis of Breast Cancer Cells through HIF-1α Stabilization

Li¹,

Tian²,

Shi³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Abstract4-Hydroxynonenal (4-HNE) is a stable end product of lipid peroxidation, which has been shown to play an important role in cell signal transduction, while increasing cell growth and differentiation. 4-HNE could inhibit phosphatase and tensin homolog (PTEN) activity in hepatocytes and increased levels have been found in human invasive breast cancer. Here we report that 4-HNE increased the cell growth of breast cancer cells as revealed by colony formation assay. Moreover, vascular endothelial growth factor (VEGF) expression was elevated, while protein levels of hypoxia inducible factor 1 alpha (HIF-1α) were up-regulated. Sirtuin-3 (SIRT3), a major mitochondria NAD+-dependent deacetylase, is reported to destabilize HIF-1α. Here, 4-HNE could inhibit the deacetylase activity of SIRT3 by thiol-specific modification. We further demonstrated that the regulation by 4-HNE of levels of HIF-1α and VEGF depends on SIRT3. Consistent with this, 4-HNE could not increase the cell growth in SIRT3 knockdown breast cancer cells. Additionally, 4-HNE promoted angiogenesis and invasion of breast cancer cells in a SIRT3-dependent manner. In conclusion, we propose that 4-HNE promotes growth, invasion and angiogenesis of breast cancer cells through the SIRT3-HIF-1α-VEGF axis.

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SIRT1 is a redox‐sensitive deacetylase that is post‐translationally modified by oxidants and carbonyl stress

Cited by 262 publications

References 75 publications

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

4-Hydroxynonenal Promotes Growth and Angiogenesis of Breast Cancer Cells through HIF-1α Stabilization

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