Oxidative Stress Activates SIRT2 to Deacetylate and Stimulate Phosphoglycerate Mutase

Xu, Yanping; Li, Fulong; Lv, Lei; Li, Tingting; Zhou, Xin; Deng, Chu Xia; Guan, Kun Liang; Lei, Qun; Xiong, Yue

doi:10.1158/0008-5472.can-13-3615

Cited by 133 publications

(106 citation statements)

References 28 publications

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“…4I). Although acetylation plays an important role in regulating the function of several metabolic enzymes (14,18,19), acetylation has been shown to modify several proteins, such as PKM2 and FOXO1, enhancing their translocation into the nucleus (18,33). Our study provided further insights into the mechanism of acetylation-regulated TyrRS nuclear localization.…”

Section: Discussionmentioning

confidence: 68%

“…1B). To further validate this result, cells overexpressing TyrRS were treated with the oxidative stressor menadione, a polycyclic aromatic ketone that generates intracellular reactive oxygen species (ROS) at multiple cellular sites via futile redox cycling (14). Menadione treatment also significantly increased the acetylation level of TyrRS (Fig.…”

Section: Significancementioning

confidence: 82%

“…Acetylation regulates diverse cellular processes, including gene silencing (13), oxidative stress (13,14), DNA repair (15), cell survival and migration (16,17), and metabolism (9,18,19). Most acetylated proteins act as transcription factors in the nucleus and as metabolic enzymes outside the nucleus (9).…”

Section: Dna Damage Repairmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 68%

Section: Significancementioning

confidence: 82%

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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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“…phosphoglycerate kinase 1 [13], glutamate oxaloacetate transaminase [14], phosphoglycerate mutase [15], and glucose-6-phosphate [16], isocitrate [17] and lactate dehydrogenase [18]). In many instances is the acetylation level coupled by signalling cascades to the nutritional state of the cell.…”

Section: Genetically Encoded Natural Protein Modifications and Their mentioning

confidence: 99%

The use of unnatural amino acids to study and engineer protein function

Neumann‐Staubitz¹,

Neumann

2016

Current Opinion in Structural Biology

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“…Conversely, oxidative stress activates PGAM by promoting binding between SIRT2 and PGAM. 47,48) PGAM may also play an important role in hypoxic condition for the pathogenesis of preeclampsia.…”

Section: -3 Pgam and Hypoxiamentioning

confidence: 99%

Hypoxia in the pathogenesis of preeclampsia

Matsubara

2017

Hypertens Res Pregnancy

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Oxidative stress is required for the development of hypoxic injury and has been investigated as a key factor in the pathogenesis of preeclampsia. In preeclampsia, hypoxia at the implantation site can contribute to lesion formation, leading to poor placentation. Hypoxia-inducible factor-1α (HIF-1α) is a known transcription factor involved in placentation. Increased levels of HIF-1α can induce secretion of soluble vascular endothelial growth factor receptor-1 (sFlt-1), which is known to be a major factor influencing the pathogenesis of preeclampsia. Meanwhile, HIF-1α and HIF-1β mediate the maintenance and production of endothelial progenitor cells and bone marrowderived stem cells, which play important roles in placental vascular development. Related dysfunction can result in preeclampsia. It is also known that glycolytic enzyme phosphoglycerate mutase (PGAM) is deacetylated and activated by reactive oxygen species (ROS), the former of which may regulate cell proliferation through the effects of ROS without the participation of HIF-1α. In this review, we characterize the roles of HIF and PGAM in the pathogenesis of preeclampsia.

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Oxidative Stress Activates SIRT2 to Deacetylate and Stimulate Phosphoglycerate Mutase

Cited by 133 publications

References 28 publications

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

The use of unnatural amino acids to study and engineer protein function

Hypoxia in the pathogenesis of preeclampsia

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