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Inhibition of SIRT2 by Targeting GSK3?-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells.

ABSTRACT: Sirtuin 2 (SIRT2) is thought to be important in the pathogenesis of Parkinson's disease (PD), and the inhibition of SIRT2 rescues ?-synuclein toxicity in a cellular model of PD. Recent studies have focused on identifying inhibitors of SIRT2, but little is known about the processes that directly regulate its function. GSK3? is a serine/threonine protein kinase that affects a wide range of biological functions, and it is localized in Lewy bodies (LBs). Therefore, we investigated whether SIRT2 is regulated by GSK3? and enhances cell death in PD. In the present study, Western blot showed that total SIRT2 levels did not change noticeably in a cellular model of PD but that SIRT2 phosphorylation was increased, and GSK3? activity was elevated. In addition, mass spectrometry (MS) studies indicated that SIRT2 was phosphorylated by GSK3? at three specific sites. Phospho- or dephospho-mimicking studies demonstrated that this postmodification (phosphorylation) increased SIRT2 toxicity in SH-SY5Y cells. Collectively, our findings identify a posttranslational mechanism that controls SIRT2 function in PD and provide evidence for a novel regulatory pathway involving GSK3?, SIRT2, and ?-synuclein.

SUBMITTER: Liu S

PROVIDER: S-EPMC6492038 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Inhibition of SIRT2 by Targeting GSK3β-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells.

Liu Shuhu S Zhou Zhihua Z Zhang Ling L Meng Siying S Li Shuji S Wang Xuemin X

Frontiers in cellular neuroscience 20190424

Sirtuin 2 (SIRT2) is thought to be important in the pathogenesis of Parkinson's disease (PD), and the inhibition of SIRT2 rescues α-synuclein toxicity in a cellular model of PD. Recent studies have focused on identifying inhibitors of SIRT2, but little is known about the processes that directly regulate its function. GSK3β is a serine/threonine protein kinase that affects a wide range of biological functions, and it is localized in Lewy bodies (LBs). Therefore, we investigated whether SIRT2 is r ...[more]

PMID: 31105527

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Project description:Oxidative stress plays a key role in cerebral ischemia/reperfusion injury. Artemisinin (ART) has antioxidative stress activity in addition to its powerful antimalarial effects. In this article, we investigated the effect of ART on OGD/R-induced oxidative stress injury and its underlying mechanisms. We used oxygen-glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model of cerebral ischemia/reperfusion (I/R) injury. CCK-8 and lactate dehydrogenase (LDH) release were used to assess cellular damage. Measurement of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and mitochondrial membrane potential (MMP) estimates oxidative stress-induced damage and protection from ART effect. OGD/R treatment aggravated oxidative stress damage, whereas ART reversed the effects of OGD/R. Autophagy is closely related to oxidative stress; in order to confirm whether the antioxidative stress effect of ART is related to PHB2-mediated autophagy, we examined the protein expression of prohibitin 2 (PHB2), TOMM20, p62, and the conversion of microtubule-associated protein light chain 3I (LC3I) to LC3II and found that the protein expression of PHB2, TOMM20, p62, and LC3II/LC3I was significantly correlated with OGD/R treatment. The colocalization of PHB2 and LC3, TOMM20, and LC3 was reduced after OGD/R treatment, and ART reversed this change. After silencing PHB2, the protective effect of ART against OGD/R-induced oxidative stress injury was reduced, the protein expressions of PHB2, TOMM20 and LC3II/LC3I and the colocalization of PHB2 and LC3, TOMM20, and LC3 were decreased. We used chloroquine to block the lysosomal pathway and found that ART increased the conversion of LC3I to LC3II, silencing PHB2 which inhibited the conversion of LC3I to LC3II, and impaired mitophagy. Our findings showed that ART attenuated OGD/R-induced oxidative stress damage through PHB2-mediated mitophagy. To the current knowledge, our study is the first to demonstrate that ART attenuates OGD/R-induced oxidative stress injury through PHB2-mediated autophagy in the human neuroblastoma SH-SY5Y cell line, which provided new insights into the treatment of OGD/R injury.

Dataset Information

Inhibition of SIRT2 by Targeting GSK3?-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells.

Publications

Inhibition of SIRT2 by Targeting GSK3β-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells.

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