O-GlcN酰化通過調(diào)控STAT3和fox01介導(dǎo)H2O2誘導(dǎo)的細(xì)胞凋亡

2024年1月，復(fù)旦大學(xué)附屬華山醫(yī)院藥理學(xué)研究中心神經(jīng)內(nèi)科腦科學(xué)研究所教育部腦科學(xué)前沿中心醫(yī)學(xué)神經(jīng)生物學(xué)國家重點(diǎn)實(shí)驗(yàn)室基礎(chǔ)醫(yī)學(xué)院；中國醫(yī)學(xué)科學(xué)院成癮記憶研究室，（1 School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai 200032, China and 2 Research Unit of Addiction Memory, Chinese Academy of Medical Sciences(2021RU009), Shanghai 200032, China ）Lan Ma1,2 and Fei-fei Wang1,2團(tuán)隊(duì)在

《acta pharmacologica sinica》上發(fā)表論文：

“O-GlcNAcylation mediates H₂O₂-induced apoptosis through regulation of STAT3 and FOXO1”

“O-GlcN酰化通過調(diào)控STAT3和fox01介導(dǎo)H₂O₂誘導(dǎo)的細(xì)胞凋亡”

Abstract：

The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H2O2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H2O2-induced apoptosis,

respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished

OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H2O2-treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H2O2-induced apoptosis of N2a cells.

摘要：

O-linked-β- n -乙酰氨基葡萄糖(O-GlcNAc)糖基化(o - glcnac酰化)是一種關(guān)鍵的翻譯后修飾，將外部刺激與細(xì)胞內(nèi)信號轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)偶聯(lián)。然而，o - glcn酰化在氧化應(yīng)激誘導(dǎo)的細(xì)胞凋亡中的關(guān)鍵蛋白靶點(diǎn)仍有待闡明。在這里，我們發(fā)現(xiàn)H2O2處理抑制o - glcn酰化，損害細(xì)胞活力，增加裂解caspase 3，加速神經(jīng)母細(xì)胞瘤N2a細(xì)胞的凋亡。O-GlcNAc轉(zhuǎn)移酶(OGT)抑制劑OSMI-1或O-GlcNAcase (OGA)抑制劑Thiamet-G分別增強(qiáng)或抑制h2o2誘導(dǎo)的細(xì)胞凋亡。OSMI-1抑制了總蛋白和磷酸化蛋白水平以及轉(zhuǎn)錄因子3 (STAT3)和叉頭盒蛋白O1 (FOXO1)的啟動(dòng)子活性。相反，過表達(dá)OGT或用Thiamet-G處理會(huì)增加STAT3和fox01的總蛋白水平。STAT3或FOXO1過表達(dá)可消除osmi -1誘導(dǎo)的細(xì)胞凋亡。而在H₂O₂處理的細(xì)胞中，OGT和Thiamet-G的抗凋亡作用通過下調(diào)內(nèi)源性STAT3或fox01的表達(dá)或活性而被消除。這些結(jié)果表明STAT3或fox01是參與h2o2誘導(dǎo)的N2a細(xì)胞凋亡的o - glcnac酰化的潛在靶點(diǎn)。

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