The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2.
The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2.
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作者：
冠状病毒病2019(新冠肺炎)患者出现脂代谢改变，但机制尚不清楚。本研究旨在探讨严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的Spike蛋白是否损害宿主细胞的脂代谢。我们利用携带Spike基因表达盒的pcDNA载体，在HEK293中建立了Spike细胞系。用空载体构建对照细胞系。研究了与脂代谢、自噬和铁性下垂途径相关的基因表达谱。用棕榈酸(PA)超负荷来评价脂毒性所致的坏死。与对照组相比，刺突细胞显示细胞膜中的脂质沉积显著增加，以及一组涉及脂代谢、自噬和铁下垂的分子的表达失调。多能转录因子核因子红系2相关因子2(Nrf2)是一种多功能转录因子。此外，与对照细胞相比，在PA诱导的脂毒性作用下，Spike细胞通过铁下垂以时间和剂量依赖的方式表现出更多的坏死，这可以被Nrf2抑制剂胡芦巴碱减弱。我们得出结论，Spike蛋白损害宿主细胞中的脂代谢和自噬途径，导致通过铁性下垂增加对脂毒性的敏感性，而铁性下垂可以被Nrf2抑制剂抑制。这一数据还表明，Nrf2在Spike诱导的脂质代谢损伤中发挥了核心作用。
Coronavirus disease 2019 (COVID-19) patients show lipid metabolic alterations, but the mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in host cells. We generated a Spike cell line in HEK293 using the pcDNA vector carrying the Spike gene expression cassette. A control cell line was generated using the empty pcDNA vector. Gene expression profiles related to lipid metabolic, autophagic, and ferroptotic pathways were investigated. Palmitic acid (PA)-overload was used to assess lipotoxicity-induced necrosis. As compared with controls, the Spike cells showed a significant increase in lipid depositions in cell membranes as well as dysregulation of expression of a panel of molecules involving lipid metabolism, autophagy, and ferroptosis. The Spike cells showed an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a multifunctional transcriptional factor, in response to PA. Furthermore, the Spike cells exhibited increased necrosis in response to PA-induced lipotoxicity compared to control cells in a time- and dose-dependent manner via ferroptosis, which could be attenuated by the Nrf2 inhibitor trigonelline. We conclude that the Spike protein impairs lipid metabolic and autophagic pathways in host cells, leading to increased susceptibility to lipotoxicity via ferroptosis which can be suppressed by a Nrf2 inhibitor. This data also suggests a central role of Nrf2 in Spike-induced lipid metabolic impairments.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
脂质筏参与SARS-COV进入Vero E6细胞。
DOI：
10.1016/j.bbrc.2008.02.023
发表时间：
2008-05-02
影响因子：
3.1
作者：
Lu Y;Liu DX;Tam JP
通讯作者：
Tam JP
影响因子：
3.7
作者：
Li G;Du L;Cao X;Wei X;Jiang Y;Lin Y;Nguyen V;Tan W;Wang H
通讯作者：
Wang H
影响因子：
28.3
作者：
Gorbalenya, Alexander E.;Baker, Susan C.;Ziebuhr, John
通讯作者：
Ziebuhr, John
影响因子：
4.6
作者：
Runwal, Gautam;Stamatakou, Eleanna;Rubinsztein, David C.
通讯作者：
Rubinsztein, David C.