Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.
Department of General Surgery, The 3rd Xiangya Hospital of Central South University, Changsha 410013, China.
Cells. 2022 Jun 14;11(12):1916. doi: 10.3390/cells11121916.
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.
新型冠状病毒病 2019（COVID-19）患者表现出脂质代谢改变，但机制尚不清楚。在这项研究中，我们旨在研究严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的刺突蛋白是否会损害宿主细胞中的脂质代谢。我们使用携带刺突基因表达盒的 pcDNA 载体在 HEK293 中生成了 Spike 细胞系。使用空 pcDNA 载体生成了对照细胞系。研究了与脂质代谢、自噬和铁死亡途径相关的基因表达谱。使用棕榈酸（PA）过载来评估脂毒性诱导的坏死。与对照组相比，Spike 细胞在细胞膜中显示出明显的脂质沉积增加以及涉及脂质代谢、自噬和铁死亡的一系列分子的表达失调。Spike 细胞对 PA 表现出核因子红细胞 2 相关因子 2（Nrf2）的上调，Nrf2 是一种多功能转录因子。此外，与对照细胞相比，Spike 细胞在 PA 诱导的脂毒性下表现出时间和剂量依赖性的增加的坏死，通过铁死亡，这可以通过 Nrf2 抑制剂三叶草素来减弱。我们得出结论，刺突蛋白会损害宿主细胞中的脂质代谢和自噬途径，导致通过铁死亡增加对脂毒性的易感性，这可以通过 Nrf2 抑制剂来抑制。这些数据还表明 Nrf2 在 Spike 诱导的脂质代谢损伤中起核心作用。
