RT Journal Article
SR Electronic
T1 The Spike protein of SARS-CoV-2 impairs lipid metabolism and increases susceptibility to lipotoxicity: implication for a role of Nrf2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.19.488806
DO 10.1101/2022.04.19.488806
A1 Vi Nguyen
A1 Yuping Zhang
A1 Chao Gao
A1 Xiaoling Cao
A1 Yan Tian
A1 Wayne Carver
A1 Hippokratis Kiaris
A1 Taixing Cui
A1 Wenbin Tan
YR 2022
UL http://biorxiv.org/content/early/2022/04/19/2022.04.19.488806.abstract
AB Background/objectives Coronavirus disease 2019 (COVID-19) patients exhibit 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.Methods A Spike cell line in HEK293 was generated 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.Results As compared with controls, the Spike cells showed a significant increase in lipid depositions on cell membranes as well as dysregulation of expression of a panel of molecules involved 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.Conclusions 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.HighlightsThe Spike protein increases lipid deposition in host cell membranesThe Spike protein impairs lipid metabolic and autophagic pathwaysThe Spike protein exaggerates PA-induced lipotoxicity in host cells via ferroptosisNrf2 inhibitor Trigonelline can mitigate the Spike protein-induced necrosisCompeting Interest StatementThe authors have declared no competing interest.