Abstract
Deaths caused by coronavirus disease 2019 (COVID-19) are largely due to the lungs edema resulting from the disruption of the lung alveolo-capillary barrier, induced by SARS-CoV-2-triggered pulmonary cell apoptosis. However, the molecular mechanism underlying the proapoptotic role of SARS-CoV-2 is still unclear. Here, we revealed that SARS-CoV-2 membrane (M) protein could induce lung epithelial cells mitochondrial apoptosis. Notably, M protein stabilized B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) via inhibiting its ubiquitination and promoted BOK mitochondria translocation. The endodomain of M protein was required for its interaction with BOK. Knockout of BOK by CRISPR/Cas9 increased cellular resistance to M protein-induced apoptosis. BOK was rescued in the BOK-knockout cells, which led to apoptosis induced by M protein. M protein induced BOK to trigger apoptosis in the absence of BAX and BAK. Furthermore, the BH2 domain of BOK was required for interaction with M protein and proapoptosis. In vivo M protein recombinant lentivirus infection induced caspase-associated apoptosis and increased alveolar-capillary permeability in the mouse lungs. BOK knockdown improved the lung edema due to lentivirus-M protein infection. Overall, M protein activated the BOK-dependent apoptotic pathway and thus exacerbated SARS-CoV-2 associated lung injury in vivo. These findings proposed a proapoptotic role for M protein in SARS-CoV-2 pathogenesis, which may provide potential targets for COVID-19 treatments.
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Data availability statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank Dr. Li Huiyan for providing plentiCRISPR v2 and pLVX-nCoV-M-mCherry.
Funding
This work was supported by grants from the National Natural Science Foundation of China (31470877), the National Science and Technology Key Projects for Major Infectious Diseases (2017ZX10302301-002), the Support Scheme of Guangzhou for Leading Talents in Innovation and Entrepreneurship (No.2017004), the Guangdong Scientific and Technological Research Project for Prevention and Treatment of COVID-19 (2020A111128022, 2020B111112003), the Guangdong Scientific and Technological Research Special Fund for COVID-19 (202020012612200001), the Zhuhai Scientific and Technological Research Project for COVID-19 containment (ZH22036302200029PWC), the Zhuhai Industrial Technological Research and Development Project for Prevention and Treatment of COVID-19 (ZH22046301200018PWC), the Three Major Scientific Research Projects of Sun Yat-sen University (20200326236) (X.H.), the Science and Technology Planning Project of Guangzhou (201704020226 and 201604020006), and Development Project of Foshan Fourth People’s Hospital (FSSYKF-2020003, FSSYKF-2020017).
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YY, WYJ, and HX conceptualized study. WYJ, YY, MXJ and WZY collected, analyzed the data and edited the manuscript. All co-authors made comments to the manuscript.
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Our studies did not include human participants, human data or human tissue. The animal studies were approved by the Ethics Committee of Sun-Yat Sen University (No.00109), in accordance with UK Animals (Scientific Procedures) Act 1986.
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Yang, Y., Wu, Y., Meng, X. et al. SARS-CoV-2 membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK. Cell Death Differ 29, 1395–1408 (2022). https://doi.org/10.1038/s41418-022-00928-x
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DOI: https://doi.org/10.1038/s41418-022-00928-x
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