SARS-CoV-2 membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK
Open accessAbstract
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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SARS-CoV-2 RNA has been detected in EVs.
“This is also true for SARS-CoV-2 RNA, which has been detected in EVs.”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [49]
The Methods sections describe qPCR and lentiviral particles, but do not report detecting SARS-CoV-2 RNA in extracellular vesicles. Searches for EVs, exosomes, and SARS-CoV-2 RNA in extracellular vesicles found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.76)
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Pathological findings of COVID-19 associated with acute respiratory distress syndrome
Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., Liu, S., Zhao, P., Liu, H., Zhu, L., et al. (2020) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(20)30076-x · Cited by 8,545 · see citing works
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Endothelial cell infection and endotheliitis in COVID-19
Varga, Z., Flammer, A. J., Steiger, P., Haberecker, M., Andermatt, R., Zinkernagel, A. S., Mehra, M. R., Schuepbach, R. A., Ruschitzka, F., & Moch, H. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30937-5 · Cited by 6,358 · see citing works
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
Gordon, D. E., Jang, G. M., Bouhaddou, M., Xu, J., Obernier, K., White, K. M., O’Meara, M. J., Rezelj, V. V., Guo, J. Z., Swaney, D. L., et al. (2020) · Nature · doi:10.1038/s41586-020-2286-9 · Cited by 4,405 · see citing works
Self-citationProapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988 · see citing works
Lindsten, T., Ross, A. J., King, A., Zong, W.-X., Rathmell, J. C., Shiels, H. A., Ulrich, E., Waymire, K. G., Mahar, P., Frauwirth, K., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00136-2 · Cited by 1,489 · see citing works
Snijder, E. J., Bredenbeek, P. J., Dobbe, J. C., Thiel, V., Ziebuhr, J., Poon, L. L. M., Guan, Y., Rozanov, M. N., Spaan, W. J. M., & Gorbalenya, A. E. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00865-9 · Cited by 1,188 · see citing works
Zamzami, N., Marchetti, P., Castedo, M., Zanin, C., Vayssière, J. L., Petit, P. X., & Kroemer, G. (1995) · The Journal of experimental medicine · doi:10.1084/jem.181.5.1661 · Cited by 1,166 · see citing works
The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice
Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., Wei, Q., Yu, P., Xu, Y., Qi, F., et al. (2020) · Nature · doi:10.1038/s41586-020-2312-y · Cited by 1,126 · see citing works
Chan, J., Zhang, A., Yuan, S.-F., Poon, V., Chan, C., Lee, A., Chan, W., Fan, Z., Tsoi, H.-W., Wen, L., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa325 · Cited by 1,034 · see citing works
Goshua, G., Pine, A., Meizlish, M. L., Chang, C.-H., Zhang, H.-M., Bahel, P., Baluha, A., Bar, N., Bona, R., Burns, A. J., et al. (2020) · The Lancet Haematology · doi:10.1016/s2352-3026(20)30216-7 · Cited by 918 · see citing works
Human Coronavirus: Host-Pathogen Interaction.
Fung, T. S., & Liu, D. X. (2019) · Annual Review of Microbiology · doi:10.1146/annurev-micro-020518-115759 · Cited by 907 · see citing works
Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2
Jiang, R.-D., Liu, M.-Q., Chen, Y., Shan, C., Zhou, Y.-W., Shen, X.-R., Li, Q., Zhang, L., Zhu, Y., Si, H.-R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.027 · Cited by 541 · see citing works
Zha, H., Aimé, C., Sato, T., & Reed, J. C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.13.7440 · Cited by 465 · see citing works
Katsura, H., Sontake, V., Tata, A., Kobayashi, Y., Edwards, C. E., Heaton, B. E., Konkimalla, A., Asakura, T., Mikami, Y., Fritch, E. J., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.10.005 · Cited by 416 · see citing works
Colmenero, I., Santonja, C., Alonso, M., Noguera‐Morel, L., Hernández‐Martín, A., Martínez, D. A., Wiesner, T., Rodriguez-Peralto, J., Requena, L., & Torrelo, A. (2020) · British Journal of Dermatology · doi:10.1111/bjd.19327 · Cited by 416 · see citing works
Patrolling Alveolar Macrophages Conceal Bacteria from the Immune System to Maintain Homeostasis
Neupane, A. S., Willson, M. E., Chojnacki, A. K., Castanheira, F. V. S., Morehouse, C. A., Carestia, A., Keller, A. E., Peiseler, M., DiGiandomenico, A., Kelly, M. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.020 · Cited by 351 · see citing works
Zheng, Y., Zhuang, M.-W., Han, L., Zhang, J., Nan, M.-L., Zhan, P., Kang, D., Liu, X., Gao, C., & Wang, P.-H. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00438-7 · Cited by 302 · see citing works
Self-citationBOK Is a Non-canonical BCL-2 Family Effector of Apoptosis Regulated by ER-Associated Degradation
Llambi, F., Wang, Y.-M., Victor, B., Yang, M., Schneider, D. M., Gingras, S., Parsons, M. J., Zheng, J. H., Brown, S. A., Pelletier, S., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.026 · Cited by 261 · see citing works
Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient
Yao, X.-H., He, Z.-C., Li, T., Zhang, H., Wang, Y., Mou, H., Guo, Q., Yu, S., Ding, Y., Liu, X., et al. (2020) · Cell Research · doi:10.1038/s41422-020-0318-5 · Cited by 215 · see citing works
BAX, BAK, and BOK: A Coming of Age for the BCL-2 Family Effector ProteinsPreprint
Moldoveanu, T., & Czabotar, P. E. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036319 · Cited by 182 · see citing works
A systemic and molecular study of subcellular localization of SARS-CoV-2 proteins
Zhang, J., Cruz‐Cosme, R., Zhuang, M., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00372-8 · Cited by 148 · see citing works
Lung Repair and Regeneration in ARDS
Villar, J., Zhang, H., & Slutsky, A. S. (2018) · CHEST Journal · doi:10.1016/j.chest.2018.10.022 · Cited by 143 · see citing works
Viruses and the Diversity of Cell Death
Danthi, P. (2016) · Annual Review of Virology · doi:10.1146/annurev-virology-110615-042435 · Cited by 141 · see citing works
Kushimoto, S., Taira, Y., Kitazawa, Y., Okuchi, K., Sakamoto, T., Ishikura, H., Endo, T., Yamanouchi, S., Tagami, T., Yamaguchi, J., et al. (2012) · Critical Care · doi:10.1186/cc11898 · Cited by 139 · see citing works
Intracellular localization of the BCL-2 family member BOK and functional implications
Echeverry, N., Bachmann, D., Ke, F., Strasser, A., Simon, H. U., & Kaufmann, T. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2013.10 · Cited by 137 · see citing works
Bi, H.-L., Zhang, X.-L., Zhang, Y., Xie, X., Xia, Y., Du, J., & Li, H. (2020) · Science Advances · doi:10.1126/sciadv.aax4826 · Cited by 105 · see citing works
Padhan, K., Minakshi, R., Towheed, A., & Jameel, S. (2008) · Journal of General Virology · doi:10.1099/vir.0.83665-0 · Cited by 103 · see citing works
Threshold of Lung Injury Required for the Appearance of Marrow‐Derived Lung Epithelia
Herzog, E. L., Arnam, J. V., Hu, B., & Krause, D. S. (2006) · Stem Cells · doi:10.1634/stemcells.2005-0579 · Cited by 100 · see citing works
Tan, K. S., Lim, R. L., Liu, J., Ong, H. H., Tan, V. J., Lim, H. F., Chung, K. F., Adcock, I. M., Chow, V. T. K., & Wang, D. Y. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00099 · Cited by 72 · see citing works
Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak
Einsele-Scholz, S., Malmsheimer, S., Bertram, K., Stehle, D., Johänning, J., Manz, M., Daniel, P. T., Gillissen, B. F., Schulze-Osthoff, K., & Essmann, F. (2016) · Journal of Cell Science · doi:10.1242/jcs.181727 · Cited by 65 · see citing works
Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis
Zheng, J. H., Grace, C. R., Guibao, C. D., McNamara, D. E., Llambi, F., Wang, Y., Chen, T., & Moldoveanu, T. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.04.060 · Cited by 57 · see citing works
Swine acute diarrhea syndrome coronavirus-induced apoptosis is caspase- and cyclophilin D- dependent
Zhang, J., Han, Y., Shi, H., Chen, J., Zhang, X., Wang, X., Zhou, L., Liu, J., Zhang, J., Ji, Z., et al. (2020) · Emerging Microbes & Infections · doi:10.1080/22221751.2020.1722758 · Cited by 56 · see citing works
Biological Mechanisms of COVID-19 Acute Respiratory Distress Syndrome
Matthay, M. A., Leligdowicz, A., & Liu, K. D. (2020) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202009-3629ed · Cited by 52 · see citing works
Plasma mediators in patients with severe COVID-19 cause lung endothelial barrier failure
Michalick, L., Weidenfeld, S., Grimmer, B., Fatykhova, D., Solymosi, P., Behrens, F., Dohmen, M., Brack, M. C., Schulz, S., Thomasch, E., et al. (2020) · European Respiratory Journal · doi:10.1183/13993003.02384-2020 · Cited by 50 · see citing works
Fernández‐Marrero, Y., Bleicken, S., Das, K. K., Bachmann, D., Kaufmann, T., & Garcia‐Saez, A. J. (2017) · The FEBS Journal · doi:10.1111/febs.14008 · Cited by 47 · see citing works
Epidermal Growth Factor receptor (EGFR) regulates mechanical ventilation–induced lung injury in mice
Bierman, A. M., Yerrapureddy, A., Reddy, N. M., et al. (2008) · Translational research · doi:10.1016/j.trsl.2008.10.004 · Cited by 43 · see citing works
Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak
Einsele‐Scholz, S., Malmsheimer, S., Bertram, K., et al. (2016) · Journal of Cell Science · doi:10.1242/jcs.193946 · Cited by 35 · see citing works
Yang, Y., Kuang, L., Li, L., Wu, Y., Zhong, B., & Huang, X. (2021) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiab400 · Cited by 34 · see citing works
Self-citationMED12 exerts an emerging role in actin-mediated cytokinesis via LIMK2/cofilin pathway in NSCLC
Xu, M., Wang, F., Li, G., et al. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1020-4 · Cited by 34 · see citing works
Coronavirus in human diseases: Mechanisms and advances in clinical treatment
Lin, P., Wang, M., Wei, Y., Kim, T., & Wei, X. (2020) · MedComm · doi:10.1002/mco2.26 · Cited by 31 · see citing works
Dawood, A. A. (2020) · Vacunas · doi:10.1016/j.vacun.2020.09.005 · Cited by 24 · see citing works
Stehle, D., Grimm, M., Einsele‐Scholz, S., Wanke, F., Johänning, J., Fischer, G., Gillissen, B. F., Schulze‐Osthoff, K., & Eßmann, F. (2018) · Scientific Reports · doi:10.1038/s41598-018-30603-6 · Cited by 20 · see citing works
Lai, C., Chan, Z., Yang, D., et al. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.06.003 · Cited by 20 · see citing works
Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2
Hekman, R. M., Hume, A. J., Goel, R. K., Abo, K. M., Huang, J., Blum, B. C., Werder, R. B., Suder, E. L., Paul, I., Phanse, S., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2020.12.028 · Cited by 19 · see citing works
Zhang, F., Ren, L., Zhou, S., Duan, P., Xue, J., Chen, H., Feng, Y., Yue, X., Yuan, P., Liu, Q., et al. (2019) · Medical Science Monitor · doi:10.12659/msm.913706 · Cited by 12 · see citing works
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Beetler, D. J., Di Florio, D. N., Bruno, K. A., Ikezu, T., March, K. L., Cooper, L. T., Wolfram, J., & Fairweather, D. (2023) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2022.101155 · Cited by 101 · see citing works
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- Authors
- Yang, Y., Wu, Y., Meng, X., Wang, Z., Younis, M., Liu, Y., Wang, P., & Huang, X.
- Affiliations
- Sun Yat-sen University (CN)
- Fifth Affiliated Hospital of Sun Yat-sen University (CN)
- Corresponding author
- Huang, Xi
- Venue
- Cell Death & Differentiation
- Published
- 2022-01-12
- Volume
- 29
- Issue
- 7
- Pages
- 1395-1408
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC8752586
- OpenAlex
- W4206515106
- Cited by
- 88
- References
- 46
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 29 · 2023: 22 · 2022: 14
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31470877)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, viral membrane proteins, BOK, mitochondrial apoptosis, pulmonary edema, lung injury, ubiquitination, mitochondrial translocation, cytochrome c release, caspase-9, Bcl-2 family proteins, alveolar-capillary permeability, lung epithelial cells, COVID-19 pathogenesis
- MeSH terms
- COVID-19, SARS-CoV-2, Coronavirus M Proteins, Animals, Edema, Mitochondria, Pulmonary Edema, Apoptosis, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, bcl-2-Associated X Protein, Mice
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