tetano
Editor, Senior Moderator
Cell Death Differ
. 2022 Jan 12.
doi: 10.1038/s41418-022-00928-x. Online ahead of print.
SARS-CoV-2 membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK
Yang Yang[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yongjian Wu[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Xiaojun Meng[SUP] 1 [/SUP], Zhiying Wang[SUP] 1 [/SUP], Muhammad Younis[SUP] 1 [/SUP], Ye Liu[SUP] 1 [/SUP], Peihui Wang[SUP] 4 [/SUP], Xi Huang[SUP] 5 6 7 [/SUP]
Affiliations
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.
. 2022 Jan 12.
doi: 10.1038/s41418-022-00928-x. Online ahead of print.
SARS-CoV-2 membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK
Yang Yang[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yongjian Wu[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Xiaojun Meng[SUP] 1 [/SUP], Zhiying Wang[SUP] 1 [/SUP], Muhammad Younis[SUP] 1 [/SUP], Ye Liu[SUP] 1 [/SUP], Peihui Wang[SUP] 4 [/SUP], Xi Huang[SUP] 5 6 7 [/SUP]
Affiliations
- PMID: 35022571
- DOI: 10.1038/s41418-022-00928-x
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.