细胞凋亡
线粒体
细胞生物学
化学
自噬
程序性细胞死亡
Bcl-2家族
内质网
细胞色素c
线粒体分裂
膜间隙
线粒体内膜
生物
线粒体膜转运蛋白
线粒体通透性转换孔
作者
Yang Yang,Yongjian Wu,Xiaojun Meng,Zhiying Wang,Muhammad Younis,Yuan Liu,Pei-Hui Wang,Xi Huang
标识
DOI:10.1038/s41418-022-00928-x
摘要
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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