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SARS-CoV-2 membrane protein causes the mitochondrial apoptosis and pulmonary edema via targeting BOK

Yang Yang1,2,3, Yongjian Wu1,2,3, Xiaojun Meng1

  • 1Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China.

Cell Death and Differentiation
|January 13, 2022
PubMed

Insights

The SARS-CoV-2 membrane protein triggers lung cell apoptosis by stabilizing BOK, a protein that induces programmed cell death. This mechanism exacerbates lung injury in COVID-19 and suggests BOK as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Virology
  • Pathogenesis

Background:

  • COVID-19 deaths often result from lung edema caused by SARS-CoV-2 disrupting the lung alveolo-capillary barrier via pulmonary cell apoptosis.
  • The precise molecular mechanisms driving SARS-CoV-2's proapoptotic effects remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which SARS-CoV-2 induces apoptosis in lung epithelial cells.
  • To investigate the role of the SARS-CoV-2 membrane (M) protein in this apoptotic process and its potential therapeutic implications.

Main Methods:

  • Investigated the interaction between SARS-CoV-2 M protein and B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) protein.
  • Utilized CRISPR/Cas9 to knockout BOK and assessed cellular apoptosis.
  • Employed recombinant lentivirus expressing M protein for in vivo mouse lung infection studies.
  • Examined the role of BOK domains and BAX/BAK in M protein-induced apoptosis.

Main Results:

  • SARS-CoV-2 M protein induces mitochondrial apoptosis in lung epithelial cells by stabilizing BOK through inhibition of ubiquitination.
  • M protein promotes BOK translocation to mitochondria, requiring the M protein's endodomain for interaction.
  • BOK knockout cells showed resistance to M protein-induced apoptosis; BOK knockdown in vivo improved lung edema in infected mice.
  • M protein-induced apoptosis via BOK occurs independently of BAX and BAK, with the BH2 domain of BOK being crucial for M protein interaction and proapoptosis.

Conclusions:

  • SARS-CoV-2 M protein activates a BOK-dependent apoptotic pathway, contributing to lung injury in COVID-19.
  • The M protein-BOK interaction represents a novel proapoptotic mechanism in SARS-CoV-2 pathogenesis.
  • Targeting the M protein-BOK interaction may offer potential therapeutic strategies for treating COVID-19-associated lung injury.

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