2. Academic Validation
  3. Bacterial effector OspB hijacks apoptosis through peptide-bond recombination of BH3 domain proteins

Bacterial effector OspB hijacks apoptosis through peptide-bond recombination of BH3 domain proteins

  • Cell Host Microbe. 2025 Oct 22:S1931-3128(25)00413-5. doi: 10.1016/j.chom.2025.09.018.
Yue Shao 1,  Dandan Yang 1,  Xinguang Gao 1,  Minghui Wang 1,  Liyuan Meng 1,  Tianye Niu 1,  Li Xia 1,  Jingjin Ding 2,  Feng Shao 3,  Yue Xu 4
Affiliations

Affiliations

  • 1 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 3 National Institute of Biological Sciences, Beijing, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
  • 4 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xuyue@shsmu.edu.cn.
PMID: 41135509 DOI: 10.1016/j.chom.2025.09.018
Abstract

Apoptosis is a defense response involving key players, including BH3-only proteins that engage Bcl-2 Family proteins Bax and Bak, initiating mitochondrial outer membrane permeabilization and Caspase activation. However, Shigella flexneri subverts these death pathways to promote Infection. Here, we identify the Shigella type III secretion system effector OspB as an enzyme that suppresses Apoptosis by targeting Bax and Bak. OspB recognizes Bax/Bak in complex with BH3-only activators, notably tBID, and catalyzes a peptide-bond recombination between their BH3 domains. This reaction generates chimeric proteins comprising the N-terminal BH3-only segment fused to the C-terminal region of Bax or Bak, irreversibly inhibiting protein function and thus mitochondrial outer membrane permeabilization and Apoptosis. OspB-mediated Apoptosis inhibition enhances S. flexneri virulence in vivo. Homologous effectors with similar catalytic activity are conserved across various Bacterial species. These findings reveal a Bacterial strategy for Apoptosis inhibition via remodeling of Bcl-2 Family proteins, offering avenues for therapeutic intervention.

Keywords

BCL-2 family proteins; BH3 domain; OspB; Shigella flexneri; T3SS; apoptosis; host-pathogen interaction; peptide-bond recombination.

Figures
Products