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

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.