Salmonella Effector SpvB Inhibits NF-κB Activity via KEAP1-Mediated Downregulation of IKKβ

Bacterial pathogens have a broad arsenal of genes that are tightly regulated and coordinated to facilitate adaptation to alter host inflammatory response and prolong intracellular bacterial survival. Salmonella enterica serovar Typhimurium utilizes a type III secretion system (T3SS) to deliver effector molecules into host cells and regulate signal transduction pathways such as NF-kappa B, thereby resulting in salmonellosis. SpvB, a pSLT-encoded cytotoxic protein secreted by Salmonella pathogenicity island-2 T3SS, is associated with enhanced Salmonella survival and intracellular replication. In this report, we characterized the effects of SpvB on NF-kappa B signaling pathway. We showed that SpvB has a potent and specific ability to prevent NF-kappa B activation by targeting I kappa B kinase beta (IKK beta). Previous studies from our laboratory showed that SpvB decreases Nrf2 through its C-terminal domain. Here we further demonstrated that KEAP1, a cytoplasmic protein that interacts with Nrf2 and mediates its proteasomal degradation, is involved in SpvB-induced downregulation of IKK beta expression and phosphorylation. Reduction of KEAP1 by small-interfering RNA prevented the suppression of IKK beta and its phosphorylation mediated by SpvB. These findings revealed a novel mechanism by which Salmonella modulates NF-kappa B activity to ultimately facilitate intracellular bacterial survival and proliferation and delay host immune response to establish infection.

Automated summary

This study characterized the effects of SpvB on the NF-κB signaling pathway, revealing that SpvB inhibits NF-κB activation by targeting IKKβ and involving KEAP1. These findings uncover a novel mechanism by which Salmonella modulates NF-κB activity.