Calpain Activation by the Shigella flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium's Epithelial Niche

Abstract

The enteropathogen Shigella flexneri invades epithelial cells, leading to inflammation and tissue destruction. We report that Shigella infection of epithelial cells induces an early genotoxic stress, but the resulting p53 response and cell death are impaired due to the bacterium's ability to promote p53 degradation, mainly through calpain protease activation. Calpain activation is promoted by the Shigella virulence effector VirA and dependent on calcium flux and the depletion of the endogenous calpain inhibitor calpastatin. Further, although VirA-induced calpain activity is critical for regulating cytoskeletal events driving bacterial uptake, calpain activation ultimately leads to necrotic cell death, thereby restricting Shigella intracellular growth. Therefore, calpains work at multiple steps in regulating Shigella pathogenesis by disrupting the p53-dependent DNA repair response early during infection and regulating both formation and ultimate death of the Shigella epithelial replicative niche.

Listeria monocytogenesinduces host DNA damage and delays the host cell cycle to promote infection

“…Producers of genotoxins, such as cytolethal distending toxins or colibactin, cause direct DNA injury, inducing genomic instability and ultimately cell cycle arrest and cell death. 7,[35][36][37] Other bacteria, such as C. trachomatis, 19 Pseudomonas aeruginosa, 38 H. pylori, 12 N. gonorrhoeae 39 , and Shigella flexneri, 40 induce the production of reactive oxygen species (ROS) that promote oxidative DNA damage, thereby increasing γH2A.X levels and impairing host DNA repair mechanisms. To our knowledge, Lm does not express toxins that can directly injure host DNA.…”

When our genome is targeted by pathogenic bacteria

“…Bacteria replicate in infected cells, triggering inflammation and tissue destruction. This pathogen utilizes mechanisms different from those used by E. coli and H. pylori, and maintains a live epithelial cellular reservoir, despite DNA break production [60]. S. flexneri induces ATM activation and H2AX phosphorylation, but these signals do not result in p53 stabilization, followed by rapid cell death (Fig.…”

“…In contrast, this bacterium activates cellular proteases of the calpain family, in a VirA virulence factor-dependent manner. Calpains then promote p53 degradation, leading to the inhibition of the p53-dependent pro-apoptotic pathway [60,61]. Bacteria highly proliferate in infected cells before cell death through necrosis [61].…”

The Inside Story of Shigella Invasion of Intestinal Epithelial Cells

“…Increase in cytosolic calcium concentration leads to the activation of protease, such as calpain, and mitochondrial damage leads to the death of infected cells via a necrotic pathway (Fig. 3) (Carneiro et al 2009;Bergounioux et al 2012).…”