title: 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.
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Département de Biologie Cellulaire et Infection, Institut Pasteur, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bergounioux
authors.forename: Ruben
authors.initials: R
authors.lastname: Elisee
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Prunier
authors.forename: Françoise
authors.initials: F
authors.lastname: Donnadieu
authors.forename: Brice
authors.initials: B
authors.lastname: Sperandio
authors.forename: Philippe
authors.initials: P
authors.lastname: Sansonetti
authors.forename: Laurence
authors.initials: L
authors.lastname: Arbibe
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology*; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012763:Shigella flexneri / Q000254:growth & development / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D037521:Virulence Factors / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C533229:VirA protein, Shigella flexneri; D037521:Virulence Factors; C033668:calpastatin; D007770:L-Lactate Dehydrogenase; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D002154:Calpain