title: Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis.
abstract: Bacterial pathogens modulate host cell apoptosis to establish a successful infection. Pore-forming toxins (PFTs) secreted by pathogenic bacteria are major virulence factors and have been shown to induce various forms of cell death in infected cells. Here we demonstrate that the highly conserved caspase-2 is required for PFT-mediated apoptosis. Despite being the second mammalian caspase to be identified, the role of caspase-2 during apoptosis remains enigmatic. We show that caspase-2 functions as an initiator caspase during Staphylococcus aureus α-toxin- and Aeromonas aerolysin-mediated apoptosis in epithelial cells. Downregulation of caspase-2 leads to a strong inhibition of PFT-mediated apoptosis. Activation of caspase-2 is PIDDosome-independent, and endogenous caspase-2 is recruited to a high-molecular-weight complex in α-toxin-treated cells. Interestingly, prevention of PFT-induced potassium efflux inhibits the formation of caspase-2 complex, leading to its inactivation, thus resisting apoptosis. These results revealed a thus far unknown, obligatory role for caspase-2 as an initiator caspase during PFT-mediated apoptosis.
authors.affiliation: Emmy Noether Group of the DFG, Institute of Biochemistry II, Goethe University, Frankfurt, Germany.
authors.forename: Gergely
authors.initials: G
authors.lastname: Imre
authors.forename: Jan
authors.initials: J
authors.lastname: Heering
authors.forename: Armelle-Natsuo
authors.initials: AN
authors.lastname: Takeda
authors.forename: Matthias
authors.initials: M
authors.lastname: Husmann
authors.forename: Bernd
authors.initials: B
authors.lastname: Thiede
authors.forename: Dagmar Meyer
authors.initials: DM
authors.lastname: zu Heringdorf
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
authors.forename: Bhanu
authors.initials: B
authors.lastname: Sinha
authors.forename: Volker
authors.initials: V
authors.lastname: Dötsch
authors.forename: Krishnaraj
authors.initials: K
authors.lastname: Rajalingam
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001427:Bacterial Toxins / Q000494:pharmacology; D053143:Caspase 2 / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015536:Down-Regulation; D006367:HeLa Cells; D006460:Hemolysin Proteins / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins / Q000494:pharmacology; D011188:Potassium / Q000032:analysis / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D052899:Pore Forming Cytotoxic Proteins; C021091:staphylococcal alpha-toxin; C032676:aerolysin; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases; D011188:Potassium