Salmonella-induced caspase-2 activation in macrophages: a novel mechanism in pathogen-mediated apoptosis.
The enterobacterial pathogen Salmonella induces phagocyte apoptosis in vitro and in vivo. These bacteria use a specialized type III secretion system to export a virulence factor, SipB, which directly activates the host's apoptotic machinery by targeting caspase-1. Caspase-1 is not involved in most apoptotic processes but plays a major role in cytokine maturation. We show that caspase-1-deficient macrophages undergo apoptosis within 4-6 h of infection with invasive bacteria. This process requires SipB, implying that this protein can initiate the apoptotic machinery by regulating components distinct from caspase-1. Invasive Salmonella typhimurium targets caspase-2 simultaneously with, but independently of, caspase-1. Besides caspase-2, the caspase-1-independent pathway involves the activation of caspase-3, -6, and -8 and the release of cytochrome c from mitochondria, none of which occurs during caspase-1-dependent apoptosis. By using caspase-2 knockout macrophages and chemical inhibition, we establish a role for caspase-2 in both caspase-1-dependent and -independent apoptosis. Particularly, activation of caspase-1 during fast Salmonella-induced apoptosis partially relies on caspase-2. The ability of Salmonella to induce caspase-1-independent macrophage apoptosis may play a role in situations in which activation of this protease is either prevented or uncoupled from the induction of apoptosis.
Jesenberger
V
V
Department of Cell- and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Vienna, Austria.
Procyk
K J
KJ
Yuan
J
J
Reipert
S
S
Baccarini
M
M
D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D053143:Caspase 2; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D008264:Macrophages / Q000166:cytology* / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D012486:Salmonella typhimurium / Q000502:physiology*
D001426:Bacterial Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; C094579:invasion protein B, Salmonella typhimurium; D053143:Caspase 2; D020169:Caspases; D020170:Caspase 1