The Journal of Experimental Medicine
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Published online 2 October 2000.
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© The Rockefeller University Press, 0022-1007/2000/10/1035/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 7, October 2, 2000 1035-1046

Original Article

Salmonella-Induced Caspase-2 Activation in Macrophages: A Novel Mechanism in Pathogen-Mediated Apoptosis



Veronika Jesenbergera, Katarzyna J. Procyka, Junying Yuanc, Siegfried Reipertb, and Manuela Baccarinia

a Department of Cell- and Microbiology, Institute of Microbiology and Genetics,
b Department of Molecular Cell Biology, Institute of Biochemistry and Molecular Cell Biology, Vienna Biocenter, 1030 Vienna, Austria
c Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115
Dept. of Cell- and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Dr-Bohrgasse 9, 1030 Vienna, Austria.431-4277-9546431-4277-54607

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.

Key Words: monocytes/macrophages • cell death • proteases • natural immunity • bacteria

Abbreviations used in this paper: SPI-1, Salmonella pathogenicity island 1; wt, wild type.

K.J. Procyk's present address is Protein Phosphorylation Lab, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.

© 2000 The Rockefeller University Press


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