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Infection and Immunity
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MOLECULAR AND CELLULAR PATHOGENESIS

Tripeptidyl Peptidase II Promotes Maturation of Caspase-1 in Shigella flexneri-Induced Macrophage Apoptosis

Hubert Hilbi, Robyn J. Puro, Arturo Zychlinsky
Hubert Hilbi
The Skirball Institute, Department of Microbiology and Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016
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Robyn J. Puro
The Skirball Institute, Department of Microbiology and Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016
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Arturo Zychlinsky
The Skirball Institute, Department of Microbiology and Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016
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DOI: 10.1128/IAI.68.10.5502-5508.2000
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ABSTRACT

The invasive enteropathogenic bacterium Shigella flexneri activates apoptosis in macrophages.Shigella-induced apoptosis requires caspase-1. We demonstrate here that tripeptidyl peptidase II (TPPII), a cytoplasmic, high-molecular-weight protease, participates in the apoptotic pathway triggered by Shigella. The TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) andclasto-lactacystin β-lactone (lactacystin), an inhibitor of both TPPII and the proteasome, protected macrophages fromShigella-induced apoptosis. AAF-cmk was more potent than lactacystin and irreversibly blocked Shigella-induced apoptosis by 95% at a concentration of 1 μM. Conversely, peptide aldehyde and peptide vinylsulfone proteasome inhibitors had little effect on Shigella-mediated cytotoxicity. Both AAF-cmk and lactacystin prevented the maturation of pro-caspase-1 and its substrate pro-interleukin 1β in Shigella-infected macrophages, indicating that TPPII is upstream of caspase-1. Neither of these compounds directly inhibited caspase-1. AAF-cmk and lactacystin did not impair macrophage phagocytosis or the ability of Shigellato escape the macrophage phagosome. TPPII was also found to be involved in apoptosis induced by ATP and the protein kinase inhibitor staurosporine. We propose that TPPII participates in apoptotic pathways.

  • Copyright © 2000 American Society for Microbiology
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Tripeptidyl Peptidase II Promotes Maturation of Caspase-1 in Shigella flexneri-Induced Macrophage Apoptosis
Hubert Hilbi, Robyn J. Puro, Arturo Zychlinsky
Infection and Immunity Oct 2000, 68 (10) 5502-5508; DOI: 10.1128/IAI.68.10.5502-5508.2000

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Tripeptidyl Peptidase II Promotes Maturation of Caspase-1 in Shigella flexneri-Induced Macrophage Apoptosis
Hubert Hilbi, Robyn J. Puro, Arturo Zychlinsky
Infection and Immunity Oct 2000, 68 (10) 5502-5508; DOI: 10.1128/IAI.68.10.5502-5508.2000
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KEYWORDS

apoptosis
Caspase 1
macrophages
Serine Endopeptidases
Shigella flexneri

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