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

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Abstract
The invasive enteropathogenic bacteriumShigella flexneriactivates 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 byShigella. 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 blockedShigella-induced apoptosis by 95% at a concentration of 1 μM. Conversely, peptide aldehyde and peptide vinylsulfone proteasome inhibitors had little effect onShigella-mediated cytotoxicity. Both AAF-cmk and lactacystin prevented the maturation of pro-caspase-1 and its substrate pro-interleukin 1β inShigella-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 ofShigellato 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.

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