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Published online July 14, 2008
doi:10.1083/jcb.200804023
The Journal of Cell Biology, Vol. 182, No. 1, 117-127
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Paschen et al.
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Article

 Cytopathicity of Chlamydia is largely reproduced by expression of a single chlamydial protease

Stefan A. Paschen1, Jan G. Christian1, Juliane Vier1, Franziska Schmidt1, Axel Walch2, David M. Ojcius3, and Georg Häcker1

1 Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, D-81675 Munich, Germany
2 Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), D-85764 Neuherberg, Germany
3 School of Natural Sciences, University of California, Merced, Merced, CA 95344

Correspondence to Georg Häcker: hacker{at}lrz.tum.de

Chlamydiae replicate in a vacuole within epithelial cells and commonly induce cell damage and a deleterious inflammatory response of unknown molecular pathogenesis. The chlamydial protease-like activity factor (CPAF) translocates from the vacuole to the cytosol, where it cleaves several cellular proteins. CPAF is synthesized as an inactive precursor that is processed and activated during infection. Here, we show that CPAF can be activated in uninfected cells by experimentally induced oligomerization, reminiscent of the activation mode of initiator caspases. CPAF activity induces proteolysis of cellular substrates including two novel targets, cyclin B1 and PARP, and indirectly results in the processing of pro-apoptotic BH3-only proteins. CPAF activation induces striking morphological changes in the cell and, later, cell death. Biochemical and ultrastructural analysis of the cell death pathway identify the mechanism of cell death as nonapoptotic. Active CPAF in uninfected human cells thus mimics many features of chlamydial infection, implicating CPAF as a major factor of chlamydial pathogenicity, Chlamydia-associated cell damage, and inflammation.

Abbreviations used in this paper: AHT, anhydrotetracycline; CHX, cycloheximide; CK8, cytokeratin 8; CM, coumermycin; CPAF, chlamydial protease-like activity factor; gyrB-CPAF, N-FLAG-3xgyrB-CPAF construct; NB, novobiocin; PARP, poly (ADP-ribose) polymerase; TET, tetracycline; TNF, tumor necrosis factor; Tsp, tail-specific protease; zVAD, zVAD-fmk.


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