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Protochlamydia Induces Apoptosis of Human HEp-2 Cells through Mitochondrial Dysfunction Mediated by Chlamydial Protease-Like Activity Factor

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Title: Protochlamydia Induces Apoptosis of Human HEp-2 Cells through Mitochondrial Dysfunction Mediated by Chlamydial Protease-Like Activity Factor
Authors: Matsuo, Junji Browse this author →KAKEN DB
Nakamura, Shinji Browse this author →KAKEN DB
Ito, Atsushi Browse this author
Yamazaki, Tomohiro Browse this author
Ishida, Kasumi Browse this author
Hayashi, Yasuhiro Browse this author →KAKEN DB
Yoshida, Mitsutaka Browse this author
Takahashi, Kaori Browse this author
Sekizuka, Tsuyoshi Browse this author
Takeuchi, Fumihiko Browse this author
Kuroda, Makoto Browse this author
Nagai, Hiroki Browse this author
Hayashida, Kyoko Browse this author
Sugimoto, Chihiro Browse this author →KAKEN DB
Yamaguchi, Hiroyuki Browse this author →KAKEN DB
Issue Date: 11-Feb-2013
Publisher: Public Library of Science
Journal Title: PLoS One
Volume: 8
Issue: 2
Start Page: e56005
Publisher DOI: 10.1371/journal.pone.0056005
Abstract: Obligate amoebal endosymbiotic bacterium Protochlamydia with ancestral pathogenic chlamydial features evolved to survive within protist hosts, such as Acanthamoba, 0.7-1.4 billion years ago, but not within vertebrates including humans. This observation raises the possibility that interactions between Protochlamydia and human cells may result in a novel cytopathic effect, leading to new insights into host-parasite relationships. Previously, we reported that Protochlamydia induces apoptosis of the immortalized human cell line, HEp-2. In this study, we attempted to elucidate the molecular mechanism underlying this apoptosis. We first confirmed that, upon stimulation with the bacteria, poly (ADP-ribose) polymerase (PARP) was cleaved at an early stage in HEp-2 cells, which was dependent on the amount of bacteria. A pan-caspase inhibitor and both caspase-3 and -9 inhibitors similarly inhibited the apoptosis of HEp-2 cells. A decrease of the mitochondrial membrane potential was also confirmed. Furthermore, lactacystin, an inhibitor of chlamydial protease-like activity factor (CPAF), blocked the apoptosis. Cytochalasin D also inhibited the apoptosis, which was dependent on the drug concentration, indicating that bacterial entry into cells was required to induce apoptosis. Interestingly, Yersinia type III inhibitors (ME0052, ME0053, and ME0054) did not have any effect on the apoptosis. We also confirmed that the Protochlamydia used in this study possessed a homologue of the cpaf gene and that two critical residues, histidine-101 and serine-499 of C. trachomatis CPAF in the active center, were conserved. Thus, our results indicate that after entry, Protochlamydia-secreted CPAF induces mitochondrial dysfunction with a decrease of the membrane potential, followed by caspase-9, caspase-3 and PARP cleavages for apoptosis. More interestingly, because C. trachomatis infection can block the apoptosis, our finding implies unique features of CPAF between pathogenic and primitive chlamydiae.
Type: article
Appears in Collections:保健科学院・保健科学研究院 (Graduate School of Health Sciences / Faculty of Health Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 山口 博之

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