Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces apoptosis in nonproliferating macrophages by a phosphatase-independent mechanism.
نویسندگان
چکیده
Aggregatibacter actinomycetemcomitans strains that express cytolethal distending toxin (Cdt) are associated with localized aggressive periodontitis. However, the in vivo targets of Cdt in the human oral cavity have not been firmly established. Here, we demonstrate that A. actinomycetemcomitans Cdt kills proliferating and nonproliferating U937 monocytic cells at a comparable specific activity, approximately 1.5-fold lower than that against the Cdt-hypersensitive Jurkat T-cell line. Cdt functioned both as a DNase and a phosphatidylinositol 3-phosphate (PIP(3)) phosphatase, and these activities were distinguished by site-specific mutagenesis of the active site residues of CdtB. Using these mutants, we determined that the DNase activity of CdtB is required for cell cycle arrest and caspase-dependent induction of apoptosis in proliferating U937 cells. In contrast, Cdt holotoxin induced apoptosis by a mechanism independent of caspase- and apoptosis-inducing factor in nonproliferating U937 cells. Furthermore, apoptosis of nonproliferating U937 cells was unaffected by the Cdt mutant possessing reduced phosphatase activity or by the addition of a specific PIP(3) phosphatase inhibitor, suggesting that the induction of apoptosis is independent of phosphatase activity. These results indicate that Cdt intoxication of proliferating and nonproliferating U937 cells occurs by distinct mechanisms and suggest that macrophages may also be potential in vivo targets of Cdt.
منابع مشابه
Apoptosis in Nonproliferating Macrophages Cytolethal Distending Toxin Induces Aggregatibacter actinomycetemcomitans
متن کامل
Cytolethal distending toxin from Aggregatibacter actinomycetemcomitans induces DNA damage, S/G2 cell cycle arrest, and caspase- independent death in a Saccharomyces cerevisiae model.
Cytolethal distending toxin (CDT) is a bacterial toxin that induces G(2)/M cell cycle arrest, cell distension, and/or apoptosis in mammalian cells. It is produced by several Gram-negative species and may contribute to their pathogenicity. The catalytic subunit CdtB has homology with DNase I and may act as a genotoxin. However, the mechanism by which CdtB leads to cell death is not yet clearly u...
متن کاملThe Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Active Subunit CdtB Contains a Cholesterol Recognition Sequence Required for Toxin Binding and Subunit Internalization.
Induction of cell cycle arrest in lymphocytes following exposure to the Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) is dependent upon the integrity of lipid membrane microdomains. Moreover, we have previously demonstrated that the association of Cdt with target cells involves the CdtC subunit which binds to cholesterol via a cholesterol recognition amino acid consens...
متن کاملThe toxicity of the Aggregatibacter actinomycetemcomitans cytolethal distending toxin correlates with its phosphatidylinositol-3,4,5-triphosphate phosphatase activity.
The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) induces G2 arrest and apoptosis in lymphocytes and other cell types. We have shown that the active subunit, CdtB, exhibits phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase activity, leading us to propose that Cdt toxicity is the result of PIP3 depletion and perturbation of phosphatidylinositol-3-kinase (PI-3K)...
متن کاملApoptotic Effects of the B Subunit of Bacterial Cytolethal Distending Toxin on the A549 Lung Cancer Cell Line.
Cytolethal distending toxin (CDT) is a secreted tripartite genotoxin produced by many pathogenic gram-negative bacteria. It is composed of three subunits, CdtA, CdtB and CdtC, and CdtB-associated deoxyribonuclease (DNase) activity is essential for the CDT toxicity. In the present study, to design a novel potentially antitumor drug against lung cancer, the possible mechanisms of cdtB anticancer ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Infection and immunity
دوره 77 8 شماره
صفحات -
تاریخ انتشار 2009