a translocated bacterial protein protects vascular endothelial cells from apoptosis进行细菌蛋白保护血管内皮细胞凋亡.pdfVIP

A Translocated Bacterial Protein Protects Vascular Endothelial Cells from Apoptosis 1 1 1 ` 1 1 1 Michael C. Schmid , Florine Scheidegger , Michaela Dehio , Nadege Balmelle-Devaux , Ralf Schulein , Patrick Guye , 2 2 1* Cuddapah S. Chennakesava , Barbara Biedermann , Christoph Dehio 1 Division of Molecular Microbiology, Biozentrum, University of Basel, Basel, Switzerland, 2 Department of Research, University Hospital, Basel, Switzerland The modulation of host cell apoptosis by bacterial pathogens is of critical importance for the outcome of the infection process. The capacity of Bartonella henselae and B. quintana to cause vascular tumor formation in immunocompro- mised patients is linked to the inhibition of vascular endothelial cell (EC) apoptosis. Here, we show that translocation of BepA, a type IV secretion (T4S) substrate, is necessary and sufficient to inhibit EC apoptosis. Ectopic expression in ECs allowed mapping of the anti-apoptotic activity of BepA to the Bep intracellular delivery domain, which, as part of the signal for T4S, is conserved in other T4S substrates. The anti-apoptotic activity appeared to be limited to BepA orthologs of B. henselae and B. quintana and correlated with (i) protein localization to the host cell plasma membrane, (ii) elevated levels of intracellular cyclic adenosine monophosphate (cAMP), and (iii) increased expression of cAMP- responsive genes. The pharmacological elevation of cAMP levels protected ECs from apoptosis, indicating that BepA mediates anti-apoptosis by heightening cAMP levels by a plasma membrane–associated mechanism. Finally, we demonstrate that BepA mediates protection of E