Latest documents http://publikationen.ub.uni-frankfurt.de/index/index/ Fri, 22 Feb 2013 10:58:29 +0100 Fri, 22 Feb 2013 10:58:29 +0100 http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/27239 Host cells infected with obligate intracellular bacteria Chlamydia trachomatis are profoundly resistant to diverse apoptotic stimuli. The molecular mechanisms underlying the block in apoptotic signaling of infected cells is not well understood. Here we investigated the molecular mechanism by which apoptosis induced via the tumor necrosis factor (TNF) receptor is prevented in infected epithelial cells. Infection with C. trachomatis leads to the up-regulation of cellular inhibitor of apoptosis (cIAP)-2, and interfering with cIAP-2 up-regulation sensitized infected cells for TNF-induced apoptosis. Interestingly, besides cIAP-2, cIAP-1 and X-linked IAP, although not differentially regulated by infection, are required to maintain apoptosis resistance in infected cells. We detected that IAPs are constitutively organized in heteromeric complexes and small interfering RNA-mediated silencing of one of these IAPs affects the stability of another IAP. In particular, the stability of cIAP-2 is modulated by the presence of X-linked IAP and their interaction is stabilized in infected cells. Our observations suggest that IAPs are functional and stable as heteromers, a thus far undiscovered mechanism of IAP regulation and its role in modulation of apoptosis. Krishnaraj Rajalingam; Manu Sharma; Nicole Paland; Robert Hurwitz; Oliver Thieck; Monique Oswald; Nikolaus Machuy; Thomas Rudel article http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/27239 Fri, 22 Feb 2013 10:58:29 +0100 http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/22674 The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (delta psi m). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of delta psi m. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce delta psi m loss and apoptosis, demonstrating that dissipation of delta psi m is a requirement for cell death caused by neisserial infection. Vera Kozjak-Pavlovic; Elke A. Dian-Lothrop; Michael Meinecke; Oliver Kepp; Katharina Ross; Krishnaraj Rajalingam; Anke Harsman; Eva Hauf; Volker Brinkmann; Dirk Günther; Ines Herrmann; Robert Hurwitz; Joachim Rassow; Richard Wagner; Thomas Rudel article http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/22674 Fri, 09 Sep 2011 12:42:36 +0200