57
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Recruitment of BAD by the Chlamydia trachomatis Vacuole Correlates with Host-Cell Survival

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Chlamydiae replicate intracellularly in a vacuole called an inclusion. Chlamydial-infected host cells are protected from mitochondrion-dependent apoptosis, partly due to degradation of BH3-only proteins. The host-cell adapter protein 14-3-3β can interact with host-cell apoptotic signaling pathways in a phosphorylation-dependent manner. In Chlamydia trachomatis-infected cells, 14-3-3β co-localizes to the inclusion via direct interaction with a C. trachomatis-encoded inclusion membrane protein. We therefore explored the possibility that the phosphatidylinositol-3 kinase (PI3K) pathway may contribute to resistance of infected cells to apoptosis. We found that inhibition of PI3K renders C. trachomatis-infected cells sensitive to staurosporine-induced apoptosis, which is accompanied by mitochondrial cytochrome c release. 14-3-3β does not associate with the Chlamydia pneumoniae inclusion, and inhibition of PI3K does not affect protection against apoptosis of C. pneumoniae-infected cells. In C. trachomatis-infected cells, the PI3K pathway activates AKT/protein kinase B, which leads to maintenance of the pro-apoptotic protein BAD in a phosphorylated state. Phosphorylated BAD is sequestered via 14-3-3β to the inclusion, but it is released when PI3K is inhibited. Depletion of AKT through short-interfering RNA reverses the resistance to apoptosis of C. trachomatis-infected cells. BAD phosphorylation is not maintained and it is not recruited to the inclusion of Chlamydia muridarum, which protects poorly against apoptosis. Thus, sequestration of BAD away from mitochondria provides C. trachomatis with a mechanism to protect the host cell from apoptosis via the interaction of a C. trachomatis-encoded inclusion protein with a host-cell phosphoserine-binding protein.

          Synopsis

          Chlamydia trachomatis is the most common cause of sexually transmitted bacterial infections in humans. These bacteria survive and replicate within a vacuole in the infected cell called an inclusion, producing up to a thousand bacteria per inclusion within a day of infection. Despite the large size of the inclusion, the infected cell survives long enough for the pathogens to complete their infection cycle and then infect new host cells. The researchers describe a novel mechanism for protection of the host cell by Chlamydia, namely activation of enzymes involved in host-cell survival. These enzymes, called kinases, cause the phosphorylation and inactivation of a protein, BAD, which can promote “cell suicide” (apoptosis) of uninfected cells. BAD phosphorylation is accompanied by recruitment of BAD to the chlamydial inclusion, where BAD binds to a cellular adapter protein, 14-3-3β. The adapter protein, in turn, is attracted to the inclusion by a membrane protein produced by Chlamydia. Thus, the chlamydial inclusion sequesters BAD away from mitochondria, where BAD could induce host-cell apoptosis. The cross talk between chlamydiae and host-cell signaling pathways demonstrates a novel mechanism of pathogen modulation of host-cell biology, and represents a potential therapeutic target for blocking infection by this prevalent pathogen.

          Related collections

          Most cited references65

          • Record: found
          • Abstract: found
          • Article: not found

          Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

          Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            Cellular survival: a play in three Akts.

              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Type III secretion machines: bacterial devices for protein delivery into host cells.

              Several Gram-negative pathogenic bacteria have evolved a complex protein secretion system termed type III to deliver bacterial effector proteins into host cells that then modulate host cellular functions. These bacterial devices are present in both plant and animal pathogenic bacteria and are evolutionarily related to the flagellar apparatus. Although type III secretion systems are substantially conserved, the effector molecules they deliver are unique for each bacterial species. Understanding the biology of these devices may allow the development of novel prevention and therapeutic approaches for several infectious diseases.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                ppat
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                May 2006
                19 May 2006
                : 2
                : 5
                : e45
                Affiliations
                [1 ] Institut Jacques Monod, Université Paris—Denis Diderot, Paris, France
                [2 ] Institute for Medical Microbiology, Technische Universität München, Munich, Germany
                [3 ] Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
                [4 ] School of Natural Sciences, University of California Merced, Merced, California, United States of America
                University of California San Francisco, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: dojcius@ 123456ucmerced.edu
                Article
                05-PLPA-RA-0122R4 plpa-02-05-05
                10.1371/journal.ppat.0020045
                1463014
                16710454
                12fd2462-ba04-4eea-a390-2791c4896872
                Copyright: © 2006 Verbeke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 5 August 2005
                : 10 April 2006
                Page count
                Pages: 10
                Categories
                Research Article
                Cell Biology
                Microbiology
                Eubacteria
                In Vitro
                Homo (Human)
                Custom metadata
                Verbeke P, Welter-Stahl L, Ying S, Hansen J, Häcker G, et al. (2006) Recruitment of BAD by the Chlamydia trachomatis vacuole correlates with host-cell survival. PLoS Pathog 2(5): e45. DOI: 10.1371/journal.ppat.0020045

                Infectious disease & Microbiology
                Infectious disease & Microbiology

                Comments

                Comment on this article