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      Mcl-1 Is a Key Regulator of Apoptosis Resistance in Chlamydia trachomatis-Infected Cells

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          Abstract

          Chlamydia are obligate intracellular bacteria that cause variety of human diseases. Host cells infected with Chlamydia are protected against many different apoptotic stimuli. The induction of apoptosis resistance is thought to be an important immune escape mechanism allowing Chlamydia to replicate inside the host cell. Infection with C. trachomatis activates the Raf/MEK/ERK pathway and the PI3K/AKT pathway. Here we show that inhibition of these two pathways by chemical inhibitors sensitized C. trachomatis infected cells to granzyme B-mediated cell death. Infection leads to the Raf/MEK/ERK-mediated up-regulation and PI3K-dependent stabilization of the anti-apoptotic Bcl-2 family member Mcl-1. Consistently, interfering with Mcl-1 up-regulation sensitized infected cells for apoptosis induced via the TNF receptor, DNA damage, granzyme B and stress. Our data suggest that Mcl-1 up-regulation is primarily required to maintain apoptosis resistance in C. trachomatis-infected cells.

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          Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1.

          Ulrich Maurer, Céline Charvet, Allan Wagman … (2006)
          We investigated the role of glycogen synthase kinase-3 (GSK-3), which is inactivated by AKT, for its role in the regulation of apoptosis. Upon IL-3 withdrawal, protein levels of MCL-1 decreased but were sustained by pharmacological inhibition of GSK-3, which prevented cytochrome c release and apoptosis. MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. A phosphorylation-site mutant (MCL-1(S159A)), expressed in IL-3-dependent cells, showed enhanced stability upon IL-3 withdrawal and conferred increased protection from apoptosis compared to wild-type MCL-1. The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT.
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            Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.

            Joseph T. Opferman, Anthony Letai, Caroline Beard … (2003)
            Regulated apoptosis is essential for both the development and the subsequent maintenance of the immune system. Interleukins, including IL-2, IL-4, IL-7 and IL-15, heavily influence lymphocyte survival during the vulnerable stages of VDJ rearrangement and later in ensuring cellular homeostasis, but the genes specifically responsible for the development and maintenance of lymphocytes have not been identified. The antiapoptotic protein MCL-1 is an attractive candidate, as it is highly regulated, appears to enhance short-term survival and functions at an apical step in genotoxic deaths. However, Mcl-1 deficiency results in peri-implantation lethality. Here we show that mice conditional for Mcl-1 display a profound reduction in B and T lymphocytes when MCL-1 is removed. Deletion of Mcl-1 during early lymphocyte differentiation increased apoptosis and arrested the development at pro-B-cell and double-negative T-cell stages. Induced deletion of Mcl-1 in peripheral B- and T-cell populations resulted in their rapid loss. Moreover, IL-7 both induced and required MCL-1 to mediate lymphocyte survival. Thus, MCL-1, which selectively inhibits the proapoptotic protein BIM, is essential both early in lymphoid development and later on in the maintenance of mature lymphocytes.
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              The CD95(APO-1/Fas) DISC and beyond.

              M Peter, P. H. Krammer (2003)
              CD95 (APO-1/Fas) is a prototype death receptor characterized by the presence of an 80 amino acid death domain in its cytoplasmic tail. This domain is essential for the recruitment of a number of signaling components upon activation by either agonistic anti-CD95 antibodies or cognate CD95 ligand that initiate apoptosis. The complex of proteins that forms upon triggering of CD95 is called the death-inducting signaling complex (DISC). The DISC consists of an adaptor protein and initiator caspases and is essential for induction of apoptosis. A number of proteins have been reported to regulate formation or activity of the DISC. This review discusses recent developments in this area of death receptor research.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2008
                Publication date (Electronic): 1 September 2008
                Volume: 3
                Issue: 9
                Electronic Location Identifier: e3102
                Affiliations
                [1 ]Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
                [2 ]Evanston Northwestern Research Institute, Evanston, Illinois, United States of America
                Duke University Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: KR TR. Performed the experiments: MS CL MO OT. Analyzed the data: KR MS TR. Contributed reagents/materials/analysis tools: CJF. Wrote the paper: KR TR.

                [¤a]

                Current address: Emmy Noether Group of the DFG, Institute of Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany

                [¤b]

                Current address: Institute for Medical Microbiology, Technische Universität München, Munich, Germany

                [¤c]

                Current address: Biocenter, Department for Microbiology, University of Würzburg, Würzburg, Germany

                Article
                Publisher ID: 08-PONE-RA-04437R1
                DOI: 10.1371/journal.pone.0003102
                PMC ID: 2518856
                PubMed ID: 18769617
                SO-VID: c2b54f6e-b3c4-45a6-a60e-406e04bfee19
                Copyright © Rajalingam 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
                Date received : 23 April 2008
                Date accepted : 29 July 2008
                Page count
                Pages: 11
                Categories
                Subject: Research Article
                Subject: Infectious Diseases
                Subject: Cell Biology/Cell Signaling
                Subject: Cell Biology/Cellular Death and Stress Responses
                Subject: Cell Biology/Microbial Growth and Development
                Subject: Immunology/Cellular Microbiology and Pathogenesis
                Subject: Infectious Diseases/Bacterial Infections

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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