Georg Häcker

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (125)726.85 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC-induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both promoters are further characterized by the presence of tri-methylated lysine 4 of histone H3, marking active chromatin. We provide evidence that in our apoptosis models cell death occurs independently of p53 or ARF. Furthermore, we demonstrate that recruitment of MYC to the NOXA as well as to the BIM gene promoters depends on MYC's interaction with the zinc finger transcription factor EGR1 and an EGR1-binding site in both promoters. Our study uncovers a novel molecular mechanism by showing that the functional cooperation of MYC with EGR1 is required for bortezomib-induced cell death. This observation may be important for novel therapeutic strategies engaging the inherent pro-death function of MYC.
    Nucleic Acids Research 08/2014; · 8.81 Impact Factor
  • Georg Häcker, David M. Ojcius, Dagmar Heuer
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    ABSTRACT: It may be worth asking whether all the hoopla about CPAF is justified. Our view is: yes, it is. As in any active scientific area, not every proposal regarding CPAF function has held up. The recent developments are very encouraging: we now have a much better idea of what CPAF can do, but also what it does not do.This article is protected by copyright. All rights reserved.
    Pathogens and Disease. 08/2014;
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    ABSTRACT: Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.
    Nature medicine. 05/2014;
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    ABSTRACT: Maintenance of T cells is determined by their survival capacity, which is regulated by Bcl-2 proteins. Cytokines signalling through the common gamma chain such as IL-2, IL-7 and IL-15 are important for T-cell survival but how these cytokines determine the expression of Bcl-2-family proteins is not clear. We report signalling events of cytokines that regulate expression of two key Bcl-2 proteins, pro-apoptotic Bim and anti-apoptotic Mcl-1, in resting C57BL/6 mouse T cells. IL-2, IL-7 and IL-15 inhibited apoptosis but paradoxically induced the expression of Bim, countered by concomitant induction of Mcl-1. Bim induction by IL-15 was found at the mRNA and protein levels and depended on both JAK/STAT and PI3K signals. A new STAT5-binding site was identified in the Bim promoter, which was occupied by STAT5 upon IL-15 stimulation. Although it also depended on JAK/STAT- and PI3K signalling, Mcl-1 regulation was independent of Mcl-1 mRNA levels and of regulation of protein stability, suggesting translational regulation. Concurrent CD3 signals inhibited some of the IL-7 but not the IL-15 effect on Bcl-2 proteins. The data suggest that cytokines induce Bim and prime T cells for apoptosis, but also inhibit apoptosis by stabilising Mcl-1. Later downregulation of short-lived Mcl-1 may induce efficient, Bim-dependent apoptosis.This article is protected by copyright. All rights reserved
    European Journal of Immunology 05/2014; · 4.97 Impact Factor
  • Georg Häcker
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    ABSTRACT: The protease CPAF is only found in Chlamydiales and in at least most bacteria that share with Chlamydia the biphasic life-style in a cytosolic inclusion. CPAF is intriguing: it appears to be secreted from the inclusion across the inclusion membrane into the cytosol. A bacterial protease ravaging in the cytosol of a human cell may cause a plethora of effects. Curiously, very few are known. The current discussion is bogged down by a focus on experimental artifact, while proposed functions of CPAF remain speculative. I here make the attempt to summarize what we know about CPAF.
    Microbes and Infection 03/2014; · 2.92 Impact Factor
  • Georg Häcker
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    ABSTRACT: During ER-stress, one of the responses a cell can choose is apoptosis. Apoptosis generally is a cell’s preferred response when other control mechanisms are overwhelmed. We now have a reasonably clear molecular picture what is happening once the apoptotic apparatus has been started. Unclear however are the majority of the upstream pathways that connect other signalling to apoptosis. During ER-stress, confirmed apoptosis-regulating targets are pro- and anti-apoptotic proteins of the Bcl-2-family, whose concerted action induces apoptosis. I will here discuss how mitochondrial apoptosis is triggered, how this is linked to the ER-stress response and in what way this may be relevant during microbial infections.
    Microbes and Infection 01/2014; · 2.92 Impact Factor
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    ABSTRACT: We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment.
    PLoS ONE 01/2014; 9(4):e93057. · 3.53 Impact Factor
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    ABSTRACT: Chlamydia grows inside a cytosolic vacuole (the inclusion) that is supplied with nutrients by the host through vesicular and non-vesicular transport. It is unclear in many respects how Chlamydia organizes this transport. One model posits that the Chlamydia-induced fragmentation of the Golgi-apparatus is required for normal transport processes to the inclusion and for chlamydial development, and the chlamydial protease CPAF has been controversially implicated in Golgi-fragmentation. We here use a model of penicillin-induced persistence of infection with Chlamydia trachomatis to test this link. Under penicillin-treatment the inclusion grew in size for the first 24 h but after that growth was severely reduced. Penicillin did not reduce the number of infected cells with fragmented Golgi-apparatus, and normal Golgi-fragmentation was found in a CPAF-deficient mutant. Surprisingly, sphingomyelin transport into the inclusion and into the bacteria, as measured by fluorescence accumulation upon addition of labelled ceramide, was not reduced during penicillin-treatment. Thus, both Golgi-fragmentation and transport of sphingomyelin to C. trachomatis still occurred in this model of persistence. The portion of cells in which CPAF was detected in the cytosol, either by immunofluorescence or by immune-electron microscopy, was drastically reduced in cells cultured in the presence of penicillin. These data argue against an essential role of cytosolic CPAF for Golgi-fragmentation or for sphingomyelin transport in chlamydial infection.
    PLoS ONE 01/2014; 9(7):e103220. · 3.53 Impact Factor
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    ABSTRACT: Inhibitor of apoptosis proteins (IAPs) were originally described to regulate apoptosis by direct binding to caspases. More recently, IAPs have been identified as important modulators of canonical and non-canonical NF-κB signalling via their ubiquitin-E3 ligase activity. IAPs are therefore not only gatekeepers of cell death but probably also involved in the regulation of inflammation as well as innate and adaptive immunity. Here we analysed the role of IAPs in T cell immunity during lymphocytic choriomeningitis virus (LCMV) infection by pharmacological targeting with an IAP-antagonist/Smac-mimetic. Expansion of virus-specific CD8 T cells was drastically reduced in LCMV-infected mice exposed to IAP-antagonist. Accordingly, virus control was substantially impaired, indicated by high virus titres in the spleen and spread of LCMV to peripheral organs. The profound negative effect of IAP-antagonists on T cell immunity was partially linked to TNF-mediated cell death of activated T cells and required inhibition of XIAP as well as cIAP1. Thus, IAPs play an important role in T cell expansion and survival in the context of a highly inflammatory environment such as a virus infection, indicating that IAP-antagonists may interfere with immune responses.
    Blood 12/2013; · 9.78 Impact Factor
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    ABSTRACT: Purulent pericarditis is a life threatening disease that usually manifests following bacteraemia or through spreading from an intrathoracic focus. Only a few cases of this disease have been reported with Lancefield group C streptococci as etiologic agents, and the primary focus in these infections remains unknown. We report a case of purulent pericarditis with septic and cardiogenic shock, caused by Streptococcus equi subspecies zooepidemicus (group C) in a 51-year-old patient. The pathogen was possibly contracted through contact with horses. Most likely, it initially caused pneumonia before spreading to the pericardium, either directly or via the blood stream. A combined therapeutic approach, consisting of antibiotic therapy and repeated pericardial drainage, was necessary to ensure a clinical cure. After discharge, long-term follow-up for development of constrictive pericarditis is considered mandatory.
    Journal of Medical Microbiology 11/2013; · 2.30 Impact Factor
  • G Häcker
    Cell death and differentiation 10/2013; 20(10):1289-90. · 8.24 Impact Factor
  • Georg Häcker
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    ABSTRACT: Apoptosis is a well-studied form of cell death in metazoans, where it has a clear role during the life of the (multicellular) animal. Some situations of cell death in unicellular eukaryotes (protozoa and yeast) have also been referred to as apoptosis. In recent years apoptosis has further been identified in bacteria several times. As a bacterial response to external stimuli, apoptosis could be important not only for the bacteria but also to the host. Here I will discuss why I believe that the term apoptosis should be avoided for these situations in bacteria, no matter how interesting the molecular background or how biologically important the underlying mechanism may be.
    Microbes and Infection 06/2013; · 2.92 Impact Factor
  • Arnim Weber, David Ausländer, Georg Häcker
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    ABSTRACT: Noxa is a member of the pro-apoptotic BH3-only group of Bcl-2 proteins that is known to bind specifically to anti-apoptotic Mcl-1 and A1, antagonizing their function. Mcl-1 has been reported to have a short half-life, and Noxa up-regulation accelerates Mcl-1 degradation by the proteasome. Unlike human Noxa, mouse Noxa has two BH3-domains, which both have affinity for Mcl-1. We here investigate two aspects of the molecular function of Noxa, namely the requirements for the two BH3-domains in mouse Noxa and the role of Noxa in Mcl-1-degradation. We found that only the C-terminal BH3-domain of mouse Noxa is active in neutralizing Mcl-1. This was the result of the targeting of Noxa to the outer mitochondrial membrane through its C-terminal alpha-helix, which allowed Mcl-1-neutralization only when the BH3-domain was immediately N-terminal of the membrane anchor. However, the N-terminal BH3-domain enhanced interaction with Mcl-1 and A1. The Noxa-dependent degradation of Mcl-1 was independent of the kinase GSK3 and the deubiquitinase Usp9x in mouse embryonic fibroblasts. These data show that Noxa is targeted to the mitochondrial membrane where it neutralises Mcl-1 via its C-terminal BH3-domain and suggest that Noxa is co-degraded with Noxa, in a way independent of ubiquitin-modifying enzymes described for Mcl-1.
    Apoptosis 06/2013; · 4.07 Impact Factor
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    ABSTRACT: Differentiation of neutrophil granulocytes (neutrophils) occurs through several steps in the bone marrow and requires a coordinate regulation of factors determining survival and lineage-specific development. A number of genes are known whose deficiency disrupts neutrophil generation in humans and in mice. One of the proteins encoded by these genes, glucose-6-phosphatase-β (G6PC3), is involved in glucose metabolism. G6PC3 deficiency causes neutropenia in humans and in mice, linked to enhanced apoptosis and ER stress. We used a model of conditional Hoxb8 expression to test molecular and functional differentiation as well as survival defects in neutrophils from G6PC3(-/-) mice. Progenitor lines were established and differentiated into neutrophils when Hoxb8 was turned off. G6PC3(-/-) progenitor cells underwent substantial apoptosis when differentiation was started. Transgenic expression of Bcl-XL rescued survival; however, Bcl-XL-protected differentiated cells showed reduced proliferation, immaturity and functional deficiency such as altered MAP kinase signaling and reduced cytokine secretion. Impaired glucose utilization was found and was associated with ER stress and apoptosis, associated with the upregulation of Bim and Bax; downregulation of Bim protected against apoptosis during differentiation. ER-stress further caused a profound loss of expression and secretion of the main neutrophil product neutrophil elastase during differentiation. Transplantation of wild-type Hoxb8-progenitor cells into irradiated mice allowed differentiation into neutrophils in the bone marrow in vivo. Transplantation of G6PC3(-/-) cells yielded few mature neutrophils in bone marrow and peripheral blood. Transgenic Bcl-XL permitted differentiation of G6PC3(-/-) cells in vivo. However, functional deficiencies and differentiation abnormalities remained. Differentiation of macrophages from Hoxb8-dependent progenitors was only slightly disturbed. A combination of defects in differentiation and survival thus underlies neutropenia in G6PC3(-/-) deficiency, both originating from a reduced ability to utilize glucose. Hoxb8-dependent cells are a model to study differentiation and survival of the neutrophil lineage.Cell Death and Differentiation advance online publication, 17 May 2013; doi:10.1038/cdd.2013.39.
    Cell death and differentiation 05/2013; · 8.24 Impact Factor
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    ABSTRACT: We conducted a case-control study using the Fungitell®-assay, the novel Platelia™ Candida-Ag/Ab-Plus-assay and the Cand-Tec™-latex agglutination-test to evaluate the usefulness of (1→3)-β-D-Glucan, Mannan-antigen with/without anti-Mannan-antibody and Cand-Tec™-Candida-antigen measurement for the diagnosis of candidemia. 56 patients fulfilled the inclusion criteria and were enrolled. 100 patients with bacteremia and 100 patients with sterile blood cultures served as negative controls.In the candidemia group, median (1→3)-β-D-Glucan, Mannan-antigen and anti-Mannan-antibody levels were 427 pg/ml, 190 pg/ml and 18.6 AU/ml, respectively. All three parameters were significantly elevated in patients with candidemia. The sensitivity and specificity was 87.5% and 85.5% for (1→3)-β-D-Glucan, 58.9% and 97.5% for Mannan-antigen, 62.5% and 65.0% for anti-Mannan-antibody, 89.3% and 63.0% for Mannan-antigen plus anti-Mannan-antibody, 89.3% and 85.0% for BDG plus Mannan-antigen and 13.0% and 93.9% for Cand-Tec™-Candida-antigen. The low Mannan-antigen sensitivity was in part caused by Candida parapsilosis- and Candida guilliermondii-fungemias, which were not detected by the Platelia™ Candida-Ag-Plus-assay. By lowering the cut-off from 125 pg/ml to 50 pg/ml Mannan-antigen sensitivity would increase to 69.6% without severely affecting the specificity (93.5%). Contrary to recently published data superficial candidiasis was not associated with elevated Mannan-antigen levels, not even after lowering the cut-off.Combining PCT with (1→3)-β-D-Glucan to increase specificity had limited advantage because the benefit of the combination did not outweigh the loss of sensitivity.Altogether, Cand-Tec™-Candida-antigen and Mannan-antigen plus anti-Mannan-antibody measurement have unacceptably low sensitivity or specificity. Of the four tests compared, (1→3)-β-D-Glucan and Mannan-antigen are the superior biomarkers depending on whether a sensitivity-driven or a specificity-driven approach is used.
    Journal of clinical microbiology 01/2013; · 4.16 Impact Factor
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    ABSTRACT: Neutrophil granulocyte (neutrophil) apoptosis plays a key role in determining inflammation in infectious and non-infectious settings. Recent work has shown that inhibitors of cyclin-dependent kinases (cdk) such as roscovitine can potently induce neutrophil apoptosis and reduce inflammation. Using a conditional Hoxb8-expression system we tested the participation of Bcl-2-family proteins to roscovitine-induced apoptosis in mouse neutrophils and in neutrophil progenitor cells. Bcl-2 strongly protected against roscovitine-induced apoptosis in neutrophils. The isolated loss of either Bim or noxa provided significant, partial protection while protection through combined loss of Bim and noxa or Bim and Puma was only slightly greater than this individual loss. The only substantial change in protein levels observed was the loss of Mcl-1, which was not transcriptional and was inhibited by proteasome blockade. In progenitor cells there was no protection by the loss of Bim alone but substantial protection by the loss of both Bim and Puma; surprisingly, strongest protection was seen by the isolated loss of noxa. The pattern of protein expression and Mcl-1-regulation in progenitor cells was very similar to the one observed in differentiated neutrophils. In addition, roscovitine strongly inhibited proliferation in progenitor cells, associated with an accumulation of cells in G2/M-phase.
    PLoS ONE 01/2013; 8(11):e79352. · 3.53 Impact Factor
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    ABSTRACT: Bacterial infections of the mucosal epithelium are a major cause of human disease. The prolonged presence of microbial pathogens stimulates inflammation of the local tissues, which leads to changes in the molecular composition of the extracellular milieu. A well-characterized molecule that is released to the extracellular milieu by stressed or infected cells is extracellular ATP, and its ecto-enzymatic degradation products, which function as signaling molecules through ligation of purinergic receptors. There has been little information, however, on the effects of the extracellular metabolites on bacterial growth in inflamed tissues. Millimolar concentrations of ATP have been previously shown to inhibit irreversibly bacterial infection through ligation of P2X(7) receptors. Here we show that the pro-inflammatory mediator, ATP, is released from Chlamydia trachomatis-infected epithelial cells. Moreover, further stimulation of the infected cells with micromolar extracellular ADP or ATP significantly impairs growth of the bacteria, with a profile characteristic of the involvement of P2X(4) receptors. A specific role for P2X(4) was confirmed using cells overexpressing P2X(4). The chlamydiae remain viable, and return to normal growth kinetics following removal of the extracellular stimulus, similar to responses previously described for persistence of chlamydial infection.
    Infection and immunity 09/2012; · 4.21 Impact Factor
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    ABSTRACT: Interleukin-1β (IL-1β) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1β activation is regulated by inhibitor of apoptosis (IAP) proteins, we treated macrophages with an IAP-antagonist "Smac mimetic" compound or genetically deleted the genes that encode the three IAP family members cIAP1, cIAP2, and XIAP. After Toll-like receptor priming, IAP inhibition triggered cleavage of IL-1β that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by caspase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1β by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demonstrate that activation of the cell death-inducing ripoptosome platform and RIP3 can generate bioactive IL-1β and implicate them as additional targets for the treatment of pathological IL-1-driven inflammatory responses.
    Immunity 02/2012; 36(2):215-27. · 19.80 Impact Factor
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    ABSTRACT: During mitochondrial apoptosis, pro-apoptotic BH3-only proteins cause the translocation of cytosolic Bcl-2-associated X protein (Bax) to the outer mitochondrial membrane (OMM) where it is activated to release cytochrome c from the mitochondrial intermembrane space, but the mechanism is under dispute. We show that most BH3-only proteins are mitochondrial proteins that are imported into the OMM via a C-terminal tail-anchor domain in isolated yeast mitochondria, independently of binding to anti-apoptotic Bcl-2 proteins. This C-terminal domain acted as a classical mitochondrial targeting signal and was sufficient to direct green fluorescent protein to mitochondria in human cells. When expressed in mouse fibroblasts, these BH3-only proteins localised to mitochondria and were inserted in the OMM. The BH3-only proteins Bcl-2-interacting mediator of cell death (Bim), tBid and p53-upregulated modulator of apoptosis sensitised isolated mitochondria from Bax/Bcl-2 homologous antagonist/killer-deficient fibroblasts to cytochrome c-release by recombinant, extramitochondrial Bax. For Bim, this activity is shown to require the C-terminal-targeting signal and to be independent of binding capacity to and presence of anti-apoptotic Bcl-2 proteins. Bim further enhanced Bax-dependent killing in yeast. A model is proposed where OMM-tail-anchored BH3-only proteins permit passive 'recruitment' and catalysis-like activation of extra-mitochondrial Bax. The recognition of C-terminal membrane-insertion of BH3-only proteins will permit the development of a more detailed concept of the initiation of mitochondrial apoptosis.
    Cell death and differentiation 02/2012; 19(8):1328-36. · 8.24 Impact Factor
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    ABSTRACT: Chlamydiae are obligate intracellular bacteria that propagate in a cytosolic vacuole. Recent work has shown that growth of Chlamydia induces the fragmentation of the Golgi apparatus (GA) into ministacks, which facilitates the acquisition of host lipids into the growing inclusion. GA fragmentation results from infection-associated cleavage of the integral GA protein, golgin-84. Golgin-84-cleavage, GA fragmentation and growth of Chlamydia trachomatis can be blocked by the peptide inhibitor WEHD-fmk. Here we identify the bacterial protease chlamydial protease-like activity factor (CPAF) as the factor mediating cleavage of golgin-84 and as the target of WEHD-fmk-inhibition. WEHD-fmk blocked cleavage of golgin-84 as well as cleavage of known CPAF targets during infection with C. trachomatis and C. pneumoniae. The same effect was seen when active CPAF was expressed in non-infected cells and in a cell-free system. Ectopic expression of active CPAF in non-infected cells was sufficient for GA fragmentation. GA fragmentation required the small GTPases Rab6 and Rab11 downstream of CPAF-activity. These results define CPAF as the first protein that is essential for replication of Chlamydia. We suggest that this role makes CPAF a potential anti-infective therapeutic target.
    PLoS Pathogens 09/2011; 7(9):e1002283. · 8.14 Impact Factor

Publication Stats

4k Citations
726.85 Total Impact Points

Institutions

  • 2011–2014
    • Universitätsklinikum Freiburg
      • • Institute of Medical Microbiology and Hygiene
      • • Department of Medical Microbiology and Hygiene
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2009–2013
    • University of Freiburg
      • Institute of Biochemistry and Molecular Biology
      Freiburg, Baden-Württemberg, Germany
  • 2006–2012
    • University of California, Merced
      • • Health Sciences Research Institute (HSRI)
      • • School of Natural Sciences
      Merced, California, United States
    • Paris Diderot University
      • Institut Jacques Monod
      Paris, Ile-de-France, France
  • 1991–2012
    • Technische Universität München
      • • Lehrstuhl für Mikrotechnik und Medizingerätetechnik
      • • Institut für Medizinische Mikrobiologie, Immunologie und Hygiene
      München, Bavaria, Germany
  • 2004
    • Universität Stuttgart
      • Institute of Cell Biology and Immunology
      Stuttgart, Baden-Wuerttemberg, Germany
  • 1995–1997
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 1994–1997
    • The Walter and Eliza Hall Institute of Medical Research
      Melbourne, Victoria, Australia
  • 1989
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany