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Dr. Panagiotis Papatheodorou
Institut für Pharmakologie und Toxikologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany

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0 bacterial toxin
0 Toxin receptor
0 Clostridial toxin
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Molecular toxicology
Published: 23 January 2021 in Archives of Toxicology
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The subtilase cytotoxin (SubAB) is secreted by certain Shiga toxin-producing Escherichia coli (STEC) strains and is composed of the enzymatically active subunit SubA and the pentameric binding/transport subunit SubB. We previously demonstrated that SubA (10 µg/ml), in the absence of SubB, binds and intoxicates the human cervix cancer-derived epithelial cell line HeLa. However, the cellular and molecular mechanisms underlying the cytotoxic activity of SubA in the absence of SubB remained unclear. In the present study, the cytotoxic effects mediated by SubA alone were investigated in more detail in HeLa cells and the human colon cancer cell line HCT116. We found that in the absence of SubB, SubA (10 µg/ml) is internalized into the endoplasmic reticulum (ER), where it cleaves the chaperone GRP78, an already known substrate for SubA after its canonical uptake into cells via SubB. The autonomous cellular uptake of SubA and subsequent cleavage of GRP78 in cells is prevented by treatment of cells with 10 µM brefeldin A, which inhibits the transport of protein toxins into the ER. In addition, by analyzing the SubA mutant SubAΔC344, we identified the C-terminal SEEL motif as an ER-targeting signal. Conclusively, our results strongly suggest that SubA alone shares the same intracellular transport route and cytotoxic activity as the SubAB holotoxin.

ACS Style

Katharina Sessler; Panagiotis Papatheodorou; Fanny Wondany; Maike Krause; Sabrina Noettger; Denise Bernhard; Jens Michaelis; Herbert Schmidt; Holger Barth. The enzyme subunit SubA of Shiga toxin-producing E. coli strains demonstrates comparable intracellular transport and cytotoxic activity as the holotoxin SubAB in HeLa and HCT116 cells in vitro. Archives of Toxicology 2021, 95, 975 -983.

AMA Style

Katharina Sessler, Panagiotis Papatheodorou, Fanny Wondany, Maike Krause, Sabrina Noettger, Denise Bernhard, Jens Michaelis, Herbert Schmidt, Holger Barth. The enzyme subunit SubA of Shiga toxin-producing E. coli strains demonstrates comparable intracellular transport and cytotoxic activity as the holotoxin SubAB in HeLa and HCT116 cells in vitro. Archives of Toxicology. 2021; 95 (3):975-983.

Chicago/Turabian Style

Katharina Sessler; Panagiotis Papatheodorou; Fanny Wondany; Maike Krause; Sabrina Noettger; Denise Bernhard; Jens Michaelis; Herbert Schmidt; Holger Barth. 2021. "The enzyme subunit SubA of Shiga toxin-producing E. coli strains demonstrates comparable intracellular transport and cytotoxic activity as the holotoxin SubAB in HeLa and HCT116 cells in vitro." Archives of Toxicology 95, no. 3: 975-983.

Brief research report article
Published: 12 August 2020 in Frontiers in Pharmacology
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Infections with the pathogenic bacterium Clostridioides (C.) difficile are coming more into focus, in particular in hospitalized patients after antibiotic treatment. C. difficile produces the exotoxins TcdA and TcdB. Since some years, hypervirulent strains are described, which produce in addition the binary actin ADP-ribosylating toxin CDT. These strains are associated with more severe clinical presentations and increased morbidity and frequency. Once in the cytosol of their target cells, the catalytic domains of TcdA and TcdB glucosylate and thereby inactivate small Rho-GTPases whereas the enzyme subunit of CDT ADP-ribosylates G-actin. Thus, enzymatic activity of the toxins leads to destruction of the cytoskeleton and breakdown of the epidermal gut barrier integrity. This causes clinical symptoms ranging from mild diarrhea to life-threatening pseudomembranous colitis. Therefore, pharmacological inhibition of the secreted toxins is of peculiar medical interest. Here, we investigated the neutralizing effect of the human antimicrobial peptide α-defensin-5 toward TcdA, TcdB, and CDT in human cells. The toxin-neutralizing effects of α-defensin-5 toward TcdA, TcdB, and CDT as well as their medically relevant combination were demonstrated by analyzing toxins-induced changes in cell morphology, intracellular substrate modification, and decrease of trans-epithelial electrical resistance. For TcdA, the underlying mode of inhibition is most likely based on the formation of inactive toxin-defensin-aggregates whereas for CDT, the binding- and transport-component might be influenced. The application of α-defensin-5 delayed intoxication of cells in a time- and concentration-dependent manner. Due to its effect on the toxins, α-defensin-5 should be considered as a candidate to treat severe C. difficile–associated diseases.

ACS Style

Michael Korbmacher; Stephan Fischer; Marc Landenberger; Panagiotis Papatheodorou; Klaus Aktories; Holger Barth. Human α-Defensin-5 Efficiently Neutralizes Clostridioides difficile Toxins TcdA, TcdB, and CDT. Frontiers in Pharmacology 2020, 11, 1204 .

AMA Style

Michael Korbmacher, Stephan Fischer, Marc Landenberger, Panagiotis Papatheodorou, Klaus Aktories, Holger Barth. Human α-Defensin-5 Efficiently Neutralizes Clostridioides difficile Toxins TcdA, TcdB, and CDT. Frontiers in Pharmacology. 2020; 11 ():1204.

Chicago/Turabian Style

Michael Korbmacher; Stephan Fischer; Marc Landenberger; Panagiotis Papatheodorou; Klaus Aktories; Holger Barth. 2020. "Human α-Defensin-5 Efficiently Neutralizes Clostridioides difficile Toxins TcdA, TcdB, and CDT." Frontiers in Pharmacology 11, no. : 1204.

Research article
Published: 19 March 2020 in The FASEB Journal
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The human pathogenic bacterium Clostridioides difficile produces two exotoxins TcdA and TcdB, which inactivate Rho GTPases thereby causing C. difficile‐associated diseases (CDAD) including life‐threatening pseudomembranous colitis. Hypervirulent strains produce additionally the binary actin ADP‐ribosylating toxin CDT. These strains are hallmarked by more severe forms of CDAD and increased frequency and severity. Once in the cytosol, the toxins act as enzymes resulting in the typical clinical symptoms. Therefore, targeting and inactivation of the released toxins are of peculiar interest. Prompted by earlier findings that human α‐defensin‐1 neutralizes TcdB, we investigated the effects of the defensin on all three C. difficile toxins. Inhibition of TcdA, TcdB, and CDT was demonstrated by analyzing toxin‐induced changes in cell morphology, substrate modification, and decrease in transepithelial electrical resistance. Application of α‐defensin‐1 protected cells and human intestinal organoids from the cytotoxic effects of TcdA, TcdB, CDT, and their combination which is attributed to a direct interaction between the toxins and α‐defensin‐1. In mice, the application of α‐defensin‐1 reduced the TcdA‐induced damage of intestinal loops in vivo. In conclusion, human α‐defensin‐1 is a specific and potent inhibitor of the C. difficile toxins and a promising agent to develop novel therapeutic options against C. difficile infections.

ACS Style

Stephan Fischer; Anna‐Katharina Ückert; Marc Landenberger; Panagiotis Papatheodorou; Carola Hoffmann‐Richter; Ann‐Katrin Mittler; Ulrich Ziener; Marlen Hägele; Carsten Schwan; Martin Müller; Alexander Kleger; Roland Benz; Michel R. Popoff; Klaus Aktories; Holger Barth. Human peptide α‐defensin‐1 interferes withClostridioides difficiletoxins TcdA, TcdB, and CDT. The FASEB Journal 2020, 34, 6244 -6261.

AMA Style

Stephan Fischer, Anna‐Katharina Ückert, Marc Landenberger, Panagiotis Papatheodorou, Carola Hoffmann‐Richter, Ann‐Katrin Mittler, Ulrich Ziener, Marlen Hägele, Carsten Schwan, Martin Müller, Alexander Kleger, Roland Benz, Michel R. Popoff, Klaus Aktories, Holger Barth. Human peptide α‐defensin‐1 interferes withClostridioides difficiletoxins TcdA, TcdB, and CDT. The FASEB Journal. 2020; 34 (5):6244-6261.

Chicago/Turabian Style

Stephan Fischer; Anna‐Katharina Ückert; Marc Landenberger; Panagiotis Papatheodorou; Carola Hoffmann‐Richter; Ann‐Katrin Mittler; Ulrich Ziener; Marlen Hägele; Carsten Schwan; Martin Müller; Alexander Kleger; Roland Benz; Michel R. Popoff; Klaus Aktories; Holger Barth. 2020. "Human peptide α‐defensin‐1 interferes withClostridioides difficiletoxins TcdA, TcdB, and CDT." The FASEB Journal 34, no. 5: 6244-6261.

Research article
Published: 11 March 2020 in Science Advances
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We identified a glucosyltransferase (YGT) and an ADP-ribosyltransferase (YART) in Yersinia mollaretii, highly related to glucosylating toxins from Clostridium difficile, the cause of antibiotics-associated enterocolitis. Both Yersinia toxins consist of an amino-terminal enzyme domain, an autoprotease domain activated by inositol hexakisphosphate, and a carboxyl-terminal translocation domain. YGT N-acetylglucosaminylates Rab5 and Rab31 at Thr52 and Thr36, respectively, thereby inactivating the Rab proteins. YART ADP-ribosylates Rab5 and Rab31 at Gln79 and Gln64, respectively. This activates Rab proteins by inhibiting GTP hydrolysis. We determined the crystal structure of the glycosyltransferase domain of YGT (YGTG) in the presence and absence of UDP at 1.9- and 3.4-Å resolution, respectively. Thereby, we identified a previously unknown potassium ion–binding site, which explains potassium ion–dependent enhanced glycosyltransferase activity in clostridial and related toxins. Our findings exhibit a novel type of inverse regulation of Rab proteins by toxins and provide new insights into the structure-function relationship of glycosyltransferase toxins.

ACS Style

G. Stefan Ost; Christophe Wirth; Xenia Bogdanović; Wei-Chun Kao; Björn Schorch; Philipp J. K. Aktories; Panagiotis Papatheodorou; Carsten Schwan; Andreas Schlosser; Thomas Jank; Carola Hunte; Klaus Aktories. Inverse control of Rab proteins by Yersinia ADP-ribosyltransferase and glycosyltransferase related to clostridial glucosylating toxins. Science Advances 2020, 6, eaaz2094 .

AMA Style

G. Stefan Ost, Christophe Wirth, Xenia Bogdanović, Wei-Chun Kao, Björn Schorch, Philipp J. K. Aktories, Panagiotis Papatheodorou, Carsten Schwan, Andreas Schlosser, Thomas Jank, Carola Hunte, Klaus Aktories. Inverse control of Rab proteins by Yersinia ADP-ribosyltransferase and glycosyltransferase related to clostridial glucosylating toxins. Science Advances. 2020; 6 (11):eaaz2094.

Chicago/Turabian Style

G. Stefan Ost; Christophe Wirth; Xenia Bogdanović; Wei-Chun Kao; Björn Schorch; Philipp J. K. Aktories; Panagiotis Papatheodorou; Carsten Schwan; Andreas Schlosser; Thomas Jank; Carola Hunte; Klaus Aktories. 2020. "Inverse control of Rab proteins by Yersinia ADP-ribosyltransferase and glycosyltransferase related to clostridial glucosylating toxins." Science Advances 6, no. 11: eaaz2094.

Research article
Published: 05 August 2019 in Stem Cells International
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Bacitracin is an established antibiotic for local application and inhibits the cell wall synthesis of Gram-positive bacteria. Recently, we discovered a completely different mode of action of bacitracin and reported that this drug protects human cells from intoxication by a variety of medically relevant bacterial protein toxins including CDT, the binary actin ADP-ribosylating toxin ofClostridium(C.)difficile. Bacitracin prevents the transport of CDT into the cytosol of target cells, most likely by inhibiting the transport function of the binding subunit of this toxin. Here, we tested the effect of bacitracin towards TcdB, a major virulence factor ofC. difficilecontributing to severeC. difficile-associated diseases (CDAD) including pseudomembranous colitis. Bacitracin protected stem cell-derived human intestinal organoids as well as human gut epithelial cells from intoxication with TcdB. Moreover, it prevented the TcdB-induced disruption of epithelia formed by gut epithelium cellsin vitroand maintained the barrier function as detected by measuring transepithelial electrical resistance (TEER). In the presence of bacitracin, TcdB was not able reach its substrate Rac1 in the cytosol of human epithelial cells, most likely because its pH-dependent transport across cell membranes into the cytosol is decreased by bacitracin. In conclusion, in addition to its direct antibiotic activity againstC. difficileand its inhibitory effect towards the toxin CDT, bacitracin neutralizes the exotoxin TcdB of this important pathogenic bacterium.

ACS Style

Ziyu Zhu; Leonie Schnell; Bastian Müller; Martin Müller; Panagiotis Papatheodorou; Holger Barth. The Antibiotic Bacitracin Protects Human Intestinal Epithelial Cells and Stem Cell-Derived Intestinal Organoids fromClostridium difficileToxin TcdB. Stem Cells International 2019, 2019, 1 -8.

AMA Style

Ziyu Zhu, Leonie Schnell, Bastian Müller, Martin Müller, Panagiotis Papatheodorou, Holger Barth. The Antibiotic Bacitracin Protects Human Intestinal Epithelial Cells and Stem Cell-Derived Intestinal Organoids fromClostridium difficileToxin TcdB. Stem Cells International. 2019; 2019 ():1-8.

Chicago/Turabian Style

Ziyu Zhu; Leonie Schnell; Bastian Müller; Martin Müller; Panagiotis Papatheodorou; Holger Barth. 2019. "The Antibiotic Bacitracin Protects Human Intestinal Epithelial Cells and Stem Cell-Derived Intestinal Organoids fromClostridium difficileToxin TcdB." Stem Cells International 2019, no. : 1-8.

Journal article
Published: 17 June 2019 in Toxins
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Clostridium difficile induces antibiotic-associated diarrhea due to the release of toxin A (TcdA) and toxin B (TcdB), the latter being its main virulence factor. The epidemic strain NAP1/027 has an increased virulence attributed to different factors. We compared cellular intoxication by TcdBNAP1 with that by the reference strain VPI 10463 (TcdBVPI). In a mouse ligated intestinal loop model, TcdBNAP1 induced higher neutrophil recruitment, cytokine release, and epithelial damage than TcdBVPI. Both toxins modified the same panel of small GTPases and exhibited similar in vitro autoprocessing kinetics. On the basis of sequence variations in the frizzled-binding domain (FBD), we reasoned that TcdBVPI and TcdBNAP1 might have different receptor specificities. To test this possibility, we used a TcdB from a NAP1 variant strain (TcdBNAP1v) unable to glucosylate RhoA but with the same receptor-binding domains as TcdBNAP1. Cells were preincubated with TcdBNAP1v to block cellular receptors, prior to intoxication with either TcdBVPI or TcdBNAP1. Preincubation with TcdBNAP1v blocked RhoA glucosylation by TcdBNAP1 but not by TcdBVPI, indicating that the toxins use different host factors for cell entry. This crucial difference might explain the increased biological activity of TcdBNAP1 in the intestine, representing a contributing factor for the increased virulence of the NAP1/027 strain.

ACS Style

Diana López-Ureña; Josué Orozco-Aguilar; Yendry Chaves-Madrigal; Andrea Ramírez-Mata; Amanda Villalobos-Jimenez; Stefan Ost; Carlos Quesada-Gómez; César Rodríguez; Panagiotis Papatheodorou; Esteban Chaves-Olarte. Toxin B Variants from Clostridium difficile Strains VPI 10463 and NAP1/027 Share Similar Substrate Profile and Cellular Intoxication Kinetics but Use Different Host Cell Entry Factors. Toxins 2019, 11, 348 .

AMA Style

Diana López-Ureña, Josué Orozco-Aguilar, Yendry Chaves-Madrigal, Andrea Ramírez-Mata, Amanda Villalobos-Jimenez, Stefan Ost, Carlos Quesada-Gómez, César Rodríguez, Panagiotis Papatheodorou, Esteban Chaves-Olarte. Toxin B Variants from Clostridium difficile Strains VPI 10463 and NAP1/027 Share Similar Substrate Profile and Cellular Intoxication Kinetics but Use Different Host Cell Entry Factors. Toxins. 2019; 11 (6):348.

Chicago/Turabian Style

Diana López-Ureña; Josué Orozco-Aguilar; Yendry Chaves-Madrigal; Andrea Ramírez-Mata; Amanda Villalobos-Jimenez; Stefan Ost; Carlos Quesada-Gómez; César Rodríguez; Panagiotis Papatheodorou; Esteban Chaves-Olarte. 2019. "Toxin B Variants from Clostridium difficile Strains VPI 10463 and NAP1/027 Share Similar Substrate Profile and Cellular Intoxication Kinetics but Use Different Host Cell Entry Factors." Toxins 11, no. 6: 348.

Journal article
Published: 25 January 2019 in The FASEB Journal
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The antibiotic bacitracin (Bac) inhibits cell wall synthesis of gram-positive bacteria. Here, we discovered a totally different activity of Bac: the neutralization of bacterial exotoxins. Bac prevented intoxication of mammalian cells with the binary enterotoxins Clostridium botulinum C2, C. perfringens ι, C. difficile transferase (CDT), and Bacillus anthracis lethal toxin. The transport (B) subunits of these toxins deliver their respective enzyme (A) subunits into cells. Following endocytosis, the B subunits form pores in membranes of endosomes, which mediate translocation of the A subunits into the cytosol. Bac inhibited formation of such B pores in lipid bilayers in vitro and in living cells, thereby preventing translocation of the A subunit into the cytosol. Bac preserved the epithelial integrity of toxin-treated CaCo-2 monolayers, a model for the human gut epithelium. In conclusion, Bac should be discussed as a therapeutic option against infections with medically relevant toxin-producing bacteria, including C. difficile and B. anthracis, because it inhibits bacterial growth and neutralizes the secreted toxins.-Schnell, L., Felix, I., Müller, B., Sadi, M., von Bank, F., Papatheodorou, P., Popoff, M. R., Aktories, K., Waltenberger, E., Benz, R., Weichbrodt, C., Fauler, M., Frick, M., Barth, H. Revisiting an old antibiotic: bacitracin neutralizes binary bacterial toxins and protects cells from intoxication.

ACS Style

Leonie Schnell; Ina Felix; Bastian Müller; Mirko Sadi; Franziska Bank; Panagiotis Papatheodorou; Michel R. Popoff; Klaus Aktories; Eva Waltenberger; Roland Benz; Conrad Weichbrodt; Michael Fauler; Manfred Frick; Holger Barth. Revisiting an old antibiotic: bacitracin neutralizes binary bacterial toxins and protects cells from intoxication. The FASEB Journal 2019, 33, 5755 -5771.

AMA Style

Leonie Schnell, Ina Felix, Bastian Müller, Mirko Sadi, Franziska Bank, Panagiotis Papatheodorou, Michel R. Popoff, Klaus Aktories, Eva Waltenberger, Roland Benz, Conrad Weichbrodt, Michael Fauler, Manfred Frick, Holger Barth. Revisiting an old antibiotic: bacitracin neutralizes binary bacterial toxins and protects cells from intoxication. The FASEB Journal. 2019; 33 (4):5755-5771.

Chicago/Turabian Style

Leonie Schnell; Ina Felix; Bastian Müller; Mirko Sadi; Franziska Bank; Panagiotis Papatheodorou; Michel R. Popoff; Klaus Aktories; Eva Waltenberger; Roland Benz; Conrad Weichbrodt; Michael Fauler; Manfred Frick; Holger Barth. 2019. "Revisiting an old antibiotic: bacitracin neutralizes binary bacterial toxins and protects cells from intoxication." The FASEB Journal 33, no. 4: 5755-5771.

Research
Published: 28 December 2018 in The FASEB Journal
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Clostridium difficile is associated with antibiotic-associated diarrhea and pseudomembranous colitis in humans. Its 2 major toxins, toxins A and B, enter host cells and inactivate GTPases of the Ras homologue/rat sarcoma family by glucosylation. Pore formation of the toxins in the endosomal membrane enables the translocation of their glucosyltransferase domain into the cytosol, and membrane cholesterol is crucial for this process. Here, we asked whether the activity of the sterol regulatory element–binding protein 2 (SREBP-2) pathway, which regulates the cholesterol content in membranes, affects the susceptibility of target cells toward toxins A and B. We show that the SREBP-2 pathway is crucial for the intoxication process of toxins A and B by using pharmacological inhibitors (PF-429242, 25-hydroxycholesterol) and cells that are specifically deficient in SREBP-2 pathway signaling. SREBP-2 pathway inhibition disturbed the cholesterol-dependent pore formation of toxin B in cellular membranes. Preincubation with the cholesterol-lowering drug simvastatin protected cells from toxin B intoxication. Inhibition of the SREBP-2 pathway was without effect when the enzyme portion of toxin B was introduced into target cells via the cell delivery property of anthrax protective antigen. Taken together, these findings allowed us to identify the SREBP-2 pathway as a suitable target for the development of antitoxin therapeutics against C. difficile toxins A and B.—Papatheodorou, P., Song, S., López-Ureña, D., Witte, A., Marques, F., Ost, G. S., Schorch, B., Chaves-Olarte, E., Aktories, K. Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP-2 pathway. FASEB J. 33, 4883–4892 (2019). www.fasebj.org

ACS Style

Panagiotis Papatheodorou; Shuo Song; Diana López‐Ureña; Alexander Witte; Felícia Marques; Gerhard Stefan Ost; Björn Schorch; Esteban Chaves‐Olarte; Klaus Aktories. Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway. The FASEB Journal 2018, 33, 4883 -4892.

AMA Style

Panagiotis Papatheodorou, Shuo Song, Diana López‐Ureña, Alexander Witte, Felícia Marques, Gerhard Stefan Ost, Björn Schorch, Esteban Chaves‐Olarte, Klaus Aktories. Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway. The FASEB Journal. 2018; 33 (4):4883-4892.

Chicago/Turabian Style

Panagiotis Papatheodorou; Shuo Song; Diana López‐Ureña; Alexander Witte; Felícia Marques; Gerhard Stefan Ost; Björn Schorch; Esteban Chaves‐Olarte; Klaus Aktories. 2018. "Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway." The FASEB Journal 33, no. 4: 4883-4892.

Review
Published: 01 October 2018 in Anaerobe
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Clostridium difficile infection causes antibiotics-associated diarrhea and pseudomembranous colitis. Major virulence factors of C. difficile are the Rho-glucosylating toxins TcdA and TcdB. In addition, many, so-called hypervirulent C. difficile strains produce the binary actin-ADP-ribosylating toxin CDT. CDT causes depolymerization of F-actin and rearrangement of the actin cytoskeleton. Thereby, many cellular functions, which depend on actin, are altered. CDT disturbs the dynamic balance between actin and microtubules in target cells. The toxin increases microtubule polymerization and induces the formation of microtubule-based protrusions at the plasma membrane of target cells. Moreover, CDT causes a redistribution of vesicles from the basolateral side to the apical side, where extracellular matrix proteins are released. These processes may increase the adherence of clostridia to target cells. Here, we review the effects of the action of CDT on the actin cytoskeleton and on the microtubule system.

ACS Style

Klaus Aktories; Panagiotis Papatheodorou; Carsten Schwan. Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton. Anaerobe 2018, 53, 21 -29.

AMA Style

Klaus Aktories, Panagiotis Papatheodorou, Carsten Schwan. Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton. Anaerobe. 2018; 53 ():21-29.

Chicago/Turabian Style

Klaus Aktories; Panagiotis Papatheodorou; Carsten Schwan. 2018. "Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton." Anaerobe 53, no. : 21-29.

Journal article
Published: 02 June 2018 in The Journal of Infectious Diseases
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The pathogenic effects of Clostridium difficile are primarily attributable to the production of the large protein toxins (C difficile toxins [Tcd]) A (TcdA) and B (TcdB). These toxins monoglucosylate Rho GTPases in the cytosol of host cells, causing destruction of the actin cytoskeleton with cytotoxic effects. Low human serum albumin (HSA) levels indicate a higher risk of acquiring and developing a severe C difficile infection (CDI) and are associated with recurrent and fatal disease. We used a combined approach based on docking simulation and biochemical analyses that were performed in vitro on purified proteins and in human epithelial colorectal adenocarcinoma cells (Caco-2), and in vivo on stem cell-derived human intestinal organoids and zebrafish embryos. Our results show that HSA specifically binds via its domain II to TcdA and TcdB and thereby induces their autoproteolytic cleavage at physiological concentrations. This process impairs toxin internalization into the host cells and reduces the toxin-dependent glucosylation of Rho proteins. Our data provide evidence for a specific HSA-dependent self-defense mechanism against C difficile toxins and provide an explanation for the clinical correlation between CDI severity and hypoalbuminemia.

ACS Style

Alessandra Di Masi; Loris Leboffe; Fabio Polticelli; Federica Tonon; Cristina Zennaro; Marianna Caterino; Pasquale Stano; Stephan Fischer; Marlen Hägele; Martin Müller; Alexander Kleger; Panagiotis Papatheodorou; Giuseppina Nocca; Alessandro Arcovito; Andrea Gori; Margherita Ruoppolo; Holger Barth; Nicola Petrosillo; Paolo Ascenzi; Stefano Di Bella. Human Serum Albumin Is an Essential Component of the Host Defense Mechanism Against Clostridium difficile Intoxication. The Journal of Infectious Diseases 2018, 218, 1424 -1435.

AMA Style

Alessandra Di Masi, Loris Leboffe, Fabio Polticelli, Federica Tonon, Cristina Zennaro, Marianna Caterino, Pasquale Stano, Stephan Fischer, Marlen Hägele, Martin Müller, Alexander Kleger, Panagiotis Papatheodorou, Giuseppina Nocca, Alessandro Arcovito, Andrea Gori, Margherita Ruoppolo, Holger Barth, Nicola Petrosillo, Paolo Ascenzi, Stefano Di Bella. Human Serum Albumin Is an Essential Component of the Host Defense Mechanism Against Clostridium difficile Intoxication. The Journal of Infectious Diseases. 2018; 218 (9):1424-1435.

Chicago/Turabian Style

Alessandra Di Masi; Loris Leboffe; Fabio Polticelli; Federica Tonon; Cristina Zennaro; Marianna Caterino; Pasquale Stano; Stephan Fischer; Marlen Hägele; Martin Müller; Alexander Kleger; Panagiotis Papatheodorou; Giuseppina Nocca; Alessandro Arcovito; Andrea Gori; Margherita Ruoppolo; Holger Barth; Nicola Petrosillo; Paolo Ascenzi; Stefano Di Bella. 2018. "Human Serum Albumin Is an Essential Component of the Host Defense Mechanism Against Clostridium difficile Intoxication." The Journal of Infectious Diseases 218, no. 9: 1424-1435.

Journal article
Published: 27 March 2018 in Oncotarget
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Clostridium perfringens toxin TpeL belongs to the family of large clostridial glycosylating toxins. The toxin causes N-acetylglucosaminylation of Ras proteins at threonine35 thereby inactivating the small GTPases. Here, we show that all main types of oncogenic Ras proteins (H-Ras, K-Ras and N-Ras) are modified by the toxin in vitro and in vivo. Toxin-catalyzed modification of Ras was accompanied by inhibition of the MAP kinase pathway. Importantly, TpeL inhibited the paradoxical activation of the MAP kinase pathway induced by the BRAF inhibitor Vemurafenib in the human melanoma cell line SBCL2. The toxin also blocked Ras signaling in a zebrafish embryo model expressing oncogenic H-RasG12V, resulting in a reduction of melanocyte number. By using the binding and translocation component of anthrax toxin (protective antigen), the glucosyltransferase domain of TpeL was effectively introduced into target cells that were not sensitive to native TpeL toxin. To reach a higher specificity towards cancer cells, a chimeric TpeL toxin was engineered that possessed the knob region of adenovirus serotype 35 fiber, which interacts with CD46 of target cells frequently overexpressed in cancer cells. The chimeric TpeL fusion toxin efficiently inhibited Ras and MAP kinases in human pancreatic cancer Capan-2 cells, which were insensitive to the wild-type toxin. The data reveal that TpeL and TpeL-related immunotoxins provide a new toolset as Ras-inactivating agents.

ACS Style

Björn Schorch; Hannah Heni; Nour-Imene Zahaf; Tilman Brummer; Marina Mione; Gudula Schmidt; Panagiotis Papatheodorou; Klaus Aktories. Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL. Oncotarget 2018, 9, 16489 -16500.

AMA Style

Björn Schorch, Hannah Heni, Nour-Imene Zahaf, Tilman Brummer, Marina Mione, Gudula Schmidt, Panagiotis Papatheodorou, Klaus Aktories. Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL. Oncotarget. 2018; 9 (23):16489-16500.

Chicago/Turabian Style

Björn Schorch; Hannah Heni; Nour-Imene Zahaf; Tilman Brummer; Marina Mione; Gudula Schmidt; Panagiotis Papatheodorou; Klaus Aktories. 2018. "Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL." Oncotarget 9, no. 23: 16489-16500.

Chapter
Published: 31 January 2018 in Advances in Experimental Medicine and Biology
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Research on the human gut pathogen Clostridium difficile and its toxins has gained much attention, particularly as a consequence of the increasing threat to human health presented by emerging hypervirulent strains. Toxin A (TcdA) and B (TcdB) are the two major virulence determinants of C. difficile. Both are single-chain proteins with a similar multidomain architecture. Certain hypervirulent C. difficile strains also produce a third toxin, namely binary toxin CDT (Clostridium difficile transferase). As C. difficile toxins are the causative agents of C. difficile-associated diseases (CDAD), such as antibiotics-associated diarrhea and pseudomembranous colitis, considerable efforts have been expended to unravel their molecular mode-of-action and the cellular mechanisms responsible for their uptake. Notably, a high proportion of studies on C. difficile toxins were performed in European laboratories. In this chapter we will highlight important recent advances in C. difficile toxins research.

ACS Style

Panagiotis Papatheodorou; Holger Barth; Nigel Minton; Klaus Aktories. Cellular Uptake and Mode-of-Action of Clostridium difficile Toxins. Advances in Experimental Medicine and Biology 2018, 1050, 77 -96.

AMA Style

Panagiotis Papatheodorou, Holger Barth, Nigel Minton, Klaus Aktories. Cellular Uptake and Mode-of-Action of Clostridium difficile Toxins. Advances in Experimental Medicine and Biology. 2018; 1050 ():77-96.

Chicago/Turabian Style

Panagiotis Papatheodorou; Holger Barth; Nigel Minton; Klaus Aktories. 2018. "Cellular Uptake and Mode-of-Action of Clostridium difficile Toxins." Advances in Experimental Medicine and Biology 1050, no. : 77-96.

Chapter
Published: 06 November 2016 in Current Topics in Microbiology and Immunology
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Binary actin-ADP-ribosylating toxins (e.g., Clostridium botulinum C2 toxin or Clostridium perfringens iota toxin) consist of two separate proteins: An ADP-ribosyltransferase, which modifies actin thereby inhibiting actin polymerization, and a binding component that forms heptamers after proteolytic activation. While C2 toxin interacts with carbohydrate structures on host cells, the group of iota-like toxins binds to lipolysis-stimulated lipoprotein receptor (LSR). Here, we review LSR and discuss the role and function of LSR in interaction of iota-like toxins with host cells.

ACS Style

Panagiotis Papatheodorou; Klaus Aktories. Receptor-Binding and Uptake of Binary Actin-ADP-Ribosylating Toxins. Current Topics in Microbiology and Immunology 2016, 406, 119 -133.

AMA Style

Panagiotis Papatheodorou, Klaus Aktories. Receptor-Binding and Uptake of Binary Actin-ADP-Ribosylating Toxins. Current Topics in Microbiology and Immunology. 2016; 406 ():119-133.

Chicago/Turabian Style

Panagiotis Papatheodorou; Klaus Aktories. 2016. "Receptor-Binding and Uptake of Binary Actin-ADP-Ribosylating Toxins." Current Topics in Microbiology and Immunology 406, no. : 119-133.

Journal article
Published: 01 October 2016 in Anaerobe
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Panagiotis Papatheodorou; Klaus Aktories. Preface for Anaerobe – Special issue on Clostpath9. Anaerobe 2016, 41, 1 .

AMA Style

Panagiotis Papatheodorou, Klaus Aktories. Preface for Anaerobe – Special issue on Clostpath9. Anaerobe. 2016; 41 ():1.

Chicago/Turabian Style

Panagiotis Papatheodorou; Klaus Aktories. 2016. "Preface for Anaerobe – Special issue on Clostpath9." Anaerobe 41, no. : 1.

Journal article
Published: 06 July 2016 in Oncotarget
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// Bernd A. Czulkies 1 , Justin Mastroianni 2 , Lisa Lutz 3 , Sarah Lang 1 , Carsten Schwan 1 , Gudula Schmidt 1 , Silke Lassmann 3, 4, 5 , Robert Zeiser 2, 5 , Klaus Aktories 1, 5, 6 , Panagiotis Papatheodorou 1, # 1 Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University (ALU), Freiburg, Germany 2 Department of Hematology and Oncology, University Medical Center, ALU, Freiburg, Germany 3 Department of Pathology, University Medical Center, ALU, Freiburg, Germany 4 German Consortium for Translational Cancer Research (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany 5 Centre for Biological Signalling Studies (BIOSS), ALU, Freiburg, Germany 6 Freiburg Institute for Advanced Studies (FRIAS), ALU, Freiburg, Germany # Present address: Institute of Pharmaceutical Biotechnology (University of Ulm) and Institute of Pharmacology and Toxicology (University of Ulm Medical Center), Ulm, Germany Correspondence to: Panagiotis Papatheodorou, email: [email protected] Keywords: tumor growth, xenograft, epithelial barrier, cell morphology, cell-cell contact Received: March 21, 2016 Accepted: June 13, 2016 Published: July 06, 2016 ABSTRACT The lipolysis-stimulated lipoprotein receptor (LSR) is a lipoprotein receptor, serves as host receptor for clostridial iota-like toxins and is involved in the formation of tricellular contacts. Of particular interest is the role of LSR in progression of various cancers. Here we aimed to study the tumor growth of LSR-deficient colon carcinoma-derived cell lines HCT116 and CaCo-2 in a mouse xenograft model. Whereas knockout of LSR had no effect on tumor growth of HCT116 cells, we observed that CaCo-2 LSR knockout tumors grew to a smaller size than their wild-type counterparts. Histological analysis revealed increased apoptotic and necrotic cell death in a tumor originating from LSR-deficient CaCo-2 cells. LSR-deficient CaCo-2 cells exhibited increased cell proliferation in vitro and an altered epithelial morphology with impaired targeting of tricellulin to tricellular contacts. In addition, loss of LSR reduced the transepithelial electrical resistance of CaCo-2 cell monolayers and increased permeability for small molecules. Moreover, LSR-deficient CaCo-2 cells formed larger cysts in 3D culture than their wild-type counterparts. Our study provides evidence that LSR affects epithelial morphology and barrier formation in CaCo-2 cells and examines for the first time the effects of LSR deficiency on the tumor growth properties of colon carcinoma-derived cell lines.

ACS Style

Bernd A. Czulkies; Justin Mastroianni; Lisa Lutz; Sarah Lang; Carsten Schwan; Gudula Schmidt; Silke Lassmann; Robert Zeiser; Klaus Aktories; Panagiotis Papatheodorou. Loss of LSR affects epithelial barrier integrity and tumor xenograft growth of CaCo-2 cells. Oncotarget 2016, 8, 37009 -37022.

AMA Style

Bernd A. Czulkies, Justin Mastroianni, Lisa Lutz, Sarah Lang, Carsten Schwan, Gudula Schmidt, Silke Lassmann, Robert Zeiser, Klaus Aktories, Panagiotis Papatheodorou. Loss of LSR affects epithelial barrier integrity and tumor xenograft growth of CaCo-2 cells. Oncotarget. 2016; 8 (23):37009-37022.

Chicago/Turabian Style

Bernd A. Czulkies; Justin Mastroianni; Lisa Lutz; Sarah Lang; Carsten Schwan; Gudula Schmidt; Silke Lassmann; Robert Zeiser; Klaus Aktories; Panagiotis Papatheodorou. 2016. "Loss of LSR affects epithelial barrier integrity and tumor xenograft growth of CaCo-2 cells." Oncotarget 8, no. 23: 37009-37022.

Journal article
Published: 01 May 2015 in Journal of Biological Chemistry
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CDT (Clostridium difficile transferase) is a binary, actin ADP-ribosylating toxin frequently associated with hypervirulent strains of the human enteric pathogen C. difficile, the most serious cause of antibiotic-associated diarrhea and pseudomembranous colitis. CDT leads to the collapse of the actin cytoskeleton and, eventually, to cell death. Low doses of CDT result in the formation of microtubule-based protrusions on the cell surface that increase the adherence and colonization of C. difficile. The lipolysis-stimulated lipoprotein receptor (LSR) is the host cell receptor for CDT, and our aim was to gain a deeper insight into the interplay between both proteins. We show that CDT interacts with the extracellular, Ig-like domain of LSR with an affinity in the nanomolar range. We identified LSR splice variants in the colon carcinoma cell line HCT116 and disrupted the LSR gene in these cells by applying the CRISPR-Cas9 technology. LSR truncations ectopically expressed in LSR knock-out cells indicated that intracellular parts of LSR are not essential for plasma membrane targeting of the receptor and cellular uptake of CDT. By generating a series of N- and C-terminal truncations of the binding component of CDT (CDTb), we found that amino acids 757-866 of CDTb are sufficient for binding to LSR. With a transposon-based, random mutagenesis approach, we identified potential LSR-interacting epitopes in CDTb. This study increases our understanding about the interaction between CDT and its receptor LSR, which is key to the development of anti-toxin strategies for preventing cell entry of the toxin.

ACS Style

Sarah Hemmasi; Bernd A. Czulkies; Björn Schorch; Antonia Veit; Klaus Aktories; Panagiotis Papatheodorou. Interaction of the Clostridium difficile Binary Toxin CDT and Its Host Cell Receptor, Lipolysis-stimulated Lipoprotein Receptor (LSR). Journal of Biological Chemistry 2015, 290, 14031 -14044.

AMA Style

Sarah Hemmasi, Bernd A. Czulkies, Björn Schorch, Antonia Veit, Klaus Aktories, Panagiotis Papatheodorou. Interaction of the Clostridium difficile Binary Toxin CDT and Its Host Cell Receptor, Lipolysis-stimulated Lipoprotein Receptor (LSR). Journal of Biological Chemistry. 2015; 290 (22):14031-14044.

Chicago/Turabian Style

Sarah Hemmasi; Bernd A. Czulkies; Björn Schorch; Antonia Veit; Klaus Aktories; Panagiotis Papatheodorou. 2015. "Interaction of the Clostridium difficile Binary Toxin CDT and Its Host Cell Receptor, Lipolysis-stimulated Lipoprotein Receptor (LSR)." Journal of Biological Chemistry 290, no. 22: 14031-14044.

Review
Published: 01 February 2015 in Current Opinion in Microbiology
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While bacterial effectors are often directly introduced into eukaryotic target cells by various types of injection machines, toxins enter the cytosol of host cells from endosomal compartments or after retrograde transport via Golgi from the ER. A first crucial step of toxin-host interaction is receptor binding. Using optimized protocols and new methods novel toxin receptors have been identified, including metalloprotease ADAM 10 for Staphylococcus aureus α-toxin, laminin receptor Lu/BCAM for Escherichia coli cytotoxic necrotizing factor CNF1, lipolysis stimulated lipoprotein receptor (LSR) for Clostridium difficile transferase CDT and low-density lipoprotein receptor-related protein (LRP) 1 for Clostridium perfringens TpeL toxin.

ACS Style

Gudula Schmidt; Panagiotis Papatheodorou; Klaus Aktories. Novel receptors for bacterial protein toxins. Current Opinion in Microbiology 2015, 23, 55 -61.

AMA Style

Gudula Schmidt, Panagiotis Papatheodorou, Klaus Aktories. Novel receptors for bacterial protein toxins. Current Opinion in Microbiology. 2015; 23 ():55-61.

Chicago/Turabian Style

Gudula Schmidt; Panagiotis Papatheodorou; Klaus Aktories. 2015. "Novel receptors for bacterial protein toxins." Current Opinion in Microbiology 23, no. : 55-61.

Journal article
Published: 15 April 2014 in Proceedings of the National Academy of Sciences
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Large glycosylating toxins are major virulence factors of various species of pathogenic Clostridia. Prototypes are Clostridium difficile toxins A and B, which cause antibiotics-associated diarrhea and pseudomembranous colitis. The current model of the toxins’ action suggests that receptor binding is mediated by a C-terminal domain of combined repetitive oligopeptides (CROP). This model is challenged by the glycosylating Clostridium perfringens large cytotoxin (TpeL toxin) that is devoid of the CROP domain but still intoxicates cells. Using a haploid genetic screen, we identified LDL receptor-related protein 1 (LRP1) as a host cell receptor for the TpeL toxin. LRP1-deficient cells are not able to take up TpeL and are not intoxicated. Expression of cluster IV of LRP1 is sufficient to rescue toxin uptake in these cells. By plasmon resonance spectroscopy, a K D value of 23 nM was determined for binding of TpeL to LRP1 cluster IV. The C terminus of TpeL (residues 1335–1779) represents the receptor-binding domain (RBD) of the toxin. RBD-like regions are conserved in all other clostridial glycosylating toxins preceding their CROP domain. CROP-deficient C. difficile toxin B is toxic to cells, depending on the RBD-like region (residues 1349–1811) but does not interact with LRP1. Our data indicate the presence of a second, CROP-independent receptor-binding domain in clostridial glycosylating toxins and suggest a two-receptor model for the cellular uptake of clostridial glycosylating toxins. Significance Glycosylating toxins are major virulence factors of pathogenic Clostridia, including Clostridium difficile toxins A and B, which cause antibiotics-associated diarrhea and pseudomembranous colitis. Host cell uptake of these toxins is suggested to be mediated via C-terminal combined repetitive oligopeptides (CROP). Here, we identified LDL receptor-related protein 1 (LRP1) as a host cell receptor of Clostridium perfringens TpeL toxin, a recently identified clostridial glycosylating toxin, which has no CROP domain. TpeL binds to LRP1 with a C-terminal receptor-binding domain, which is conserved in all other clostridial glycosylating toxins and precedes the CROP domain. Thus, our study identifies LRP1 as TpeL receptor and suggests a two-receptor model for clostridial glycosylating toxins, which offers additional perspectives in antitoxin strategies.

ACS Style

Björn Schorch; Shuo Song; Ferdy R. van Diemen; Hans H. Bock; Petra May; Joachim Herz; Thijn R. Brummelkamp; Panagiotis Papatheodorou; Klaus Aktories. LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins. Proceedings of the National Academy of Sciences 2014, 111, 6431 -6436.

AMA Style

Björn Schorch, Shuo Song, Ferdy R. van Diemen, Hans H. Bock, Petra May, Joachim Herz, Thijn R. Brummelkamp, Panagiotis Papatheodorou, Klaus Aktories. LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins. Proceedings of the National Academy of Sciences. 2014; 111 (17):6431-6436.

Chicago/Turabian Style

Björn Schorch; Shuo Song; Ferdy R. van Diemen; Hans H. Bock; Petra May; Joachim Herz; Thijn R. Brummelkamp; Panagiotis Papatheodorou; Klaus Aktories. 2014. "LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins." Proceedings of the National Academy of Sciences 111, no. 17: 6431-6436.

Research article
Published: 16 January 2014 in PLOS Pathogens
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The Cytotoxic Necrotizing Factor 1 (CNF1) is a protein toxin which is a major virulence factor of pathogenic Escherichia coli strains. Here, we identified the Lutheran (Lu) adhesion glycoprotein/basal cell adhesion molecule (BCAM) as cellular receptor for CNF1 by co-precipitation of cell surface molecules with tagged toxin. The CNF1-Lu/BCAM interaction was verified by direct protein-protein interaction analysis and competition studies. These studies revealed amino acids 720 to 1014 of CNF1 as the binding site for Lu/BCAM. We suggest two cell interaction sites in CNF1: first the N-terminus, which binds to p37LRP as postulated before. Binding of CNF1 to p37LRP seems to be crucial for the toxin's action. However, it is not sufficient for the binding of CNF1 to the cell surface. A region directly adjacent to the catalytic domain is a high affinity interaction site for Lu/BCAM. We found Lu/BCAM to be essential for the binding of CNF1 to cells. Cells deficient in Lu/BCAM but expressing p37LRP could not bind labeled CNF1. Therefore, we conclude that LRP and Lu/BCAM are both required for toxin action but with different functions. We study a crucial virulence factor produced by pathogenic Escherichia coli strains, the Cytotoxic Necrotizing Factor 1 (CNF1). More than 80% of urinary tract infections (UTIs), which are counted among the most common bacterial infections of humans, are caused by Uropathogenic Escherichia coli (UPEC) strains. We and others elucidated the molecular mechanism of the E. coli toxin CNF1. It constitutively activates Rho GTPases by a direct covalent modification. The toxin enters mammalian cells by receptor-mediated endocytosis. Here, we identified the protein receptor for CNF1 by co-precipitation of cell surface molecules with the tagged toxin and subsequent Maldi-TOF analysis. We identified the Lutheran (Lu) adhesion glycoprotein/basal cell adhesion molecule (BCAM) as receptor for CNF1 and located its interaction site to the C-terminal part of the toxin. We performed direct protein-protein interaction analysis and competition studies. Moreover, cells deficient in Lu/BCAM could not bind labeled CNF1. The identification of a toxin's cellular receptor and receptor binding region is an important task for understanding the pathogenic function of the toxin and, moreover, to make the toxin accessible for its use as a cellbiological and pharmacological tool, for example for the generation of immunotoxins.

ACS Style

Marianne Piteau; Panagiotis Papatheodorou; Carsten Schwan; Andreas Schlosser; Klaus Aktories; Gudula Schmidt. Lu/BCAM Adhesion Glycoprotein Is a Receptor for Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1). PLOS Pathogens 2014, 10, e1003884 .

AMA Style

Marianne Piteau, Panagiotis Papatheodorou, Carsten Schwan, Andreas Schlosser, Klaus Aktories, Gudula Schmidt. Lu/BCAM Adhesion Glycoprotein Is a Receptor for Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1). PLOS Pathogens. 2014; 10 (1):e1003884.

Chicago/Turabian Style

Marianne Piteau; Panagiotis Papatheodorou; Carsten Schwan; Andreas Schlosser; Klaus Aktories; Gudula Schmidt. 2014. "Lu/BCAM Adhesion Glycoprotein Is a Receptor for Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1)." PLOS Pathogens 10, no. 1: e1003884.

Journal article
Published: 05 November 2013 in Cellular Microbiology
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TccC3 and TccC5 from Photorhabdus luminescens are ADP-ribosyltransferases, which modify actin and Rho GTPases, respectively, thereby inducing polymerization and clustering of actin. The bacterial proteins are components of the Photorhabdus toxin complexes, consisting of the binding and translocation component TcdA1, a proposed linker component TcdB2 and the enzymatic component TccC3/5. While the action of the toxins on target proteins is clearly defined, uptake and translocation of the toxins into the cytosol of target cells are not well understood. Here we show by using pharmacological inhibitors that heat shock protein 90 (Hsp90) and peptidyl prolyl cis/trans isomerases (PPIases) including cyclophilins and FK506-binding proteins (FKBPs) facilitate the uptake of the ADP-ribosylating toxins into the host cell cytosol. Inhibition of Hsp90 and/or PPIases resulted in decreased intoxication of target cells by Photorhabdus toxin complexes determined by cell rounding and reduction of transepithelial electrical resistance of cell monolayers. ADP-ribosyltransferase activity of toxins and toxin-induced pore formation were notimpaired by the inhibitors of Hsp90 and PPIases. The Photorhabdus toxins interacted with Hsp90, FKBP51, Cyp40 and CypA, suggesting a role of these host cell factors in translocation and/or refolding of the ADP-ribosyltransferases.

ACS Style

Alexander E. Lang; Katharina Ernst; Haram Lee; Panagiotis Papatheodorou; Carsten Schwan; Holger Barth; Klaus Aktories. The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation ofPhotorhabdus luminescens ADP-ribosyltransferases. Cellular Microbiology 2013, 16, 490 -503.

AMA Style

Alexander E. Lang, Katharina Ernst, Haram Lee, Panagiotis Papatheodorou, Carsten Schwan, Holger Barth, Klaus Aktories. The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation ofPhotorhabdus luminescens ADP-ribosyltransferases. Cellular Microbiology. 2013; 16 (4):490-503.

Chicago/Turabian Style

Alexander E. Lang; Katharina Ernst; Haram Lee; Panagiotis Papatheodorou; Carsten Schwan; Holger Barth; Klaus Aktories. 2013. "The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation ofPhotorhabdus luminescens ADP-ribosyltransferases." Cellular Microbiology 16, no. 4: 490-503.