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Toxins
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Intracellular Traffic and Transport of Bacterial Protein Toxins
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Intracellular Traffic and Transport of Bacterial Protein Toxins

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (31 May 2014) | Viewed by 39748

Special Issue Editor

Prof. Dr. Holger Barth

E-Mail Website
Guest Editor
Institut für Pharmakologie und Toxikologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany
Interests: actin; bacterial protein toxins; macrophages; rho-gtpases; cellular uptake and intracellular membrane transport of bacterial toxins; interaction of bacterial toxins with host cell chaperones; bacterial toxins as molecular trojan horses for drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bacterial protein toxins which act as enzymes in the cytosol of mammalian cells are the causative agents for a variety of severe human and animals diseases. Significant progress was made in understanding the cellular uptake, the intracellular traffic of bacterial toxins and their interaction with host cell factors including chaperones and folding helper enzymes during transport of their enzymatic active subunits across intracellular membranes into the host cell cytosol. However, for many toxins their cellular receptors as well as the detailed molecular mechanisms underlying their membrane translocation are still not known. Since uptake into the cytosol of target cells is essential for the cytotoxic mode of action of most medically relevant toxins, a targeted pharmacological inhibition of toxin uptake into cells could result in novel therapeutic strategies against toxin-associated diseases. On the other hand, non-toxic portions of bacterial toxins can serve as "Molecular Trojan Horses" for efficient delivery of therapeutic molecules into target cells.

This special issue of Toxins covers new findings about the intracellular traffic and transport of bacterial protein toxins as well as their pharmacological exploitations.

Prof. Dr. Holger Barth
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

  • bacterial protein toxins
  • cellular uptake
  • receptors
  • intracellular traffic
  • membrane transport
  • role of host cell factors in toxin translocation
  • pharmacological strategies to inhibit toxin uptake into cells

Published Papers (5 papers)

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Research

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964 KiB  
Article
Tailored Cyclodextrin Pore Blocker Protects Mammalian Cells from Clostridium difficile Binary Toxin CDT
by Maurice Roeder, Ekaterina M. Nestorovich, Vladimir A. Karginov, Carsten Schwan, Klaus Aktories and Holger Barth
Toxins 2014, 6(7), 2097-2114; https://doi.org/10.3390/toxins6072097 - 15 Jul 2014
Cited by 14 | Viewed by 6534
Abstract
Some Clostridium difficile strains produce, in addition to toxins A and B, the binary toxin Clostridium difficile transferase (CDT), which ADP-ribosylates actin and may contribute to the hypervirulence of these strains. The separate binding and translocation component CDTb mediates transport of the enzyme [...] Read more.
Some Clostridium difficile strains produce, in addition to toxins A and B, the binary toxin Clostridium difficile transferase (CDT), which ADP-ribosylates actin and may contribute to the hypervirulence of these strains. The separate binding and translocation component CDTb mediates transport of the enzyme component CDTa into mammalian target cells. CDTb binds to its receptor on the cell surface, CDTa assembles and CDTb/CDTa complexes are internalised. In acidic endosomes, CDTb mediates the delivery of CDTa into the cytosol, most likely by forming a translocation pore in endosomal membranes. We demonstrate that a seven-fold symmetrical positively charged β-cyclodextrin derivative, per-6-S-(3-aminomethyl)benzylthio-β-cyclodextrin, which was developed earlier as a potent inhibitor of the translocation pores of related binary toxins of Bacillus anthracis, Clostridium botulinum and Clostridium perfringens, protects cells from intoxication with CDT. The pore blocker did not interfere with the CDTa-catalyzed ADP-ribosylation of actin or toxin binding to Vero cells but inhibited the pH-dependent membrane translocation of CDTa into the cytosol. In conclusion, the cationic β-cyclodextrin could serve as the lead compound in a development of novel pharmacological strategies against the CDT-producing strains of C. difficile. Full article
(This article belongs to the Special Issue Intracellular Traffic and Transport of Bacterial Protein Toxins)
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3146 KiB  
Article
Reporter Assay for Endo/Lysosomal Escape of Toxin-Based Therapeutics
by Roger Gilabert-Oriol, Mayank Thakur, Benedicta Von Mallinckrodt, Cheenu Bhargava, Burkhard Wiesner, Jenny Eichhorst, Matthias F. Melzig, Hendrik Fuchs and Alexander Weng
Toxins 2014, 6(5), 1644-1666; https://doi.org/10.3390/toxins6051644 - 22 May 2014
Cited by 7 | Viewed by 7184
Abstract
Protein-based therapeutics with cytosolic targets are capable of exhibiting their therapeutic effect once they have escaped from the endosomes or lysosomes. In this study, the reporters—horseradish peroxidase (HRP), Alexa Fluor 488 (Alexa) and ricin A-chain (RTA)—were investigated for their capacity to [...] Read more.
Protein-based therapeutics with cytosolic targets are capable of exhibiting their therapeutic effect once they have escaped from the endosomes or lysosomes. In this study, the reporters—horseradish peroxidase (HRP), Alexa Fluor 488 (Alexa) and ricin A-chain (RTA)—were investigated for their capacity to monitor the endo/lysosomal escape of the ribosome-inactivating protein, saporin. The conjugates—saporin-HRP, Alexasaporin and saporin-KQ-RTA—were constructed, and the endo/lysosomal escape of these conjugates alone (lack of endo/lysosomal release) or in combination with certain structurally-specific triterpenoidal saponins (efficient endo/lysosomal escape) was characterized. HRP failed in reporting the endo/lysosomal escape of saporin. Contrastingly, Alexa Fluor 488 successfully allowed the report of the process at a toxin concentration of 1000 nM. In addition, single endo/lysosome analysis facilitated the determination of the amount of Alexasaporin released from each vesicle. RTA was also successful in reporting the endo/lysosomal escape of the enzymatically inactive mutant, saporin-KQ, but in this case, the sensitivity of the method reached a toxin concentration of 10 nM. In conclusion, the simultaneous usage of Alexa Fluor 488 and RTA as reporters may provide the possibility of monitoring the endo/lysosomal escape of protein-based therapeutics in the concentration range of 10–1000 nM. Full article
(This article belongs to the Special Issue Intracellular Traffic and Transport of Bacterial Protein Toxins)
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Review

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1086 KiB  
Review
Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion
by Ana-Cristina Sotomayor-Pérez, Daniel Ladant and Alexandre Chenal
Toxins 2015, 7(1), 1-20; https://doi.org/10.3390/toxins7010001 - 31 Dec 2014
Cited by 33 | Viewed by 6428
Abstract
The past decade has seen a fundamental reappraisal of the protein structure-to-function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the biological functions of many [...] Read more.
The past decade has seen a fundamental reappraisal of the protein structure-to-function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the biological functions of many proteins that contain intrinsically disordered regions. This trait is exhibited by RTX (Repeat in ToXin) motifs found in more than 250 virulence factors secreted by Gram-negative pathogenic bacteria. We have investigated several RTX-containing polypeptides of different lengths, all derived from the Bordetella pertussis adenylate cyclase toxin, CyaA. Using a combination of experimental approaches, we showed that the RTX proteins exhibit the hallmarks of intrinsically disordered proteins in the absence of calcium. This intrinsic disorder mainly results from internal electrostatic repulsions between negatively charged residues of the RTX motifs. Calcium binding triggers a strong reduction of the mean net charge, dehydration and compaction, folding and stabilization of secondary and tertiary structures of the RTX proteins. We propose that the intrinsically disordered character of the RTX proteins may facilitate the uptake and secretion of virulence factors through the bacterial secretion machinery. These results support the hypothesis that the folding reaction is achieved upon protein secretion and, in the case of proteins containing RTX motifs, could be finely regulated by the calcium gradient across bacterial cell wall. Full article
(This article belongs to the Special Issue Intracellular Traffic and Transport of Bacterial Protein Toxins)
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1200 KiB  
Review
Uptake and Processing of the Cytolethal Distending Toxin by Mammalian Cells
by Joseph M. DiRienzo
Toxins 2014, 6(11), 3098-3116; https://doi.org/10.3390/toxins6113098 - 31 Oct 2014
Cited by 37 | Viewed by 7337
Abstract
The cytolethal distending toxin (Cdt) is a heterotrimeric holotoxin produced by a diverse group of Gram-negative pathogenic bacteria. The Cdts expressed by the members of this group comprise a subclass of the AB toxin superfamily. Some AB toxins have hijacked the retrograde transport [...] Read more.
The cytolethal distending toxin (Cdt) is a heterotrimeric holotoxin produced by a diverse group of Gram-negative pathogenic bacteria. The Cdts expressed by the members of this group comprise a subclass of the AB toxin superfamily. Some AB toxins have hijacked the retrograde transport pathway, carried out by the Golgi apparatus and endoplasmic reticulum (ER), to translocate to cytosolic targets. Those toxins have been used as tools to decipher the roles of the Golgi and ER in intracellular transport and to develop medically useful delivery reagents. In comparison to the other AB toxins, the Cdt exhibits unique properties, such as translocation to the nucleus, that present specific challenges in understanding the precise molecular details of the trafficking pathway in mammalian cells. The purpose of this review is to present current information about the mechanisms of uptake and translocation of the Cdt in relation to standard concepts of endocytosis and retrograde transport. Studies of the Cdt intoxication process to date have led to the discovery of new translocation pathways and components and most likely will continue to reveal unknown features about the mechanisms by which bacterial proteins target the mammalian cell nucleus. Insight gained from these studies has the potential to contribute to the development of novel therapeutic strategies. Full article
(This article belongs to the Special Issue Intracellular Traffic and Transport of Bacterial Protein Toxins)
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1816 KiB  
Review
Channel-Forming Bacterial Toxins in Biosensing and Macromolecule Delivery
by Philip A. Gurnev and Ekaterina M. Nestorovich
Toxins 2014, 6(8), 2483-2540; https://doi.org/10.3390/toxins6082483 - 21 Aug 2014
Cited by 38 | Viewed by 11718
Abstract
To intoxicate cells, pore-forming bacterial toxins are evolved to allow for the transmembrane traffic of different substrates, ranging from small inorganic ions to cell-specific polypeptides. Recent developments in single-channel electrical recordings, X-ray crystallography, protein engineering, and computational methods have generated a large body [...] Read more.
To intoxicate cells, pore-forming bacterial toxins are evolved to allow for the transmembrane traffic of different substrates, ranging from small inorganic ions to cell-specific polypeptides. Recent developments in single-channel electrical recordings, X-ray crystallography, protein engineering, and computational methods have generated a large body of knowledge about the basic principles of channel-mediated molecular transport. These discoveries provide a robust framework for expansion of the described principles and methods toward use of biological nanopores in the growing field of nanobiotechnology. This article, written for a special volume on “Intracellular Traffic and Transport of Bacterial Protein Toxins”, reviews the current state of applications of pore-forming bacterial toxins in small- and macromolecule-sensing, targeted cancer therapy, and drug delivery. We discuss the electrophysiological studies that explore molecular details of channel-facilitated protein and polymer transport across cellular membranes using both natural and foreign substrates. The review focuses on the structurally and functionally different bacterial toxins: gramicidin A of Bacillus brevis, α-hemolysin of Staphylococcus aureus, and binary toxin of Bacillus anthracis, which have found their “second life” in a variety of developing medical and technological applications. Full article
(This article belongs to the Special Issue Intracellular Traffic and Transport of Bacterial Protein Toxins)
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