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Special Issue "ADP-Ribosylating Toxin"

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

Deadline for manuscript submissions: closed (31 May 2019)

Special Issue Editor

Guest Editor
Prof. Joseph T. Barbieri

Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Website | E-Mail
Interests: the cellular and molecular basis of microbial pathogenesis; the action of bacterial toxins; botulinum and tetanus neurotoxins; type III cytotoxins; Certhrax, an ADP-ribosylating exotoxin

Special Issue Information

Dear Colleagues,

Studies on the family of ADP-ribosylating toxins have provided significant insight into host­–pathogen interactions at several levels of resolution.  Structural studies showed the A-B organization of these toxins and provided a basis for understanding how protein toxins enter host cells and traffic within the host cell endosomal pathway to translocate the catalytic A fragment into the host cell cytosol to modulate host cell physiology through the ADP-ribosylation of host substrates. Cell biological studies were among the first to show the prototypical ADP-ribosylating toxin, diphtheria toxin, to form ion-conducting channels via a pH-triggered insertion of the translocation domains into host cells, which correlated with the ability of the toxin to translocate the catalytic domain into host cells. Early utilities of these toxins included modification to produce a potent chemically inactivated toxoid, utilization as a platform for conjugate vaccines, a catalytic domain for first-generation immunotoxins, and recently as targets of nanobodies to inactivate intracellular and extracellular ADP-ribosylating proteins. Some members of the cholera toxin-like family of ADP-ribosylating toxins are used as targeted adjuvants to develop efficacious mucosal vaccines. Of note is the ADP-ribosylation cycle of eukaryotic cells, which modulates an endogenous ADP-ribosylation cycle to modulate of several cellular processes via the action of ADP-ribosylation factors and ADP-ribosyl hydrolases. Derivatives of the ADP-ribosylating toxins include the single catalytic domain RhoA-targeting proteins which function in bacterial-host interactions of animals and plants. Continued development of structure-based alignments continues to predict distantly related members of the family of ADP-ribosylating toxins, which may provide new reagents for human therapies, while molecular approaches have extended the number of ADP-ribosylating variants for family members that possess different modes of action.    

Prof. Joseph T. Barbieri
Guest Editor

Manuscript Submission Information

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Keywords

  • ADP-ribosylation
  • NAD
  • Bacterial toxins
  • A-B organization
  • Vaccines
  • Immunotoxins

Published Papers (3 papers)

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Research

Open AccessArticle
CesH Represses Cereulide Synthesis as an Alpha/Beta Fold Hydrolase in Bacillus cereus
Received: 18 March 2019 / Revised: 13 April 2019 / Accepted: 20 April 2019 / Published: 21 April 2019
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Abstract
Cereulide is notorious as a heat-stable emetic toxin produced by Bacillus cereus and glucose is supposed to be an ingredient supporting its formation. This study showed that glucose addition benefited on cell growth and the early transcription of genes involved in substrate accumulation [...] Read more.
Cereulide is notorious as a heat-stable emetic toxin produced by Bacillus cereus and glucose is supposed to be an ingredient supporting its formation. This study showed that glucose addition benefited on cell growth and the early transcription of genes involved in substrate accumulation and toxin synthesis, but it played a negative role in the final production of cereulide. Meanwhile, a lasting enhancement of cesH transcription was observed with the addition of glucose. Moreover, the cereulide production in ΔcesH was obviously higher than that in the wild type. This indicates that CesH has a repression effect on cereulide production. Bioinformatics analysis revealed that CesH was an alpha/beta hydrolase that probably associated with the cell membrane, which was verified by subcellular localization. The esterase activity against para-nitrophenyl acetate (PNPC2) of the recombinant CesH was confirmed. Although no sign of ester bond cleavage in cereulide or valinomycin was demonstrated in in vitro assays, CesH could reverse the cereulide analogue sensitivity of Bacillus subtilis in vivo, by which toxin degradation was facilitated. Moreover, site directed mutations identified that the conserved catalytic triad of CesH might consist of Serine 86, Glutamate 199, and Histidine 227. These results help us to understand the regulation of cereulide production and provide clues for developing control measurements. Full article
(This article belongs to the Special Issue ADP-Ribosylating Toxin)
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Open AccessArticle
Protein Synthesis Inhibition Activity of Mesothelin Targeting Immunotoxin LMB-100 Decreases Concentrations of Oncogenic Signaling Molecules and Secreted Growth Factors
Toxins 2018, 10(11), 447; https://doi.org/10.3390/toxins10110447
Received: 25 September 2018 / Revised: 25 October 2018 / Accepted: 27 October 2018 / Published: 31 October 2018
PDF Full-text (2661 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
LMB-100 is a mesothelin-targeted recombinant immunotoxin (iTox) that carries a modified Pseuodomonas exotoxin A (PE) payload. PE kills cells by inhibiting synthesis of new proteins. We found that treatment of pancreatic cancer cells with LMB-100 for 24–48 h did not change total protein [...] Read more.
LMB-100 is a mesothelin-targeted recombinant immunotoxin (iTox) that carries a modified Pseuodomonas exotoxin A (PE) payload. PE kills cells by inhibiting synthesis of new proteins. We found that treatment of pancreatic cancer cells with LMB-100 for 24–48 h did not change total protein level despite inducing protein synthesis inhibition (PSI). Further, increased levels of ubiquitinated proteins were detected, indicating that cells may have limited ability to compensate for PSI by reducing protein degradation. Together, these data suggest that PE depletes concentrations of a minority of cellular proteins. We used reverse phase protein array and Luminex assay to characterize this subset. LMB-100 decreased the abundance of 24 of 32 cancer-related proteins (including Bcl-x, Her2, Her3 and MUC16) without compensatory increases in other analytes. Further, cancer cells failed to maintain extracellular concentrations of cancer cell secreted growth factors (CCSGFs), including Vascular Endothelial Growth Factor (VEGF) following treatment with cytostatic LMB-100 doses both in culture and in mouse tumors. Decreased VEGF concentration did not change tumor vasculature density, however, LMB-100 caused tissue-specific changes in concentrations of secreted factors made by non-cancer cells. In summary, our data indicate that PSI caused by cytostatic LMB-100 doses preferentially depletes short-lived proteins such as oncogenic signaling molecules and CCSGFs. Full article
(This article belongs to the Special Issue ADP-Ribosylating Toxin)
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Open AccessArticle
Interaction of Clostridium perfringens Iota Toxin and Lipolysis-Stimulated Lipoprotein Receptor (LSR)
Toxins 2018, 10(10), 405; https://doi.org/10.3390/toxins10100405
Received: 7 September 2018 / Revised: 29 September 2018 / Accepted: 4 October 2018 / Published: 8 October 2018
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Abstract
Iota toxin produced by Clostridium perfringens is a binary, actin ADP-ribosylating toxin that is organized into the enzymatically active component Ia and the binding component Ib. Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a cellular receptor of Ib. Here, we investigated the [...] Read more.
Iota toxin produced by Clostridium perfringens is a binary, actin ADP-ribosylating toxin that is organized into the enzymatically active component Ia and the binding component Ib. Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a cellular receptor of Ib. Here, we investigated the functional interaction between Ib and LSR, where siRNA for LSR blocked the toxin-mediated cytotoxicity and the binding of Ib. The addition of Ib to LSR-green fluorescence protein (GFP)-transfected cells at 4 °C resulted in colocalization with LSR and Ib on the cell surface. Upon transfer of the cells from 4 °C to 37 °C, LSR and Ib were internalized and observed in cytoplasmic vesicles. When the cells were incubated with Ib at 37 °C and fractionated using the Triton-insoluble membrane, Ib oligomer was localized in insoluble factions that fulfilled the criteria of lipid rafts, and LSR was clustered in lipid rafts. To examine the interaction between N-terminal extracellular region of LSR and Ib, we constructed a series of LSR N-terminal deletions. Ten amino acids residues can be deleted from this end without any reduction of Ib binding. However, deletion of 15 N-terminal residues drastically reduces its ability to bind Ib. These results demonstrate that Ib binds to the LSR N-terminal 10 to 15 residues and endocytoses into trafficking endosomes together with LSR. Full article
(This article belongs to the Special Issue ADP-Ribosylating Toxin)
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