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Toxins
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ADP-Ribosylating Toxin
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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) | Viewed by 22639

Special Issue Editor

Prof. Dr. Joseph Barbieri

E-Mail Website
Guest Editor
Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Microbiology and Immunology, BSB-255, Milwaukee, WI 53226, USA
Interests: protein toxins; type-III effectors; structure-based mechanisms of toxin action; botulinum toxins; tetanus toxin; cellular microbiology
Special Issues, Collections and Topics in MDPI journals

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

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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

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

Published Papers (5 papers)

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Research

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24 pages, 6694 KiB  
Article
An In-Silico Sequence-Structure-Function Analysis of the N-Terminal Lobe in CT Group Bacterial ADP-Ribosyltransferase Toxins
by Miguel R. Lugo and A. Rod Merrill
Toxins 2019, 11(6), 365; https://doi.org/10.3390/toxins11060365 - 21 Jun 2019
Cited by 6 | Viewed by 3406
Abstract
The C3-like toxins are single-domain proteins that represent a minimal mono-ADP-ribosyl transferase (mART) enzyme with a simple model scaffold for the entire cholera toxin (CT)-group. These proteins possess a single (A-domain) that modifies Rho proteins. In contrast, C2-like toxins require a binding/translocation partner [...] Read more.
The C3-like toxins are single-domain proteins that represent a minimal mono-ADP-ribosyl transferase (mART) enzyme with a simple model scaffold for the entire cholera toxin (CT)-group. These proteins possess a single (A-domain) that modifies Rho proteins. In contrast, C2-like toxins require a binding/translocation partner (B-component) for intoxication. These are A-only toxins that contain the E-x-E motif, modify G-actin, but are two-domains with a C-domain possessing enzymatic activity. The N-domain of the C2-like toxins is unstructured, and its function is currently unknown. A sequence-structure-function comparison was performed on the N-terminal region of the mART domain of the enzymatic component of the CT toxin group in the CATCH fold (3.90.210.10). Special consideration was given to the N-domain distal segment, the α-lobe (α1–α4), and its different roles in these toxin sub-groups. These results show that the role of the N-terminal α-lobe is to provide a suitable configuration (i) of the α2–α3 helices to feature the α3-motif that has a role in NAD+ substrate binding and possibly in the interaction with the protein target; (ii) the α3–α4 helices to provide the α3/4-loop with protein-protein interaction capability; and (iii) the α1-Ntail that features specialized motif(s) according to the toxin type (A-only or A-B toxins) exhibiting an effect on the catalytic activity via the ARTT-loop, with a role in the inter-domain stability, and with a function in the binding and/or translocation steps during the internalization process. Full article
(This article belongs to the Special Issue ADP-Ribosylating Toxin)
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14 pages, 1767 KiB  
Article
CesH Represses Cereulide Synthesis as an Alpha/Beta Fold Hydrolase in Bacillus cereus
by Shen Tian, Hairong Xiong, Peiling Geng, Zhiming Yuan and Xiaomin Hu
Toxins 2019, 11(4), 231; https://doi.org/10.3390/toxins11040231 - 21 Apr 2019
Cited by 9 | Viewed by 3807
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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16 pages, 2661 KiB  
Article
Protein Synthesis Inhibition Activity of Mesothelin Targeting Immunotoxin LMB-100 Decreases Concentrations of Oncogenic Signaling Molecules and Secreted Growth Factors
by Salma El-Behaedi, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Rakan Albalawy, Xianyu Zhang, Tapan Bera, Keith Collins, Serguei Kozlov and Christine Alewine
Toxins 2018, 10(11), 447; https://doi.org/10.3390/toxins10110447 - 31 Oct 2018
Cited by 9 | Viewed by 3678
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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10 pages, 1414 KiB  
Article
Interaction of Clostridium perfringens Iota Toxin and Lipolysis-Stimulated Lipoprotein Receptor (LSR)
by Masahiro Nagahama, Masaya Takehara and Keiko Kobayashi
Toxins 2018, 10(10), 405; https://doi.org/10.3390/toxins10100405 - 08 Oct 2018
Cited by 11 | Viewed by 3310
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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Review

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16 pages, 1778 KiB  
Review
The ADP-Ribosylating Toxins of Salmonella
by Rachel A. Cheng and Martin Wiedmann
Toxins 2019, 11(7), 416; https://doi.org/10.3390/toxins11070416 - 16 Jul 2019
Cited by 16 | Viewed by 7305
Abstract
A number of pathogenic bacteria utilize toxins to mediate disease in a susceptible host. The foodborne pathogen Salmonella is one of the most important and well-studied bacterial pathogens. Recently, whole genome sequence characterizations revealed the presence of multiple novel ADP-ribosylating toxins encoded by [...] Read more.
A number of pathogenic bacteria utilize toxins to mediate disease in a susceptible host. The foodborne pathogen Salmonella is one of the most important and well-studied bacterial pathogens. Recently, whole genome sequence characterizations revealed the presence of multiple novel ADP-ribosylating toxins encoded by a variety of Salmonella serovars. In this review, we discuss both the classical (SpvB) and novel (typhoid toxin, ArtAB, and SboC/SeoC) ADP-ribosylating toxins of Salmonella, including the structure and function of these toxins and our current understanding of their contributions to virulence. Full article
(This article belongs to the Special Issue ADP-Ribosylating Toxin)
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