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Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine

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

Deadline for manuscript submissions: 20 June 2024 | Viewed by 13641

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Special Issue Editor

Dr. Monika Slominska-Wojewodzka

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Guest Editor

Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
Interests: endoplasmic reticulum; intracellular transport of toxins

Special Issue Information

Dear Colleagues,

Protein toxins from bacteria and plants utilize different intracellular pathways that determine how their toxicity is regulated. Toxins are internalized via several endocytic mechanisms in reaching early endosomes. From these compartments, toxins can be recycled back to the cell surface, transported to late endosomes and further to lysosomes for degradation, or undergo retrograde sorting to the Golgi apparatus and the endoplasmic reticulum. Some bacterial toxins are translocated to the cytosol from both early and late endosomes, where they exert their cytotoxic effects. Toxins that reach the Golgi are sent to the endoplasmic reticulum to be transported to the cytosol through the endoplasmic reticulum associated degradation (ERAD) pathway. All of these aspects of intracellular transport have been intensely studied in recent years. Such studies provide an important and interesting research topic because they allow: i) investigating the exact mechanisms of action of toxins and their cytotoxicity; ii) using toxins as model proteins to determine the involvement of cellular proteins at specific steps of intracellular transport; and iii) applying toxins in a growing number of different medical applications. The medical approach includes construction of vaccines and neutralizing antibodies against particular toxins, since the most potent and lethal toxins pose a serious threat to human life. On the other hand, the unique features of protein toxins provide opportunities for their use in biomedical research. These studies include therapy of cancer using immunotoxins, delivery of therapeutic drugs to cells using nanoparticle-conjugated toxins, or the use of toxins to treat protein misfolding diseases.

This Special Issue aims to bring together the latest research on the intracellular trafficking of toxins as well as to include up-to-date studies centered on broad aspects of toxin applications in cell biology and medicine. Original research articles and reviews are welcome in this Special Issue.

Dr. Monika Slominska-Wojewodzka
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

toxins
intracellular trafficking
ERAD
immunotoxins
nanoparticle-conjugated toxins
protein misfolding diseases
therapy

Published Papers (6 papers)

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Research

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20 pages, 4262 KiB

Open AccessArticle

Domperidone Inhibits Clostridium botulinum C2 Toxin and Bordetella pertussis Toxin

by Jinfang Jia, Maria Braune-Yan, Stefanie Lietz, Mary Wahba, Arto T. Pulliainen, Holger Barth and Katharina Ernst

Toxins 2023, 15(7), 412; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins15070412 - 25 Jun 2023

Cited by 1 | Viewed by 1302

Abstract

Bordetella pertussis toxin (PT) and Clostridium botulinum C2 toxin are ADP-ribosylating toxins causing severe diseases in humans and animals. They share a common translocation mechanism requiring the cellular chaperones Hsp90 and Hsp70, cyclophilins, and FK506-binding proteins to transport the toxins’ enzyme subunits into the cytosol. Inhibitors of chaperone activities have been shown to reduce the amount of transported enzyme subunits into the cytosol of cells, thus protecting cells from intoxication by these toxins. Recently, domperidone, an approved dopamine receptor antagonist drug, was found to inhibit Hsp70 activity. Since Hsp70 is required for cellular toxin uptake, we hypothesized that domperidone also protects cells from intoxication with PT and C2. The inhibition of intoxication by domperidone was demonstrated by analyzing the ADP-ribosylation status of the toxins’ specific substrates. Domperidone had no inhibitory effect on the receptor-binding or enzyme activity of the toxins, but it inhibited the pH-driven membrane translocation of the enzyme subunit of the C2 toxin and reduced the amount of PTS1 in cells. Taken together, our results indicate that domperidone is a potent inhibitor of PT and C2 toxins in cells and therefore might have therapeutic potential by repurposing domperidone to treat diseases caused by bacterial toxins that require Hsp70 for their cellular uptake. Full article

(This article belongs to the Special Issue Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine)

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23 pages, 5583 KiB

Open AccessEditor’s ChoiceArticle

The Clostridium botulinum C2 Toxin Subunit C2IIa Delivers Enzymes with Positively Charged N-Termini into the Cytosol of Target Cells

by Sebastian Heber, Joscha Borho, Nicole Stadler, Fanny Wondany, Irina König, Jens Michaelis, Panagiotis Papatheodorou, Holger Barth and Maximilian Fellermann

Toxins 2023, 15(6), 390; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins15060390 - 09 Jun 2023

Viewed by 1741

Abstract

The binary Clostridium (C.) botulinum C2 toxin consists of two non-linked proteins. The proteolytically activated binding/transport subunit C2IIa forms barrel-shaped homoheptamers, which bind to cell surface receptors, mediate endocytosis, and translocate the enzyme subunit C2I into the cytosol of target cells. Here, we investigate whether C2IIa can be harnessed as a transporter for proteins/enzymes fused to polycationic tags, as earlier demonstrated for the related anthrax toxin transport subunit PA₆₃. To test C2IIa-mediated transport in cultured cells, reporter enzymes are generated by fusing different polycationic tags to the N- or C-terminus of other bacterial toxins’ catalytic A subunits. C2IIa as well as PA₆₃ deliver N-terminally polyhistidine-tagged proteins more efficiently compared to C-terminally tagged ones. However, in contrast to PA₆₃, C2IIa does not efficiently deliver polylysine-tagged proteins into the cytosol of target cells. Moreover, untagged enzymes with a native cationic N-terminus are efficiently transported by both C2IIa and PA₆₃. In conclusion, the C2IIa-transporter serves as a transport system for enzymes that harbor positively charged amino acids at their N-terminus. The charge distribution at the N-terminus of cargo proteins and their ability to unfold in the endosome and subsequently refold in the cytosol determine transport feasibility and efficiency. Full article

(This article belongs to the Special Issue Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine)

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9 pages, 19353 KiB

Open AccessArticle

Incobotulinum Toxin Type A for Treatment of Ultraviolet-B-Induced Hyperpigmentation: A Prospective, Randomized, Controlled Trial

by Vasanop Vachiramon, Tanaporn Anuntrangsee, Pasita Palakornkitti, Natthachat Jurairattanaporn and Sarawin Harnchoowong

Toxins 2022, 14(6), 417; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14060417 - 17 Jun 2022

Viewed by 2020

Abstract

Incobotulinum toxin A (IncoBoNT-A) is effective in preventing ultraviolet B (UVB)-induced hyperpigmentation. This prospective, randomized, controlled study aimed to evaluate the effect of IncoBoNT-A on the treatment of UVB-induced hyperpigmentation in 15 volunteers. Five hyperpigmentation squares (2 × 2 cm) were induced by local UVB on the abdomen at baseline. At Day 7, each site was randomized to receive no treatment (control), normal saline, or intradermal IncoBoNT-A injection with 1:2.5, 1:5, and 1:7.5 dilutions (12, 6, and 4 units, respectively). The mean lightness index (L*), hyperpigmentation improvement score evaluated by blinded dermatologists, and participant satisfaction scores were obtained at Days 21, 28, and 35. At Day 21, improvements in mean L* of 1:2.5, 1:5, and 1:7.5 IncoBoNT-A-treated, saline-treated, and control sites were 14.30%, 12.28%, 6.62%, 0.32%, and 4.98%, respectively (p = 0.86). At Day 28, the improvement in mean L* in IncoBoNT-A-treated groups was superior to that in the other groups. In terms of the hyperpigmentation improvement score, 12 participants (80%) experienced better outcomes with the IncoBoNT-A-injected site compared with the other sites. IncoBoNT-A, especially at higher concentrations, showed some positive effects on the treatment of UVB-induced hyperpigmentation. This may serve as an adjuvant treatment for hyperpigmentary conditions that are aggravated by UVB. Full article

(This article belongs to the Special Issue Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine)

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13 pages, 2612 KiB

Open AccessArticle

Modulation of Ricin Intoxication by the Autophagy Inhibitor EACC

by Kirsten Sandvig, Simona Kavaliauskiene, Anne Grethe Myrann, Tore Geir Iversen and Tore Skotland

Toxins 2022, 14(5), 360; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14050360 - 22 May 2022

Cited by 1 | Viewed by 2089

Abstract

The compound EACC (ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate) was recently reported to inhibit fusion of autophagosomes with lysosomes in a reversible manner by inhibiting recruitment of syntaxin 17 to autophagosomes. We report here that this compound also provides a strong protection against the protein toxin ricin as well as against other plant toxins such as abrin and modeccin. The protection did not seem to be caused by inhibition of endocytosis and retrograde transport, but rather by inhibited release of the enzymatically active A-moiety to the cytosol. The TANK-binding kinase 1 (TBK1) has been reported to phosphorylate syntaxin 17 and be required for initiation of autophagy. The inhibitor of TBK1, MRT68601, induced in itself a strong sensitization to ricin, apparently by increasing transport to the Golgi apparatus. Importantly, MRT68601 increased Golgi transport of ricin even in the presence of EACC, but EACC was still able to inhibit intoxication, supporting the idea that EACC protects at a late step along the retrograde pathway. These results also indicate that phosphorylation of syntaxin 17 is not required for the protection observed. Full article

(This article belongs to the Special Issue Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine)

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Review

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30 pages, 1287 KiB

Open AccessReview

Bacterial Toxin-Antitoxin Systems’ Cross-Interactions—Implications for Practical Use in Medicine and Biotechnology

by Lidia Boss and Barbara Kędzierska

Toxins 2023, 15(6), 380; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins15060380 - 04 Jun 2023

Cited by 2 | Viewed by 2639

Abstract

Toxin-antitoxin (TA) systems are widely present in bacterial genomes. They consist of stable toxins and unstable antitoxins that are classified into distinct groups based on their structure and biological activity. TA systems are mostly related to mobile genetic elements and can be easily acquired through horizontal gene transfer. The ubiquity of different homologous and non-homologous TA systems within a single bacterial genome raises questions about their potential cross-interactions. Unspecific cross-talk between toxins and antitoxins of non-cognate modules may unbalance the ratio of the interacting partners and cause an increase in the free toxin level, which can be deleterious to the cell. Moreover, TA systems can be involved in broadly understood molecular networks as transcriptional regulators of other genes’ expression or modulators of cellular mRNA stability. In nature, multiple copies of highly similar or identical TA systems are rather infrequent and probably represent a transition stage during evolution to complete insulation or decay of one of them. Nevertheless, several types of cross-interactions have been described in the literature to date. This implies a question of the possibility and consequences of the TA system cross-interactions, especially in the context of the practical application of the TA-based biotechnological and medical strategies, in which such TAs will be used outside their natural context, will be artificially introduced and induced in the new hosts. Thus, in this review, we discuss the prospective challenges of system cross-talks in the safety and effectiveness of TA system usage. Full article

(This article belongs to the Special Issue Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine)

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12 pages, 1067 KiB

Open AccessReview

Botulinum Toxin Type A for the Treatment of Skin Ulcers: A Review Article

by Waranaree Winayanuwattikun and Vasanop Vachiramon

Toxins 2022, 14(6), 406; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14060406 - 14 Jun 2022

Cited by 3 | Viewed by 2612

Abstract

The normal biological wound healing process consists of three precisely and highly programmed phases that require optimal conditions including internal and external factors. Any negative factors that disrupt the sequence or time frame of the healing mechanism can result in a non-healing wound or chronic ulcers. Botulinum neurotoxin A (BoNT-A) which is generally known as anti-contraction of muscles has been reported as a successful treatment in various types of chronic ulcers. The aim of this study is to review the outcome of treatment with BoNT-A for chronic skin ulcers. The results demonstrated some positive effects of BoNT-A on chronic ulcers. Ischemic ulcers secondary to Raynaud’s phenomenon seem to be the most promising type of ulcers that have benefited from BoNT-A. The rationale behind using BoNT-A to fasten the wound healing process is also discussed. Further clinical trial studies should be conducted to affirm the efficacy of wound healing using BoNT-A administration. Full article

(This article belongs to the Special Issue Intracellular Transport of Toxins: Insights into Mechanisms of Cytotoxicity and Applications in Cell Biology and Medicine)

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