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Special Issue "Molecular Mechanisms of Action of Natural and Synthetic Protein Toxins and Their Applications"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editors

Prof. Dr. Alexander Tonevitsky
E-Mail Website
Guest Editor
Faculty of Biology and Biotechnology, National Research University Higher School of Economics, 101000 Moscow, Russia
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia
Far Eastern Federal University, 690091 Vladivostok, Russia
Interests: mechanisms of intracellular transport of proteins and the creation of models for selective cytotoxic effects on target cells; molecular mechanisms of cancer progression; the role of gene expression regulation by miRNAs for homeostasis and in pathology processes; microphysiological systems - Organ-on-a-Chip; development of methods for non-invasive study of key mechanisms of homeostasis
Dr. Diana Maltseva
E-Mail
Guest Editor Assistant
Faculty of Biology and Biotechnology, National Research University Higher School of Economics, 101000 Moscow, Russia;
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia

Special Issue Information

Dear Colleagues,

Toxic proteins naturally occur in a wide variety of species, where they play a major role in defense against feeding animals and various insects and pathogens, giving them an advantage in a particular niche shaped by evolution. Protein toxins are present in human foods and cosmetics and play a major role as etiological agents in the development of diseases. Many bacterial and plant toxins utilize cellular mechanisms of retrograde vesicular transport to be delivered into the cell, particularly into the cytoplasm, where they realize their cytotoxic potential. Some toxins serve as powerful tools for studying endocytic and protein degradation machineries. Because of their cytotoxicity, protein toxins show great potential in broad therapeutic and biotechnological applications, including vaccinations, treatment of chronic migraines and autoimmunity diseases, and anticancer therapy. This Special Issue will focus on the novel insights concerning the mechanisms by which natural and bioengineered protein toxins enter into cell, their achievements in target cell delivery, their utilization of different cellular mechanisms for the development of a toxic effect, as well as on new strategies and recent strides taken with respect to the application of protein toxins. Fundamental, functional, and methodological studies are welcome, as well as clinical studies with biomolecular experiments and reviews highlighting the most significant protein toxin-related breakthroughs of the last decade.

Prof. Dr. Alexander Tonevitsky
Dr. Diana Maltseva
Guest Editors

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 papers will be 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 single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • protein toxin
  • immunotoxin
  • intracellular vesicle transport
  • toxin fusions
  • biotechnology
  • endocytosis
  • retrograde transport
  • transcytosis
  • protein degradation
  • ERAD
  • proteasome degradation
  • endoplasmic reticulum
  • ER
  • translocation
  • anticancer therapy
  • clinical applications
  • therapeutic applications

Published Papers (4 papers)

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Research

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Article
Proteus mirabilis Urease: Unsuspected Non-Enzymatic Properties Relevant to Pathogenicity
Int. J. Mol. Sci. 2021, 22(13), 7205; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137205 - 04 Jul 2021
Cited by 1 | Viewed by 822
Abstract
Infection by Proteus mirabilis causes urinary stones and catheter incrustation due to ammonia formed by urease (PMU), one of its virulence factors. Non-enzymatic properties, such as pro-inflammatory and neurotoxic activities, were previously reported for distinct ureases, including that of the gastric pathogen Helicobacter [...] Read more.
Infection by Proteus mirabilis causes urinary stones and catheter incrustation due to ammonia formed by urease (PMU), one of its virulence factors. Non-enzymatic properties, such as pro-inflammatory and neurotoxic activities, were previously reported for distinct ureases, including that of the gastric pathogen Helicobacter pylori. Here, PMU was assayed on isolated cells to evaluate its non-enzymatic properties. Purified PMU (nanomolar range) was tested in human (platelets, HEK293 and SH-SY5Y) cells, and in murine microglia (BV-2). PMU promoted platelet aggregation. It did not affect cellular viability and no ammonia was detected in the cultures’ supernatants. PMU-treated HEK293 cells acquired a pro-inflammatory phenotype, producing reactive oxygen species (ROS) and cytokines IL-1β and TNF-α. SH-SY5Y cells stimulated with PMU showed high levels of intracellular Ca2+ and ROS production, but unlike BV-2 cells, SH-SY5Y did not synthesize TNF-α and IL-1β. Texas Red-labeled PMU was found in the cytoplasm and in the nucleus of all cell types. Bioinformatic analysis revealed two bipartite nuclear localization sequences in PMU. We have shown that PMU, besides urinary stone formation, can potentially contribute in other ways to pathogenesis. Our data suggest that PMU triggers pro-inflammatory effects and may affect cells beyond the renal system, indicating a possible role in extra-urinary diseases. Full article
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Article
A cis-Acting Mutation in the PxABCG1 Promoter Is Associated with Cry1Ac Resistance in Plutella xylostella (L.)
Int. J. Mol. Sci. 2021, 22(11), 6106; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116106 - 05 Jun 2021
Cited by 1 | Viewed by 772
Abstract
The molecular mechanisms of insect resistance to Cry toxins generated from the bacterium Bacillus thuringiensis (Bt) urgently need to be elucidated to enable the improvement and sustainability of Bt-based products. Although downregulation of the expression of midgut receptor genes is a pivotal mechanism [...] Read more.
The molecular mechanisms of insect resistance to Cry toxins generated from the bacterium Bacillus thuringiensis (Bt) urgently need to be elucidated to enable the improvement and sustainability of Bt-based products. Although downregulation of the expression of midgut receptor genes is a pivotal mechanism of insect resistance to Bt Cry toxins, the underlying transcriptional regulation of these genes remains elusive. Herein, we unraveled the regulatory mechanism of the downregulation of the ABC transporter gene PxABCG1 (also called Pxwhite), a functional midgut receptor of the Bt Cry1Ac toxin in Plutella xylostella. The PxABCG1 promoters of Cry1Ac-susceptible and Cry1Ac-resistant strains were cloned and analyzed, and they showed clear differences in activity. Subsequently, a dual-luciferase reporter assay, a yeast one-hybrid (Y1H) assay, and RNA interference (RNAi) experiments demonstrated that a cis-mutation in a binding site of the Hox transcription factor Antennapedia (Antp) decreased the promoter activity of the resistant strain and eliminated the binding and regulation of Antp, thereby enhancing the resistance of P. xylostella to the Cry1Ac toxin. These results advance our knowledge of the roles of cis- and trans-regulatory variations in the regulation of midgut Cry receptor genes and the evolution of Bt resistance, contributing to a more complete understanding of the Bt resistance mechanism. Full article
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Article
The Role of Cholesterol on Triterpenoid Saponin-Induced Endolysosomal Escape of a Saporin-Based Immunotoxin
Int. J. Mol. Sci. 2020, 21(22), 8734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228734 - 19 Nov 2020
Viewed by 525
Abstract
Cholesterol seems to play a central role in the augmentation of saporin-based immunotoxin (IT) cytotoxicity by triterpenoid saponins. Endolysosomal escape has been proposed as one mechanism for the saponin-mediated enhancement of targeted toxins. We investigated the effects of lipid depletion followed by repletion [...] Read more.
Cholesterol seems to play a central role in the augmentation of saporin-based immunotoxin (IT) cytotoxicity by triterpenoid saponins. Endolysosomal escape has been proposed as one mechanism for the saponin-mediated enhancement of targeted toxins. We investigated the effects of lipid depletion followed by repletion on Saponinum album (SA)-induced endolysosomal escape of Alexa Fluor labelled saporin and the saporin-based immunotoxin OKT10-SAP, directed against CD38, in Daudi lymphoma cells. Lipid deprived cells showed reduced SA-induced endolysosomal escape at two concentrations of SA, as determined by a flow cytometric method. The repletion of membrane cholesterol by low density lipoprotein (LDL) restored SA-induced endolysosomal escape at a concentration of 5 µg/mL SA but not at 1 µg/mL SA. When LDL was used to restore the cholesterol levels in lipid deprived cells, the SA augmentation of OKT10-SAP cytotoxicity was partially restored at 1 µg/mL SA and fully restored at 5 µg/mL SA. These results suggest that different mechanisms of action might be involved for the two different concentrations of SA and that endosomal escape may not be the main mechanism for the augmentation of saporin IT cytotoxicity by SA at the sub-lytic concentration of 1 µg/mL SA. Full article
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Review

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Review
Natural and Designed Toxins for Precise Therapy: Modern Approaches in Experimental Oncology
Int. J. Mol. Sci. 2021, 22(9), 4975; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094975 - 07 May 2021
Cited by 1 | Viewed by 661
Abstract
Cancer cells frequently overexpress specific surface receptors providing tumor growth and survival which can be used for precise therapy. Targeting cancer cell receptors with protein toxins is an attractive approach widely used in contemporary experimental oncology and preclinical studies. Methods of targeted delivery [...] Read more.
Cancer cells frequently overexpress specific surface receptors providing tumor growth and survival which can be used for precise therapy. Targeting cancer cell receptors with protein toxins is an attractive approach widely used in contemporary experimental oncology and preclinical studies. Methods of targeted delivery of toxins to cancer cells, different drug carriers based on nanosized materials (liposomes, nanoparticles, polymers), the most promising designed light-activated toxins, as well as mechanisms of the cytotoxic action of the main natural toxins used in modern experimental oncology, are discussed in this review. The prospects of the combined therapy of tumors based on multimodal nanostructures are also discussed. Full article
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