Special Issue "New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms, Functions and Applications"

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

Deadline for manuscript submissions: closed (30 September 2021).

Special Issue Editors

Dr. Uris Ros
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Guest Editor
CECAD research center, Joseph-Stelzmann-Straße 26, 50931 Köln, Germany
Interests: Pore-Forming Toxins
Dr. Katia Cosentino
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Guest Editor
Department of Biology/Chemistry, Center of Cellular Nanoanalytics (CellNanOs), Barbarastr. 11, 49076 Osnabrueck, Germany

Special Issue Information

Dear Colleagues,

Pore-forming proteins (PFPs) are a large and structurally heterogeneous group of proteins that have the common ability to punch holes in the membrane. Amongst them, pore-forming toxins (PFTs) use this function to attack their host and represent some of the most potent virulence factors found in nature. PFTs share structural and mechanistic similarities with small host defense peptides (or antimicrobial peptides, AMPs) and other large endogenous PFPs that permeabilize membranes as part of host defense mechanisms against microorganisms or as components of regulatory signaling pathways in plants and animals. The general mode of action of these proteins and peptides involves membrane binding and insertion, oligomerization and eventually pore formation. Pore opening is usually lethal for the cell. However, despite these similarities, the sequence of events and detailed mechanisms how oligomeric structures assemble and form pores is highly variable from protein to protein and still obscure in several aspects. On a functional level, why did nature develop different ways of piercing membranes to kill a cell? Do different mechanisms of pore formation and different pore structures define different functionalities? Is cell death the unique consequence of membrane permeabilization? Which are the consequences of the sub-lytic action of these molecules? Understanding how membrane permeabilization is regulated holds a significant therapeutic potential to control this process in different biological processes such as infection, host defense, immunity and cell death. In this Special Issue we will welcome both reviews and research articles to provide an overview of the current knowledge about the molecular mechanisms and broad function of membrane pore formation for different proteins and peptides. Further studies on the biomedical applications of these proteins and peptides, as well as on the use of new state-of-art techniques that facilitate the characterization of membrane pores, are also encouraged.

Dr. Uris Ros
Dr. Katia Cosentino
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 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 2400 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

  • pore-forming proteins
  • pore-forming toxins
  • antimicrobial peptides
  • membrane pores
  • virulence factors
  • host-defense mechanisms
  • cell death
  • inflammation
  • immunity

Published Papers (3 papers)

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Research

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Article
Force Mapping Study of Actinoporin Effect in Membranes Presenting Phase Domains
Toxins 2021, 13(9), 669; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13090669 - 18 Sep 2021
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Abstract
Equinatoxin II (EqtII) and Fragaceatoxin C (FraC) are pore-forming toxins (PFTs) from the actinoporin family that have enhanced membrane affinity in the presence of sphingomyelin (SM) and phase coexistence in the membrane. However, little is known about the effect of these proteins on [...] Read more.
Equinatoxin II (EqtII) and Fragaceatoxin C (FraC) are pore-forming toxins (PFTs) from the actinoporin family that have enhanced membrane affinity in the presence of sphingomyelin (SM) and phase coexistence in the membrane. However, little is known about the effect of these proteins on the nanoscopic properties of membrane domains. Here, we used combined confocal microscopy and force mapping by atomic force microscopy to study the effect of EqtII and FraC on the organization of phase-separated phosphatidylcholine/SM/cholesterol membranes. To this aim, we developed a fast, high-throughput processing tool to correlate structural and nano-mechanical information from force mapping. We found that both proteins changed the lipid domain shape. Strikingly, they induced a reduction in the domain area and circularity, suggesting a decrease in the line tension due to a lipid phase height mismatch, which correlated with proteins binding to the domain interfaces. Moreover, force mapping suggested that the proteins affected the mechanical properties at the edge, but not in the bulk, of the domains. This effect could not be revealed by ensemble force spectroscopy measurements supporting the suitability of force mapping to study local membrane topographical and mechanical alterations by membranotropic proteins. Full article
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Article
Internalization of Clostridium botulinum C2 Toxin Is Regulated by Cathepsin B Released from Lysosomes
Toxins 2021, 13(4), 272; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13040272 - 09 Apr 2021
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Abstract
Clostridium botulinum C2 toxin is a clostridial binary toxin consisting of actin ADP-ribosyltransferase (C2I) and C2II binding components. Activated C2II (C2IIa) binds to cellular receptors and forms oligomer in membrane rafts. C2IIa oligomer assembles with C2I and contributes to the transport of C2I [...] Read more.
Clostridium botulinum C2 toxin is a clostridial binary toxin consisting of actin ADP-ribosyltransferase (C2I) and C2II binding components. Activated C2II (C2IIa) binds to cellular receptors and forms oligomer in membrane rafts. C2IIa oligomer assembles with C2I and contributes to the transport of C2I into the cytoplasm of host cells. C2IIa induces Ca2+-induced lysosomal exocytosis, extracellular release of the acid sphingomyelinase (ASMase), and membrane invagination and endocytosis through generating ceramides in the membrane by ASMase. Here, we reveal that C2 toxin requires the lysosomal enzyme cathepsin B (CTSB) during endocytosis. Lysosomes are a rich source of proteases, containing cysteine protease CTSB and cathepsin L (CTSL), and aspartyl protease cathepsin D (CTSD). Cysteine protease inhibitor E64 blocked C2 toxin-induced cell rounding, but aspartyl protease inhibitor pepstatin-A did not. E64 inhibited the C2IIa-promoted extracellular ASMase activity, indicating that the protease contributes to the activation of ASMase. C2IIa induced the extracellular release of CTSB and CTSL, but not CTSD. CTSB knockdown by siRNA suppressed C2 toxin-caused cytotoxicity, but not siCTSL. These findings demonstrate that CTSB is important for effective cellular entry of C2 toxin into cells through increasing ASMase activity. Full article
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Review

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Review
Panorama of the Intracellular Molecular Concert Orchestrated by Actinoporins, Pore-Forming Toxins from Sea Anemones
Toxins 2021, 13(8), 567; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13080567 - 13 Aug 2021
Viewed by 726
Abstract
Actinoporins (APs) are soluble pore-forming proteins secreted by sea anemones that experience conformational changes originating in pores in the membranes that can lead to cell death. The processes involved in the binding and pore-formation of members of this protein family have been deeply [...] Read more.
Actinoporins (APs) are soluble pore-forming proteins secreted by sea anemones that experience conformational changes originating in pores in the membranes that can lead to cell death. The processes involved in the binding and pore-formation of members of this protein family have been deeply examined in recent years; however, the intracellular responses to APs are only beginning to be understood. Unlike pore formers of bacterial origin, whose intracellular impact has been studied in more detail, currently, we only have knowledge of a few poorly integrated elements of the APs’ intracellular action. In this review, we present and discuss an updated landscape of the studies aimed at understanding the intracellular pathways triggered in response to APs attack with particular reference to sticholysin II, the most active isoform produced by the Caribbean Sea anemone Stichodactyla helianthus. To achieve this, we first describe the major alterations these cytolysins elicit on simpler cells, such as non-nucleated mammalian erythrocytes, and then onto more complex eukaryotic cells, including tumor cells. This understanding has provided the basis for the development of novel applications of sticholysins such as the construction of immunotoxins directed against undesirable cells, such as tumor cells, and the design of a cancer vaccine platform. These are among the most interesting potential uses for the members of this toxin family that have been carried out in our laboratory. Full article
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