Special Issue "Pore-Forming Toxins (PFTs): Never Out of Fashion"

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (31 May 2019).

Special Issue Editors

Prof. Dr. Alvaro Martínez-del-Pozo
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Guest Editor
Departamento de Bioquímica, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
Dr. Sara García Linares
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Guest Editor
Cell Biology Department, Harvard Medical School, Boston, MA 02115, USA

Special Issue Information

Dear Colleagues,

Pore-forming toxins (PFTs) are ubiquitous peptides and proteins present in a wide variety of organisms, from prokaryotes to multicellular eukaryotes. Given their toxic character, they abound in venoms. Usually produced as water-soluble components, they suffer different conformational and oligomerization arrangements to become integral membrane structures, forming a pore. Typically, this pore leads to the death of the target cell by osmotic shock. Although most of them share a general mode of action, there is still much to learn about the particulars of their mechanism. Some PFTs recognize specific protein membrane receptors to achieve their action, but many others take advantage of the different membrane composition among organisms and/or cellular organelles. Accordingly, in many instances, PFTs target specific lipids such as sphingomyelin or cholesterol. Overall, further understanding PFTs molecular mechanisms will expand the available repertoire of pharmacological and biotechnological tools and will help to improve our knowledge of venoms composition and envenomation.

Prof. Dr. Alvaro Martínez-del-Pozo
Dr. Sara García Linares
Guest Editors

Manuscript Submission Information

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Keywords

  • Venom
  • Toxin
  • Pore
  • Ion channel
  • Lipid rafts
  • Cholesterol
  • Sphingomyelin
  • Oligomerization
  • Membrane-protein interactions

Published Papers (7 papers)

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Research

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Article
The Isolation of New Pore-Forming Toxins from the Sea Anemone Actinia fragacea Provides Insights into the Mechanisms of Actinoporin Evolution
Toxins 2019, 11(7), 401; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11070401 - 10 Jul 2019
Cited by 5 | Viewed by 1441
Abstract
Random mutations and selective pressure drive protein adaptation to the changing demands of the environment. As a consequence, nature favors the evolution of protein diversity. A group of proteins subject to exceptional environmental stress and known for their widespread diversity are the pore-forming [...] Read more.
Random mutations and selective pressure drive protein adaptation to the changing demands of the environment. As a consequence, nature favors the evolution of protein diversity. A group of proteins subject to exceptional environmental stress and known for their widespread diversity are the pore-forming hemolytic proteins from sea anemones, known as actinoporins. In this study, we identified and isolated new isoforms of actinoporins from the sea anemone Actinia fragacea (fragaceatoxins). We characterized their hemolytic activity, examined their stability and structure, and performed a comparative analysis of their primary sequence. Sequence alignment reveals that most of the variability among actinoporins is associated with non-functional residues. The differences in the thermal behavior among fragaceatoxins suggest that these variability sites contribute to changes in protein stability. In addition, the protein–protein interaction region showed a very high degree of identity (92%) within fragaceatoxins, but only 25% among all actinoporins examined, suggesting some degree of specificity at the species level. Our findings support the mechanism of evolutionary adaptation in actinoporins and reflect common pathways conducive to protein variability. Full article
(This article belongs to the Special Issue Pore-Forming Toxins (PFTs): Never Out of Fashion)
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Article
Binding to The Target Cell Surface Is The Crucial Step in Pore Formation of Hemolysin BL from Bacillus cereus
Toxins 2019, 11(5), 281; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11050281 - 20 May 2019
Cited by 14 | Viewed by 1669
Abstract
A major virulence factor involved in Bacillus cereus food poisoning is the three-component enterotoxin hemolysin BL. It consists of the binding component B and the two lytic components L1 and L2. Studying its mode of action has been challenging, as [...] Read more.
A major virulence factor involved in Bacillus cereus food poisoning is the three-component enterotoxin hemolysin BL. It consists of the binding component B and the two lytic components L1 and L2. Studying its mode of action has been challenging, as natural culture supernatants additionally contain Nhe, the second three-component enterotoxin, and purification of recombinant (r) Hbl components has been difficult. In this study, we report on pore-forming, cytotoxic, cell binding and hemolytic activity of recently generated rHbl components expressed in E. coli. It is known that all three Hbl components are necessary for cytotoxicity and pore formation. Here we show that an excess of rHbl B enhances, while an excess of rHbl L1 hinders, the velocity of pore formation. Most rapid pore formation was observed with ratios L2:L1:B = 1:1:10 and 10:1:10. It was further verified that Hbl activity is due to sequential binding of the components B - L1 - L2. Accordingly, all bioassays proved that binding of Hbl B to the cell surface is the crucial step for pore formation and cytotoxic activity. Binding of Hbl B took place within minutes, while apposition of the following L1 and L2 occurred immediately. Further on, applying toxin components simultaneously, it seemed that Hbl L1 enhanced binding of B to the target cell surface. Overall, these data contribute significantly to the elucidation of the mode of action of Hbl, and suggest that its mechanism of pore formation differs substantially from that of Nhe, although both enterotoxin complexes are sequentially highly related. Full article
(This article belongs to the Special Issue Pore-Forming Toxins (PFTs): Never Out of Fashion)
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Article
Structural Insights to the Heterotetrameric Interaction between the Vibrio parahaemolyticus PirAvp and PirBvp Toxins and Activation of the Cry-Like Pore-Forming Domain
Toxins 2019, 11(4), 233; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11040233 - 22 Apr 2019
Cited by 13 | Viewed by 1889
Abstract
Acute hepatopancreatic necrosis disease (AHPND) is a newly emergent penaeid shrimp disease which can cause 70–100% mortality in Penaeus vannamei and Penaeus monodon, and has resulted in enormous economic losses since its appearance. AHPND is caused by the specific strains of Vibrio [...] Read more.
Acute hepatopancreatic necrosis disease (AHPND) is a newly emergent penaeid shrimp disease which can cause 70–100% mortality in Penaeus vannamei and Penaeus monodon, and has resulted in enormous economic losses since its appearance. AHPND is caused by the specific strains of Vibrio parahaemolyticus that harbor the pVA1 plasmid and express PirAvp and PirBvp toxins. These two toxins have been reported to form a binary complex. When both are present, they lead to the death of shrimp epithelial cells in the hepatopancreas and cause the typical histological symptoms of AHPND. However, the binding mode of PirAvp and PirBvp has not yet been determined. Here, we used isothermal titration calorimetry (ITC) to measure the binding affinity of PirAvp and PirBvp. Since the dissociation constant (Kd = 7.33 ± 1.20 μM) was considered too low to form a sufficiently stable complex for X-ray crystallographic analysis, we used alternative methods to investigate PirAvp-PirBvp interaction, first by using gel filtration to evaluate the molecular weight of the PirAvp/PirBvp complex, and then by using cross-linking and hydrogen-deuterium exchange (HDX) mass spectrometry to further understand the interaction interface between PirAvp and PirBvp. Based on these results, we propose a heterotetrameric interaction model of this binary toxin complex. This model provides insight of how conformational changes might activate the PirBvp N-terminal pore-forming domain and should be helpful for devising effective anti-AHPND strategies in the future. Full article
(This article belongs to the Special Issue Pore-Forming Toxins (PFTs): Never Out of Fashion)
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Review

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Review
Inhibition of Pore-Forming Proteins
Toxins 2019, 11(9), 545; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11090545 - 19 Sep 2019
Cited by 7 | Viewed by 1690
Abstract
Perforation of cellular membranes by pore-forming proteins can affect cell physiology, tissue integrity, or immune response. Since many pore-forming proteins are toxins or highly potent virulence factors, they represent an attractive target for the development of molecules that neutralize their actions with high [...] Read more.
Perforation of cellular membranes by pore-forming proteins can affect cell physiology, tissue integrity, or immune response. Since many pore-forming proteins are toxins or highly potent virulence factors, they represent an attractive target for the development of molecules that neutralize their actions with high efficacy. There has been an assortment of inhibitors developed to specifically obstruct the activity of pore-forming proteins, in addition to vaccination and antibiotics that serve as a plausible treatment for the majority of diseases caused by bacterial infections. Here we review a wide range of potential inhibitors that can specifically and effectively block the activity of pore-forming proteins, from small molecules to more specific macromolecular systems, such as synthetic nanoparticles, antibodies, antibody mimetics, polyvalent inhibitors, and dominant negative mutants. We discuss their mechanism of inhibition, as well as advantages and disadvantages. Full article
(This article belongs to the Special Issue Pore-Forming Toxins (PFTs): Never Out of Fashion)
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Review
Phobalysin: Fisheye View of Membrane Perforation, Repair, Chemotaxis and Adhesion
Toxins 2019, 11(7), 412; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11070412 - 16 Jul 2019
Viewed by 1547
Abstract
Phobalysin P (PhlyP, for photobacterial lysin encoded on a plasmid) is a recently described small β-pore forming toxin of Photobacterium damselae subsp. damselae (Pdd). This organism, belonging to the family of Vibrionaceae, is an emerging pathogen of fish and various marine animals, which [...] Read more.
Phobalysin P (PhlyP, for photobacterial lysin encoded on a plasmid) is a recently described small β-pore forming toxin of Photobacterium damselae subsp. damselae (Pdd). This organism, belonging to the family of Vibrionaceae, is an emerging pathogen of fish and various marine animals, which occasionally causes life-threatening soft tissue infections and septicemia in humans. By using genetically modified Pdd strains, PhlyP was found to be an important virulence factor. More recently, in vitro studies with purified PhlyP elucidated some basic consequences of pore formation. Being the first bacterial small β-pore forming toxin shown to trigger calcium-influx dependent membrane repair, PhlyP has advanced to a revealing model toxin to study this important cellular function. Further, results from co-culture experiments employing various Pdd strains and epithelial cells together with data on other bacterial toxins indicate that limited membrane damage may generally enhance the association of bacteria with target cells. Thereby, remodeling of plasma membrane and cytoskeleton during membrane repair could be involved. In addition, a chemotaxis-dependent attack-and track mechanism influenced by environmental factors like salinity may contribute to PhlyP-dependent association of Pdd with cells. Obviously, a synoptic approach is required to capture the regulatory links governing the interaction of Pdd with target cells. The characterization of Pdd’s secretome may hold additional clues because it may lead to the identification of proteases activating PhlyP’s pro-form. Current findings on PhlyP support the notion that pore forming toxins are not just killer proteins but serve bacteria to fulfill more subtle functions, like accessing their host. Full article
(This article belongs to the Special Issue Pore-Forming Toxins (PFTs): Never Out of Fashion)
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Review
Membrane Permeabilization by Pore-Forming RTX Toxins: What Kind of Lesions Do These Toxins Form?
Toxins 2019, 11(6), 354; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060354 - 18 Jun 2019
Cited by 14 | Viewed by 2106
Abstract
Pore-forming toxins (PFTs) form nanoscale pores across target membranes causing cell death. The pore-forming cytolysins of the RTX (repeats in toxin) family belong to a steadily increasing family of proteins characterized by having in their primary sequences a number of glycine- and aspartate-rich [...] Read more.
Pore-forming toxins (PFTs) form nanoscale pores across target membranes causing cell death. The pore-forming cytolysins of the RTX (repeats in toxin) family belong to a steadily increasing family of proteins characterized by having in their primary sequences a number of glycine- and aspartate-rich nonapeptide repeats. They are secreted by a variety of Gram-negative bacteria and form ion-permeable pores in several cell types, such as immune cells, epithelial cells, or erythrocytes. Pore-formation by RTX-toxins leads to the dissipation of ionic gradients and membrane potential across the cytoplasmic membrane of target cells, which results in cell death. The pores formed in lipid bilayers by the RTX-toxins share some common properties such as cation selectivity and voltage-dependence. Hemolytic and cytolytic RTX-toxins are important virulence factors in the pathogenesis of the producing bacteria. And hence, understanding the function of these proteins at the molecular level is critical to elucidating their role in disease processes. In this review we summarize the current state of knowledge on pore-formation by RTX toxins, and include recent results from our own laboratory regarding the pore-forming activity of adenylate cyclase toxin (ACT or CyaA), a large protein toxin secreted by Bordetella pertussis, the bacterium causative of whooping cough. Full article
(This article belongs to the Special Issue Pore-Forming Toxins (PFTs): Never Out of Fashion)
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Other

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Perspective
Pore-Forming Proteins from Cnidarians and Arachnids as Potential Biotechnological Tools
Toxins 2019, 11(6), 370; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060370 - 25 Jun 2019
Cited by 6 | Viewed by 2260
Abstract
Animal venoms are complex mixtures of highly specialized toxic molecules. Cnidarians and arachnids produce pore-forming proteins (PFPs) directed against the plasma membrane of their target cells. Among PFPs from cnidarians, actinoporins stand out for their small size and molecular simplicity. While native actinoporins [...] Read more.
Animal venoms are complex mixtures of highly specialized toxic molecules. Cnidarians and arachnids produce pore-forming proteins (PFPs) directed against the plasma membrane of their target cells. Among PFPs from cnidarians, actinoporins stand out for their small size and molecular simplicity. While native actinoporins require only sphingomyelin for membrane binding, engineered chimeras containing a recognition antibody-derived domain fused to an actinoporin isoform can nonetheless serve as highly specific immunotoxins. Examples of such constructs targeted against malignant cells have been already reported. However, PFPs from arachnid venoms are less well-studied from a structural and functional point of view. Spiders from the Latrodectus genus are professional insect hunters that, as part of their toxic arsenal, produce large PFPs known as latrotoxins. Interestingly, some latrotoxins have been identified as potent and highly-specific insecticides. Given the proteinaceous nature of these toxins, their promising future use as efficient bioinsecticides is discussed throughout this Perspective. Protein engineering and large-scale recombinant production are critical steps for the use of these PFPs as tools to control agriculturally important insect pests. In summary, both families of PFPs, from Cnidaria and Arachnida, appear to be molecules with promising biotechnological applications. Full article
(This article belongs to the Special Issue Pore-Forming Toxins (PFTs): Never Out of Fashion)
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