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New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms,...
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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 (28 February 2023) | Viewed by 17008

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 and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, D-49076 Osnabrück, Germany
Interests: membrane proteins; regulated cell death; single molecule imaging; high resolution microscopy; atomic force microscopy
Special Issues, Collections and Topics in MDPI journals

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

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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

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

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Published Papers (6 papers)

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Research

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14 pages, 3559 KiB  
Article
Histidine Protonation and Conformational Switching in Diphtheria Toxin Translocation Domain
by Mykola V. Rodnin, Victor Vasques-Montes, Alexander Kyrychenko, Nuno F. B. Oliveira, Maithri M. Kashipathy, Kevin P. Battaile, Justin Douglas, Scott Lovell, Miguel Machuqueiro and Alexey S. Ladokhin
Toxins 2023, 15(7), 410; https://doi.org/10.3390/toxins15070410 - 25 Jun 2023
Cited by 3 | Viewed by 1927
Abstract
Protonation of key histidine residues has been long implicated in the acid-mediated cellular action of the diphtheria toxin translocation (T-) domain, responsible for the delivery of the catalytic domain into the cell. Here, we use a combination of computational (constant-pH Molecular Dynamics simulations) [...] Read more.
Protonation of key histidine residues has been long implicated in the acid-mediated cellular action of the diphtheria toxin translocation (T-) domain, responsible for the delivery of the catalytic domain into the cell. Here, we use a combination of computational (constant-pH Molecular Dynamics simulations) and experimental (NMR, circular dichroism, and fluorescence spectroscopy along with the X-ray crystallography) approaches to characterize the initial stages of conformational change happening in solution in the wild-type T-domain and in the H223Q/H257Q double mutant. This replacement suppresses the acid-induced transition, resulting in the retention of a more stable protein structure in solutions at pH 5.5 and, consequently, in reduced membrane-disrupting activity. Here, for the first time, we report the pKa values of the histidine residues of the T-domain, measured by NMR-monitored pH titrations. Most peaks in the histidine side chain spectral region are titrated with pKas ranging from 6.2 to 6.8. However, the two most up-field peaks display little change down to pH 6, which is a limiting pH for this protein in solution at concentrations required for NMR. These peaks are absent in the double mutant, suggesting they belong to H223 and H257. The constant-pH simulations indicate that for the T-domain in solution, the pKa values for histidine residues range from 3.0 to 6.5, with those most difficult to protonate being H251 and H257. Taken together, our experimental and computational data demonstrate that previously suggested cooperative protonation of all six histidines in the T-domain does not occur. Full article
(This article belongs to the Special Issue New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms, Functions and Applications)
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14 pages, 2739 KiB  
Article
Engineering BinB Pore-Forming Toxin for Selective Killing of Breast Cancer Cells
by Tipaporn Kumkoon, Chalongrat Noree and Panadda Boonserm
Toxins 2023, 15(4), 297; https://doi.org/10.3390/toxins15040297 - 18 Apr 2023
Viewed by 2620
Abstract
Breast cancer is one of the most common cancers in women worldwide. Conventional cancer chemotherapy always has adverse side effects on the patient’s healthy tissues. Consequently, combining pore-forming toxins with cell-targeting peptides (CTPs) is a promising anticancer strategy for selectively destroying cancer cells. [...] Read more.
Breast cancer is one of the most common cancers in women worldwide. Conventional cancer chemotherapy always has adverse side effects on the patient’s healthy tissues. Consequently, combining pore-forming toxins with cell-targeting peptides (CTPs) is a promising anticancer strategy for selectively destroying cancer cells. Here, we aim to improve the target specificity of the BinB toxin produced from Lysinibacillus sphaericus (Ls) by fusing a luteinizing hormone-releasing hormone (LHRH) peptide to its pore-forming domain (BinBC) to target MCF-7 breast cancer cells as opposed to human fibroblast cells (Hs68). The results showed that LHRH-BinBC inhibited MCF-7 cell proliferation in a dose-dependent manner while leaving Hs68 cells unaffected. BinBC, at any concentration tested, did not affect the proliferation of MCF-7 or Hs68 cells. In addition, the LHRH-BinBC toxin caused the efflux of the cytoplasmic enzyme lactate dehydrogenase (LDH), demonstrating the efficacy of the LHRH peptide in directing the BinBC toxin to damage the plasma membranes of MCF-7 cancer cells. LHRH-BinBC also caused MCF-7 cell apoptosis by activating caspase-8. In addition, LHRH-BinBC was predominantly observed on the cell surface of MCF-7 and Hs68 cells, without colocalization with mitochondria. Overall, our findings suggest that LHRH-BinBC could be investigated further as a potential cancer therapeutic agent. Full article
(This article belongs to the Special Issue New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms, Functions and Applications)
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19 pages, 6269 KiB  
Article
The Important Role of Membrane Fluidity on the Lytic Mechanism of the α-Pore-Forming Toxin Sticholysin I
by Lohans Pedrera, Uris Ros, Maria Laura Fanani, María E. Lanio, Richard M. Epand, Ana J. García-Sáez and Carlos Álvarez
Toxins 2023, 15(1), 80; https://doi.org/10.3390/toxins15010080 - 16 Jan 2023
Cited by 1 | Viewed by 2655
Abstract
Actinoporins have emerged as archetypal α-pore-forming toxins (PFTs) that promote the formation of pores in membranes upon oligomerization and insertion of an α-helix pore-forming domain in the bilayer. These proteins have been used as active components of immunotoxins, therefore, understanding their lytic mechanism [...] Read more.
Actinoporins have emerged as archetypal α-pore-forming toxins (PFTs) that promote the formation of pores in membranes upon oligomerization and insertion of an α-helix pore-forming domain in the bilayer. These proteins have been used as active components of immunotoxins, therefore, understanding their lytic mechanism is crucial for developing this and other applications. However, the mechanism of how the biophysical properties of the membrane modulate the properties of pores generated by actinoporins remains unclear. Here we studied the effect of membrane fluidity on the permeabilizing activity of sticholysin I (St I), a toxin that belongs to the actinoporins family of α-PFTs. To modulate membrane fluidity we used vesicles made of an equimolar mixture of phosphatidylcholine (PC) and egg sphingomyelin (eggSM), in which PC contained fatty acids of different acyl chain lengths and degrees of unsaturation. Our detailed single-vesicle analysis revealed that when membrane fluidity is high, most of the vesicles are partially permeabilized in a graded manner. In contrast, more rigid membranes can be either completely permeabilized or not, indicating an all-or-none mechanism. Altogether, our results reveal that St I pores can be heterogeneous in size and stability, and that these properties depend on the fluid state of the lipid bilayer. We propose that membrane fluidity at different regions of cellular membranes is a key factor to modulate the activity of the actinoporins, which has implications for the design of different therapeutic strategies based on their lytic action. Full article
(This article belongs to the Special Issue New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms, Functions and Applications)
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15 pages, 3856 KiB  
Article
Force Mapping Study of Actinoporin Effect in Membranes Presenting Phase Domains
by Katia Cosentino, Edward Hermann, Nicolai von Kügelgen, Joseph D. Unsay, Uris Ros and Ana J. García-Sáez
Toxins 2021, 13(9), 669; https://doi.org/10.3390/toxins13090669 - 18 Sep 2021
Cited by 4 | Viewed by 2787
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
(This article belongs to the Special Issue New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms, Functions and Applications)
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8 pages, 6572 KiB  
Article
Internalization of Clostridium botulinum C2 Toxin Is Regulated by Cathepsin B Released from Lysosomes
by Masahiro Nagahama, Keiko Kobayashi, Sadayuki Ochi and Masaya Takehara
Toxins 2021, 13(4), 272; https://doi.org/10.3390/toxins13040272 - 9 Apr 2021
Cited by 5 | Viewed by 2640
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
(This article belongs to the Special Issue New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms, Functions and Applications)
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Review

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19 pages, 1309 KiB  
Review
Panorama of the Intracellular Molecular Concert Orchestrated by Actinoporins, Pore-Forming Toxins from Sea Anemones
by Carlos Alvarez, Carmen Soto, Sheila Cabezas, Javier Alvarado-Mesén, Rady Laborde, Fabiola Pazos, Uris Ros, Ana María Hernández and María Eliana Lanio
Toxins 2021, 13(8), 567; https://doi.org/10.3390/toxins13080567 - 13 Aug 2021
Cited by 7 | Viewed by 3333
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
(This article belongs to the Special Issue New Frontiers in Pore-Forming Toxins and Related Proteins: Molecular Mechanisms, Functions and Applications)
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