Structural Basis and Functional Implications of the Membrane Pore-Formation Mechanisms of Bacterial Pore-Forming Toxins

Mondal, Anish Kumar; Sreekumar, Amritha; Kundu, Nidhi; Kathuria, Reema; Verma, Pratima; Gandhi, Shraddha; Chattopadhyay, Kausik

doi:10.1007/978-981-13-3065-0_19

Cited by 16 publications

(16 citation statements)

References 68 publications

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“…Mounting evidence also points to important roles of membrane damage during various pathophysiological conditions including muscular dystrophies, diabetes, or ischemia-reperfusion injuries associated with strokes or heart attacks (Howard et al 2011;Tzeng et al 2014;Barthélémy et al 2018). Membrane disruption by pore-forming drugs is common in host-pathogen interactions, where the cellular armory involves attack or defense compounds, such as plant saponins, which target the membrane and cause its disintegration (Dal Peraro and van der Goot 2016; Mondal et al 2018). The saponin tomatine, for example, belongs to the group of steroidal glycoalkaloids and is produced by Solanum species, such as tomato (Solanum lycopersicum), as a preformed defense compound against fungal infections (Friedman 2002).…”

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confidence: 99%

Plasma Membrane Integrity During Cell–Cell Fusion and in Response to Pore-Forming Drugs Is Promoted by the Penta-EF-Hand Protein PEF1 inNeurospora crassa

Schumann¹,

Brandt²,

Adis³

et al. 2019

Genetics

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Plasma membrane damage commonly occurs during cellular growth and development. To counteract these potentially lethal injuries, membrane repair mechanisms have evolved, which promote the integrity of the lipid bilayer. Although the membrane of fungi is the target of important clinical drugs and agricultural fungicides, the molecular mechanisms which mediate membrane repair in these organisms remain elusive. Here we identify the penta-EF-hand protein PEF1 of the genetic model fungus Neurospora crassa as part of a cellular response mechanism against different types of membrane injury. Deletion of the pef1 gene in the wild type and different lysis-prone gene knockout mutants revealed a function of the protein in maintaining cell integrity during cell-cell fusion and in the presence of pore-forming drugs, such as the plant defense compound tomatine. By fluorescence and live-cell imaging we show that green fluorescent protein (GFP)-tagged PEF1 accumulates at the sites of membrane injury in a Ca 2+-dependent manner. Sitedirected mutagenesis identified Ca 2+-binding domains essential for the spatial dynamics and function of the protein. In addition, the subcellular localization of PEF1 revealed that the syncytial fungal colony undergoes compartmentation in response to antifungal treatment. We propose that plasma membrane repair in fungi constitutes an additional line of defense against membrane-disturbing drugs, thereby expanding the current model of fungal drug resistance mechanisms. KEYWORDS membrane repair; penta-EF-hand protein; cell fusion; Neurospora crassa; antifungal drug

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confidence: 99%

Plasma Membrane Integrity During Cell–Cell Fusion and in Response to Pore-Forming Drugs Is Promoted by the Penta-EF-Hand Protein PEF1 inNeurospora crassa

Schumann¹,

Brandt²,

Adis³

et al. 2019

Genetics

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“…In primed snails subjected to a secondary challenge with homologous parasites, the plasma compartment seems to support parasite clearance and as such Biomphalysin was identified as a principal circulatory component consumed in hemolymph following this immune challenge [61,62]. PFTs are most commonly described in bacteria and are known to play a role in bacterial virulence [46,63,64]. However, more and more aerolysin-like molecules are being characterized in plants and animals, venomous or not [65][66][67][68][69][70][71][72][73][74].…”

Section: Discussionmentioning

confidence: 99%

“…The β-pore-forming toxin family is an important family of proteins that can be divided into five subfamilies, the aerolysins, the haemolysins, the cholesterol dependent cytolysins (CDCs), the membrane attack complex/perforins (MACPF) and the repeated toxins (RTX). Beta-pore-forming toxins are known to form pores in targeted cell membranes to trigger cytosolic release, osmotic stress and cell lysis [46]. To facilitate the discovery of -pore-forming toxin family members, a non-targeted approach using the B. glabrata genome [44] was used.…”

Section: Introductionmentioning

confidence: 99%

Glabralysins, Potential New β-Pore-Forming Toxin Family Members from the Schistosomiasis Vector Snail Biomphalaria glabrata

Lassalle

Tetreau

Pinaud

et al. 2020

Genes

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Biomphalaria glabrata is a freshwater Planorbidae snail. In its environment, this mollusk faces numerous microorganisms or pathogens, and has developed sophisticated innate immune mechanisms to survive. The mechanisms of recognition are quite well understood in Biomphalaria glabrata, but immune effectors have been seldom described. In this study, we analyzed a new family of potential immune effectors and characterized five new genes that were named Glabralysins. The five Glabralysin genes showed different genomic structures and the high degree of amino acid identity between the Glabralysins, and the presence of the conserved ETX/MTX2 domain, support the hypothesis that they are pore-forming toxins. In addition, tertiary structure prediction confirms that they are structurally related to a subset of Cry toxins from Bacillus thuringiensis, including Cry23, Cry45, and Cry51. Finally, we investigated their gene expression profiles in snail tissues and demonstrated a mosaic transcription. We highlight the specificity in Glabralysin expression following immune stimulation with bacteria, yeast or trematode parasites. Interestingly, one Glabralysin was found to be expressed in immune-specialized hemocytes, and two others were induced following parasite exposure.

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“…This α-helical bundle structure suggested that actinoporin protomers might directly assemble into a pore conformation without a pre-pore intermediate state, although the mechanism of the actinoporin subfamily is not completely clear. In manyα-PFTs, it is coupled and synchronous events for oligomerization and membrane insertion to finally form transmembrane pore [80]. Hydrophobic residues located external lumen towards the membrane lipid, while hydrophilic residues located interior lumen towards water molecules.…”

Section: The Actinoporin Subfamilymentioning

confidence: 99%

Structural Basis of the Pore-Forming Toxin/Membrane Interaction

Mengist

et al. 2021

Toxins

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With the rapid growth of antibiotic-resistant bacteria, it is urgent to develop alternative therapeutic strategies. Pore-forming toxins (PFTs) belong to the largest family of virulence factors of many pathogenic bacteria and constitute the most characterized classes of pore-forming proteins (PFPs). Recent studies revealed the structural basis of several PFTs, both as soluble monomers, and transmembrane oligomers. Upon interacting with host cells, the soluble monomer of bacterial PFTs assembles into transmembrane oligomeric complexes that insert into membranes and affect target cell-membrane permeability, leading to diverse cellular responses and outcomes. Herein we have reviewed the structural basis of pore formation and interaction of PFTs with the host cell membrane, which could add valuable contributions in comprehensive understanding of PFTs and searching for novel therapeutic strategies targeting PFTs and interaction with host receptors in the fight of bacterial antibiotic-resistance.

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Structural Basis and Functional Implications of the Membrane Pore-Formation Mechanisms of Bacterial Pore-Forming Toxins

Cited by 16 publications

References 68 publications

Plasma Membrane Integrity During Cell–Cell Fusion and in Response to Pore-Forming Drugs Is Promoted by the Penta-EF-Hand Protein PEF1 inNeurospora crassa

Plasma Membrane Integrity During Cell–Cell Fusion and in Response to Pore-Forming Drugs Is Promoted by the Penta-EF-Hand Protein PEF1 inNeurospora crassa

Glabralysins, Potential New β-Pore-Forming Toxin Family Members from the Schistosomiasis Vector Snail Biomphalaria glabrata

Structural Basis of the Pore-Forming Toxin/Membrane Interaction

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