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Review Bacterial Pore-Forming Toxins Cell. Mol. Life Sci. 65 (2008) 493 – 507 1420-682X/08/030493-15 Cellular and Molecular Life Sciences DOI 10.1007/s00018-007-7434-y Birkhuser Verlag, Basel, 2007 Review Bacterial pore-forming toxins: The (w)hole story? M. R. Gonzalez, M. Bischofberger, L. Pernot, F. G. van der Goot* and B. FrÞche Ecole Polytechnique Fdrale de Lausanne, Global Health Institute, Station 15, 1015 Lausanne (Switzerland), Fax : +41-21-693-9538, e-mail: [email protected] Received 19 September 2007; received after revision 18 October 2007; accepted 23 October 2007 Online First 9 November 2007 Abstract. Pore-forming toxins (PFTs) are the most variety of signal-transduction pathways and sophisti- common class of bacterial protein toxins and consti- cated cellular mechanisms such as the pathway tute important bacterial virulence factors. The mode regulating lipid metabolism. In this review we discuss of action of PFT is starting to be better understood. In the different classes of bacterial PFTs and their modes contrast, little is known about the cellular response to of action, and provide examples of how the different this threat. Recent studies reveal that cells do not just bacteria use PFTs. Finally, we address the more recent swell and lyse, but are able to sense and react to pore field dealing with the eukaryotic cell response to PFT- formation, mount a defense, even repair the damaged induced damage. membrane and thus survive. These responses involve a Keywords. Pore-forming toxins, aerolysin, cholesterol-dependent cytolysin, cellular response, caspase-1. Introduction pathic structure that finally inserts in the target cell membrane and forms a pore (Fig. 1). This ability to Pore-forming toxins (PFTs) represent the largest class convert from a soluble to a transmembrane form is of bacterial protein toxins and are often important common to all PFTs and constitutes one of their most virulence factors of a pathogen [1]. Forming pores in remarkable features. In this review, we discuss the the membrane of target cells, which leads to cellular different classes of bacterial PFTs and their modes of ion imbalance, is a widely used form of attack. Beside action. We also provide a few examples of how the bacteria, many organisms as different as cnidarians, different bacteria use PFTs and then address the more mushrooms and plants also produce PFTs [2–4]. recent field of eukaryotic cell responses to the damage Strikingly, even mammals utilize PFT-like proteins induced by the PFTs. However, it should be noted such as perforins as a part of their innate immune already here that the knowledge about toxin-induced defense [5]. The fact that the use of pore formation is cellular phenomena lags behind our understanding of so widely spread suggests that PFTs evolved early in the structural mechanisms. This is probably because time and, therefore, represent an ancient form of cell lysis was previously assumed to be the only cell attack. Until now, bacterial PFTs are the best descri- fate after pore formation and, as such, the (w)hole bed (for a review see [1, 6]). They are secreted by the story. Most probably it is just the beginning. pathogens in a water-soluble form that binds to the target cell and generally multimerizes into an amphi- * Corresponding author. 494 M. R. Gonzalez et al. Pore-forming toxins this family have confirmed this hypothesis and led to the elucidation of an overall common mode of action. As all toxins, b-PFTs are synthesized as soluble proteins. At high concentration, they have the ability to multimerize into circular polymers, a step that for certain toxins, such as aerolysin, requires proteolytic activation [15, 16]. Upon multimerization, each mon- omer contributes one (aerolysin from Aeromonas hydrophila and a-toxin from Staphylococcus aureus) or 2 (cholesterol-dependent cytolysins [17]) amphi- patic b-hairpins, which together generate an amphi- pathic b-barrel. This b-barrel exhibits a hydrophilic Figure 1. General mechanism of pore formation by b-pore-form- cavity and a hydrophobic outer surface thus allowing ing toxins (PFTs). Most PFTs are produced by the bacteria in form of soluble precursor toxins that diffuse towards the target cell and membrane insertion [17–20]. The number of mono- bind with high affinity through the interaction with a specific mers varies from 7 in the case of aerolysin and receptor (1). Some PFTs may then require activation by proteolytic staphylococcal a-toxin [21–23] to up to 50 in the case cleavage (2). Common to all b-PFTs is the absolute requirement for of the cholesterol-dependent cytolysins (CDC), which oligomerization (3), a process that can be promoted by lipid rafts, into ring like structures that insert into the membrane and form include streptolysin O (SLO) and perfringolysin O pores (4). [24, 25]. The pores formed by b-PFTs vary greatly in size, from 2 nm in diameter for aerolysin and a-toxin, to 50 nm in diameter for CDC [6]. CDC pores can Classifications of PFTs allow the passage of fully folded proteins and have, therefore, widely been used in cell biology to generate PFTs are best classified according to the type of semi-permeabilized cell systems [26]. The difference structures they use to insert into the lipid bilayer upon in size between aerolysin- and CDC-type PFTs has a pore formation, i.e., a-PFT cross the membrane as a- number of cellular consequences that are discussed helices and b-PFTs as b-sheets (Fig. 2). Pore-forming below. It is presently not clear why different bacteria colicins secreted by Escherichia coli are representa- have evolved to produce toxins that generate pores of tive members of the a-PFTs family [7]. This family different sizes. The required cellular response during also includes the translocation domain of Diphtheria infection might provide the key to this interesting toxin [8], as well as the mammalian anti-apoptotic question. protein Bcl2 [9]. The pore-forming domains of multi- A number of proteins that do not fully qualify as PFTs ple a-PFTs such as colicins and Cry toxins from should also be mentioned briefly. Most prominent Bacillus thuringiensis have been crystallized in their amongst these are the translocation domains of water-soluble forms [6, 10–13]. They all form a three- certain non-pore-forming toxins. These are the so- layered structure of up to ten a-helices, which called AB toxins, where the B subunit is responsible sandwich a hydrophobic helical hairpin. Partial un- for binding to the target cell and translocation of the A folding of the protein, triggered by locally low pH and subunit into the cytoplasm. The A subunit bears the possibly other mechanisms, is thought to expose this enzymatic activity. Examples include the already central hydrophobic helical hairpin that then sponta- mentioned Diphtheria toxin, the translocation do- neously inserts into the lipid bilayer [6]. Whereas main of which resembles colicins [27], and anthrax partial unfolding might be sufficient to allow mem- toxin, the B subunit of which forms a heptameric brane insertion, channel formation most likely re- transmembrane channel reminiscent of the aerolysin quires oligomerization of the protein. No definitive and Staphylococcal a-toxin channel [19, 28, 29]. In proof for multimerization is available for this class of contrast to bona fide PFTs, B subunits of AB toxins do toxins and thus the exact mechanism of pore forma- not insert into the plasma membrane of target cells tion remains unclear (Fig. 2a). because they require an acidic environment for Formation of the transmembrane channel is much membrane insertion to occur. Pore formation by B better understood for the b-PFT family. In contrast to subunits only occurs in the endocytic pathway upon a-PFTs, sequence analysis predicts entirely soluble b- internalization [30–32]. PFTs with no detectable hydrophobic stretches [1, 6]. Also related to PFTs are the tips of bacterial type III b-PFTs contain a high percentage of b-structure, and, or type IV secretion systems (for review see [33]). in the early 90 s, it was suggested that these toxins Many pathogenic Gram-negative bacteria inject bac- might cross lipid bilayers as b-barrels as observed for terial proteins into the host cell cytoplasm [34]. They bacterial porins [14]. Studies on different toxins from do so by injecting proteins directly from their cyto- Cell. Mol. Life Sci. Vol. 65, 2008 Review Article 495 Figure 2. a- and b-PFTs. Ribbon representations of a-and b-PFT structures. For each toxin, the region involved in forming the lipid- spanning region of the pore is highlighted by dark shading. (a) a-PFT family member colicin B secreted by Escherichia coli. (b)The structure of the water-soluble aerolysin by Aeromonas hydrophila. (c) The water-soluble LukF monomer. LukF is a PFT produced by Staphylococcus aureus and is thought to have a structure similar to that of the a-toxin from the same organism. (d) b-PFT family member a- toxin protomer, produced by S. aureus, as observed in the pore structure shown in (e, f). (e, f) S. aureus a-toxin heptameric pore viewed (e) perpendicular to the pore axis, and (f) down the axis [45]. (g) Clostridium perfringens perfringolysin O as an example of a water-soluble CDC monomer. (h) Cryo-EM reconstruction of the Streptococcus pneumoniae pneumolysin pore [90]. Note the difference in monomer number and size between (f) and (h) (not same scale). All figures were produced by the computer program PyMol, except (h) which was taken from [90]. plasm into that of the host cell through syringe-like cell-type-specific intoxication. In the absence of structures called type III and IV secretion system. The toxin-specific receptors, cells are indeed resistant to type III secretion system (T3SS) is evolutionarily the action of the PFTs [38].
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