Pore Forming Proteins

Available online at www.sciencedirect.com

Membrane injury by pore-forming proteinsMirko Bischofberger, Manuel R Gonzalez and F Gisou van der Goot

The plasma membrane defines the boundary of every living cell,

and its integrity is essential for life. The plasma membrane may,

however, be challenged by mechanical stress or pore-forming

proteins produced by the organism itself or invading

pathogens. We will here review recent findings about

pore-forming proteins from different organisms, highlighting

their structural and functional similarities, and describe the

mechanisms that lead to membrane repair, since remarkably,

cells can repair breaches in their plasma membrane of up to

10 000 mm2.

Address

Ecole Polytechnique Federale de Lausanne, Global Health Institute,

Station 15, CH-1015 Lausanne, Switzerland

Corresponding author: van der Goot, F Gisou

([email protected])

Current Opinion in Cell Biology 2009, 21:589–595

This review comes from a themed issue on

Membranes and organelles

Edited by Greg Odorizzi and Peter Rehling

Available online 11th May 2009

0955-0674/$ – see front matter

# 2009 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.ceb.2009.04.003

IntroductionThe etymological definition of a cell (from latin cellula,

‘small compartment’) implies a boundary structure

enclosing a compartment. Life, as known today, would

not be possible without plasma membranes, and their

formation has most probably been a crucial event during

evolution [1]. Given that their integrity is required for

survival, membranes constitute a sort of cellular Achilles

heel, sensitive both to mechanical rupture and molecule

driven alterations. Not surprisingly, many organisms have

developed pore-forming molecules designed to disturb

membrane integrity for a variety of purposes [2–5]. We

will here limit ourselves to discussing pore-forming

proteins (PFPs) as opposed to peptides. These molecules

are found in many phyla and share the remarkable prop-

erty of being synthesized as soluble proteins that can

convert, in a controlled manner, to transmembrane pores.

Many pathogenic microorganisms – bacteria or parasites –produce PFP to promote infections. In fact bacterial pore-

forming toxins (PFT) are the best characterized family of

PFPs and studies on these toxins has paved the way for a

better understanding of PFPs encountered in other sys-

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tems [2]. Not only monocellular organisms produce PFPs.

In humans for example, pore formation by perforin is

involved in counteracting infection by microorganisms

[6], while pore formation by the Bcl2 family member Bax

triggers apoptosis [7]. Furthermore, it has been proposed

that the causative agents of Alzheimer or Parkinson

disease are proteins capable of adopting pore-forming

configurations that lead to membrane injury [8]. Inter-

estingly, cells have evolved mechanisms that allow them

to cope with breaches in their plasma membrane – pro-

viding the insult is not overwhelming – and to restore

plasma membrane continuity [4,9,10].

After briefly reviewing the mode of action and purpose of

PFTs, we will cover recent findings that illustrate the

parallel between PFTs, proteins of the immune system,

and intermediates in fibril formation in neurodegenera-

tive diseases. Finally we will describe the cellular con-

sequences of breaches in the plasma membrane, how cells

sense such events and respond to them. For structural

aspects of PFPs, the reader is referred to the numerous

recent reviews [4,5,8,11–13].

Pore-forming toxins (PFTs)Despite a great diversity of sequences and structures, all

bacterial PFTs follow the same overall mode of action [3]

(Figure 1A). They are secreted by the bacterium as

soluble proteins that can diffuse toward target cells to

which they bind via specific receptors [3,4]. For many

PFTs, the receptors have been identified and include

transmembrane or GPI-anchored proteins, lipids or clus-

ter of lipids [14–18]. Most, if not all PFTs, require

subsequent oligomerization for channel formation to

occur. This step is generally promoted by cholesterol-

rich membrane domains, or lipid rafts, that act as con-

centration platforms [3], although exceptions have been

reported [19]. Oligomerization occurs in a circular manner

leading to ring-like structures. The stochiometry, and

thus the pore diameter, depends on the toxin: Staphylo-

coccal a-toxin and Aeromonas aerolysin form heptameric

pores, Staphylococcal leukotoxins octameric pores [4],

Escherichia coli ClyA 13-meric pores [20], and members

of the Cholesterol-dependent Cytolysins (CDCs) pores of

variable sizes that can be formed of up to 50 monomers

(diameter 30–50 nm) [11]. Channel formation leads to

permeabilization of ions and small molecules such as

ATP, and, in the case of CDCs, to proteins [4,11].

Purposes of pore formationPore formation can serve multiple purposes, largely

depending on the site, and amount, of toxin production.

Since PFTs have the ability to kill almost any cell and, in


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http://dx.doi.org/10.1016/j.ceb.2009.04.003

590 Membranes and organelles

Figure 1

Similarities of pore-forming proteins (PFPs). (A) Mechanism of action for different PFPs. Bacterial, parasitic, and PFPs from the immune system first

have to bind to the membrane, before they can oligomerize and insert into the lipid bilayer to form the functional pore. How endogenous proteins from

conformational diseases such as b-amyloid or a-synuclein form pores remains to be established. (B) Structural similarities between the bacterial PFT

perfringolysin O (PFO), the MACPF domain that also occurs in PFPs from the immune system and the parasitic PFP TgPLP1 from Toxoplasma gondii

(after a homology model [32�]). The five helices (in black) surrounding the common b-sheet are thought to insert into the lipid bilayer during pore

formation. (C) Pores formed by different PFPs visualized by electron microscopy (with permission from [67,36,68]).

particular, cells of the immune system, they will contrib-

ute to spreading of the bacterium by subverting antimi-

crobial control. Pore formation in the plasma membrane

may also increase the availability of nutrients to the

bacterium. Gram-positive bacteria, such as Streptococci,

which lack secretion systems allowing the injection of

bacterial proteins into the target cell cytosol [21], may

utilize pore formation for protein delivery [22]. Finally,

pore formation allows certain bacteria that have entered

target cells by phagocytosis, to escape from the phago-

somes and replicate in the cytoplasm. The best studied

example is Listeriolysin O (LLO), produced by Listeriamonocytogenes [23]. While LLO can form pores at the

plasma membrane of target cells, its activity is more

potent in the phagosome, partly owing to an increase

in pore-forming ability at acidic pH [24]. It was, however,

recently shown that LLO gets additionally activated by a

lysosomal thiol reductase called GILT [25�], reminding

us that the initial name of CDCs was thiol-activated

toxins [26]. But phagosome lysis is only observed when

LLO activity is sufficient. When LLO activity is low,

Listeria is observed in a spacious late endosome-like


vacuole [27��]. This vacuole was found to form in an

LLO-dependent manner (LLO deficient Listeria are

targeted to lysosomes), to be non-acidic, of autophagic

origin and to allow slow replication of the bacterium

[27��]. Thus depending on the LLO activity, this PFT

will allow the bacterium to replicate in the target cell

cytoplasm or to persist in an autophagic-like vacuole.

Pore-forming proteins in eukaryoticorganismsCytotoxic T cells (CTLs) and hepatocytes produce PFPs,

perforin (PF) and the 9th component (C9) of comp-

lement, respectively. Perforin is released upon degranu-

lation of CTLs. It forms transmembrane pores that allow,

through mechanisms that remain debated, translocation

of granzymes into the cytoplasm of pathogen-infected

cells, leading to their apoptotic death. C9 also forms pores

and is involved in the last step of the assembly of the

membrane attack complex (MAC). The lytic membrane

inserting part of both proteins is formed by the MACPF

domain [6]. Two recent structural studies revealed the

similarity between the MACPF domain and the bacterial


Membrane injury by pore-forming proteins Bischofberger, Gonzalez and van der Goot 591

Figure 2

Different cellular sites where pore formation can occur. After pore

formation on the plasma membrane, ions such as K+ or Ca2+ flow along

their respective gradients. Many signaling pathways, such as the Map

kinase p38 are then activated. Exit of ATP leads to activation of the P2X

receptors, which in turn trigger opening of the pannexin hemichannels

enhancing changes in ion composition and loss of the membrane

potential. Pore formation in mitochondria leads to loss of mitochondrial

potential and release of cytochrome C that induces apoptosis. Lesion in

membranes of endosomes (LE) and/or lysosomes leads to the leakage

of lysosomal enzymes into the cytoplasm.

CDCs [28��,29��] (Figure 1B), which was unexpected

considering the lack of sequence similarity.

As a side note, the revealed similarity between MACPF

and CDCs is not the first example of convergence be-

tween bacterial PFTs and mammalian PFPs. In the

1990s, pro-apoptotic and anti-apoptotic members of the

Bcl2 family were found to have the same overall fold as

the pore-forming domain of the bacterial diphtheria toxin

(for review see [30]). It was subsequently shown that, for

example, the pro-apoptotic protein Bax can form oligo-

meric protein-permeable channels in the outer mem-

brane of mitochondria (reviewed in [7]).

MACPF domain containing proteins are also found in

Apicomplexa parasites, including Toxoplasma and Plas-modium [31]. Modeling of the Perforin-Like Protein 1

(TgPLP1) of Toxoplasma gondii showed that its structure

is indeed similar to that of CDCs [32�] (Figure 1B). T.gondii enters mammalian cells using an unusual gliding

mechanism and replicates in a parasitophorous vacuole

from which it escapes before exiting the cells and spread-

ing to other sites [33]. TgPLP1 was found to be required

for the egress of Toxoplasma from the parasitophorus

vacuole [32�], reminiscent of the role of LLO during

Listeria infection.

In Plasmodium, perforin like proteins (PLPs) were found

to be important for the traversal of the mosquito midgut

epithelium [34] and the mammalian hepatic cells

[35]. Cell traversal results in a characteristic wounding

of the plasma membrane. Since wounding has not been

observed for Toxoplasma, the PLPs from the two parasites

are thought to play different roles.

Pore formation and neurodegenerativediseasesAs mentioned above, pore formation by PFPs requires

oligomerization. Moreover, PFPs are often rich in b-sheet

and their oligomerization leads to highly stable structures.

Highly stable b-rich oligomeric structures are also

encountered during neuron degenerative diseases such

as Alzheimer or Parkinson disease [8]. These diseases are

characterized by the formation of fibrillar amyloid depos-

its [36,37�], but the link between the deposits and disease

is unclear. It has been proposed that intermediate oligo-

meric species that form before fibril formation might be

the toxic form. Electron microscopy analysis of such

intermediates revealed that they form ring-shape struc-

tures reminiscent of bacterial PFTs [8] (Figure 1C) and it

was subsequently shown that they have membrane-per-

forating activity [38]. Quite remarkably, cross-reactivity

of conformation specific antibodies was observed be-

tween amyloid ring-like intermediates and staphylococcal

a-toxin [37�]. Further similarities with PFTs include the

promotion of amyloid ring formation by lipids [37�] and

cholesterol dependent pore formation [39,40].


Consequences of pore formationThe consequences of the formation of non-selective

transmembrane pores, or occurrence of membrane

damage, will depend on where the event occurs

(Figure 2). Formation of pores in mitochondria, by mem-

bers of the Bcl2 family [7] or bacterial toxins [41], may

lead to loss of mitochondrial potential, leakage of toxic

compounds into the cytoplasm, and triggering of apop-

tosis. It was recently proposed that rupture of lysosomal

membranes leads to the activation of the Nalp3-

inflammasome, a multi-subunit danger sensing complex

involved in the activation of caspase-1 and subsequently

interleukin-1b [42], through the spilling of lysosomal

enzymes into the cytoplasm [43].

But most PFPs target the plasma membrane, which is also

the victim of mechanical rupture. The primary effect of

impaired plasma membrane integrity is a change in

cytoplasmic ion composition and loss of membrane poten-

tial (Figure 2). In particular, concentrations of potassium

decrease and of calcium increase, and this has numerous

secondary consequences, some of which will be described

below. Interestingly, ion flow might not be solely

mediated by the pores themselves. It has recently been

shown that E. coli hemolysin (HlyA) takes advantage of a

cellular amplification system to inflict a full-blown

response in erythrocytes, that is, hemolysis [44�]. Skals

et al. found that extracellular ATP, presumably released



through the HlyA pores, activates PX2 receptors – ligand-

gated cation channels activated by extracellular ATP –which in turn trigger the opening of the hemi-channel

pannexin, as previously shown [45,46] (Figure 2). The

fact that, in the 1960s–1970s, suramin, a non-selective

P2X antagonist, was found to affect the hemolytic activity

of both Staphylococcal a-toxin [47], and complement [48]

suggests that P2X mediated amplification of plasma

membrane permeabilization might occur for other PFPs.

The secondary consequences of pore formation, many of

which are probably triggered by changes in the cyto-

plasmic ion composition, are numerous and the list is

continuously extending. We will restrict ourselves to

three selected recent examples that illustrate the diver-

sity of the responses (for more extensive review see [3]).

Through mechanisms that remain to be unraveled, PFTs

were found to activate the p38 MAP kinase pathway [49–51]. This activation was found to be important for recovery

of intracellular ATP levels and cell survival [50,51]. Using

C. elegans, Aroian and co-workers found that p38 activation

was important for survival at the organism level [49] and

that one of the downstream consequences of p38 activation

was the activation of the ER unfolded protein response

(UPR) [52��]. The relevance of the UPR pathway to

mammalian systems and how the UPR promotes survival

at the cellular or organism levels remain to be established.

The decrease of intracellular potassium triggered by

PFTs was found to be a potent activator of the inflam-

masome, the multiprotein danger-sensing complex that is

involved in caspase-1 activation [53��]. In non-myeloid

cells, PFT-induced inflammasome assembly and caspase-

1 activation was found to, in turn, activate the master

regulators of lipid metabolism: the sterol responsive

element binding proteins (SREBPs) [53��]. SREBP acti-

vation was found to promote cell survival through yet to

be established mechanisms.

Finally, various CDCs were found to have effects in the

nucleus, namely the dephosphorylation of histone H3 and

the deacetylation of histone H4 [54�], suggesting that

membrane perforation could lead to epigenetic repro-

gramming of affected cells. Again, the underlying path-

ways have not yet been established nor has the crosstalk

that may exist between the different pathways activated

by PFPs been addressed.

Recovery of plasma membrane integrityDespite the drastic consequences of membrane perfor-

ation, cells can, depending on the extent and duration

of the membrane damage, recover the integrity of their

plasma membrane.

Intuitively several, not mutually exclusive, mechanisms

can be suggested: the lesion/pore could be clogged, the


injury site could be removed from the surface either by

endocytosis or shedding of vesicles, or the injury could

induce adaptation through gene expression that would

help injured cells either to reseal their wounded plasma

membrane or the tissue to recover as a whole. We will first

review the limited information available on membrane

repair following pore formation and finish with the mem-

brane sealing following mechanical damage for which

interesting recent findings have been made.

Counter intuitively, cells can rapidly (<1 h) restore plasma

membrane integrity following the formation of large pores

(30–50 nm in diameter) formed by CDCs or perforin

[55,56] but take a long time (>6 h) or fail to recover upon

formation of small pores (�2 nm in diameter) by toxins

such as Staphylococcal a-toxin [50,57] or aerolysin (our

unpublished observations). Recovery from large pores

requires influx of extracellular calcium but is p38-inde-

pendent, while recovery from smaller pores does not rely

on calcium but involves p38 (reviewed in [10]). How

calcium and p38, respectively, favor membrane repair in

these two situations is not known, nor is there a clear

explanation for the difference in mechanisms, and thus

of timescales, and why rapid repair seems to fail for small

pores. Removal of pores from the cell surface by endocy-

tosis, while not providing a full explanation for the differ-

ences, could however be important for cell recovery in both

situations (Figure 3). Using time-lapse video microscopy,

SLO was found to undergo rapid (<1 min) calcium-de-

pendent endocytosis [58], suggesting that pores are

removed from the cell surface, although this has not been

directly shown. Clearance of pores from the cell surface was

also observed for Staphylococcal a-toxin [57]. Both the

monomeric and heptameric forms of the toxin disappeared

from the surface of the human keratinocyte cell line HaCat

over a period of 2 h via a dynamin-dependent pathway [57].

Inhibition of dynamin with the drug dynasore led to an

increase in cell death [57]. Triggered endocytosis of the

perforin pore was also proposed to be important for the

delivery of granzymes upon CTL induced cell death of

infected cells [55]. It was thought that granzymes, which

trigger apoptosis once in the cytoplasm, passed the plasma

membrane through the perforin channels. Recent data,

however, indicate that cells actually repair perforin-

induced pores through a mechanism that involves per-

forin-triggered endocytosis, which would simultaneously

bring perforin and granzymes into the cells [55].

Once inside the cells, the oligomeric pores formed by

PFPs should in principle be destroyed, since they would

render endosomes leaky and affect their function. Gutier-

rez et al. [59�] proposed that intracellular destruction, or

sequestration, could occur through autophagy – the cata-

bolic process that degrades components of the cell

through the lysosomal machinery [60] – on the basis of

the observation that cells deficient in autophagy were

more sensitive to Vibrio cholera cytolyin induced cell death



Figure 3

Membrane repair after mechanical rupture or pore formation. Small

lesions such as those occurring during electroporation (<1 mm)

spontaneously seal. Bigger ruptures, induced by physical stress, trigger,

within seconds, the tethering and fusion of intracellular organelles at the

site of injury (see text). The attack by big, CDC type, PFPs also seems to

activate this machinery, but it is then followed by endocytosis of the

pores, leading to their physical removal from the plasma membrane. For

small PFTs a similar phenomenon has been observed, but following

slower kinetics. Subsequent degradation of PFTs by autophagy has

been proposed.

(Figure 3). Considering the high stability of the pore-

forming complex, Husmann et al., by contrast, proposed

that cells get rid of the Staphylococcal a-toxin pores

through regurgitation via an exosomal pathway [57].

Intracellular sequestration of PFPs has also been proposed

for both amyloid proteins and LLO as a means to avoid

further damage. Following the hypothesis that amyloid

proteins can form pore-like intermediates, it has been

proposed that the fibrillar deposits actually constitute a

defense mechanism to sequester the deadly intermediate

structures [61]. Along these lines, LLO inside Listeria

infected cells was found to form higher order aggregates

that were polyubiquitinated and contained the protein p62,

both typical components of aggregates found in neurode-

generative diseases [62]. Formation of these deposits was

proposed to protect the infected cells from massive pore

formation.

While the mechanisms leading to recovery of membrane

integrity following pore formation remain somewhat

obscure, a quite clear picture is emerging regarding seal-

ing after mechanical injury leading to lesion of >1 mm in

diameter. Resealing occurs on the second time scale,

requires entry of extracellular calcium as well as tethering


and recruitment of intracellular membranes at the injury

site (reviewed in [9,63]) (Figure 3). The source of orga-

nelles depends on the size of the lesion and whether it is

the first or the second wound. Exocytosis after the first

wound may involve a variety of organelles such as lyso-

somes, endosomes, and enlargeosomes, among others,

while exocytosis after the second wound seems to involve

the Golgi apparatus [63]. Since not all events that lead to

an increase in intracellular calcium trigger fusion of

intracellular vesicles with the plasma membrane, it was

postulated that additional molecular sensors of plasma

membrane integrity must exist. It was recently shown

that exposure to the extracellular oxidizing milieu con-

tributes to the resealing process in muscle cells [64��].Oxidation was found to trigger tethering of vesicles at the

injury site through the action of the MG53 protein [64��].MG53 has the dual capacity to bind to phosphatidyl

serine on the inner leaflet of the plasma membrane

and on vesicles, and to oligomerize under oxidizing

conditions through disulfide bond formation [64��]. Sub-

sequent calcium dependent vesicle fusion completes

the repair by restoring plasma membrane continuity

(Figure 3). The fact that changes in the oxidative state

of the cytoplasm constitute a signal – in addition to

potassium decrease and calcium increase – is very attrac-

tive, and it will be interesting to determine if similar

mechanisms operate when cells are challenged by PFTs.

Two alternative mechanisms for membrane sealing after

mechanical injury have however been proposed

[58,65,66]. Calcium-triggered activation of transglutami-

nase, an enzyme catalyzing protein cross-linking reac-

tions, was found to promote membrane resealing after

mechanical damage [65] possibly by forming a kind of clot

at the injury site that would prevent entry of the extra-

cellular milieu [65,66]. Alternatively, as for repair after

SLO pore formation, mechanical lesions were found to

undergo calcium-dependent endocytosis [58].

Conclusion and outlookMammalian cells are susceptible to breaches in their

plasma membrane. The lesions they encounter can be

of different sizes – ranging from a few nm to a few mm in

diameter – and can be lined by proteins and/or by lipids.

Recent findings suggest that these different lesions can all

be repaired by cells but involve different mechanisms and

operate on different time scales. Future research should

elucidate whether different lesions are sensed differently,

whether different pathways are activated, or whether all

pathways are activated under all conditions, but depend-

ing on the lesion type and size, only a given pathway will

succeed in restoring plasma membrane continuity.

AcknowledgementsWe thank Vern Carruthers for sharing the coordinates of the model of theToxoplasma perforin like protein. This work was supported by the SwissNational Science Foundation and by the Swiss SystemsX.ch initiative



evaluated by the Swiss National Science Foundation. MB is a recipient ofan iPhD SystemsX.ch fellowship. GvdG is an international Fellow of theHoward Hughes Medical Institute

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traversal is important for progression of the malaria parasitethrough the dermis to the liver. Cell Host Microbe 2008, 3:88-96.

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Kayed R, Pensalfini A, Margol L, Sokolov Y, Sarsoza F, Head E,Hall J, Glabe C: Annular protofibrils are a structurally andfunctionally distinct type of amyloid oligomer. J Biol Chem2009, 284:4230-4237.

Using conformational antibodies, the authors report the similarity instructure between protofibrils, which show to be different from amyloidoligomers, and the pore forming alpha toxin from Staphylococcusaureus.

38. Yoshiike Y, Kayed R, Milton SC, Takashima A, Glabe CG: Pore-forming proteins share structural and functional homologywith amyloid oligomers. Neuromol Med 2007, 9:270-275.

39. Arispe N, Doh M: Plasma membrane cholesterol controls thecytotoxicity of Alzheimer’s disease AbetaP (1-40) and (1-42)peptides. FASEB J 2002, 16:1526-1536.

40. Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ:Metal ions, pH, and cholesterol regulate the interactions ofAlzheimer’s disease amyloid-beta peptide with membranelipid. J Biol Chem 2003, 278:2977-2982.

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This study reports that E. coli hemolysin HlyA amplifies its hemolyticactivity on erythrocytes by triggering the opening of the endogenouspannexin hemichannels through the release of ATP.

45. Locovei S, Scemes E, Qiu F, Spray DC, Dahl G: Pannexin1 is partof the pore forming unit of the P2X(7) receptor death complex.FEBS Lett 2007, 581:483-488.

46. Pelegrin P, Surprenant A: Pannexin-1 mediates large poreformation and interleukin-1beta release by the ATP-gatedP2X7 receptor. EMBO J 2006, 25:5071-5082.

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49. Huffman DL, Abrami L, Sasik R, Corbeil J, van der Goot FG,Aroian RV: Mitogen-activated protein kinase pathways defendagainst bacterial pore-forming toxins. Proc Natl Acad Sci U S A2004, 101:10995-11000.

50. Husmann M, Dersch K, Bobkiewicz W, Beckmann E,Veerachato G, Bhakdi S: Differential role of p38 mitogenactivated protein kinase for cellular recovery from attack bypore-forming S. aureus alpha-toxin or streptolysin O. BiochemBiophys Res Commun 2006, 344:1128-1134.

51. Ratner AJ, Hippe KR, Aguilar JL, Bender MH, Nelson AL,Weiser JN: Epithelial cells are sensitive detectors of bacterialpore-forming toxins. J Biol Chem 2006.

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Bischof LJ, Kao CY, Los FC, Gonzalez MR, Shen Z, Briggs SP, vander Goot FG, Aroian RV: Activation of the unfolded proteinresponse is required for defenses against bacterial pore-forming toxin in vivo. PLoS Pathog 2008, 4:e1000176.


Using worms the authors show that the activation of the unfolded proteinresponse (UPR) lies downstream of p38 activation and defends theorganisms against attacks by PFTs.

53.��

Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG:Caspase-1 activation of lipid metabolic pathways in responseto bacterial pore-forming toxins promotes cell survival. Cell2006, 126:1135-1145.

In this study the decrease of intracellular potassium triggered by PFTswas found to activate the inflammasomes leading to the subsequentactivation of caspase-1, the activation of the master regulators of lipidmetabolisms, the SREBPs, and the promotion of cellular survival.

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Hamon MA, Batsche E, Regnault B, Tham TN, Seveau S,Muchardt C, Cossart P: Histone modifications induced by afamily of bacterial toxins. Proc Natl Acad Sci U S A 2007,104:13467-13472.

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57. Husmann M, Beckmann E, Boller K, Kloft N, Tenzer S,Bobkiewicz W, Neukirch C, Bayley H, Bhakdi S: Elimination of abacterial pore-forming toxin by sequential endocytosis andexocytosis. FEBS Lett 2009, 583:337-344.

58. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW:Repair of injured plasma membrane by rapid Ca2+-dependentendocytosis. J Cell Biol 2008, 180:905-914.

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Gutierrez MG, Saka HA, Chinen I, Zoppino FC, Yoshimori T,Bocco JL, Colombo MI: Protective role of autophagy againstVibrio cholerae cytolysin, a pore-forming toxin from V.cholerae. Proc Natl Acad Sci U S A 2007, 104:1829-1834.

This is the first report on the potential role of autophagy in the protectionof cells toward pore-forming toxins.

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Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M,Ko JK, Lin P, Thornton A, Zhao X et al.: MG53 nucleates assemblyof cell membrane repair machinery. Nat Cell Biol 2009, 11:56-64.

Using muscle cells the authors show that the protein MG53 triggerstethering of vesicles to the injury site after mechanical wounding throughoxidation. Calcium subsequently completes the repair by inducing vesiclefusion.

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Pore Forming Proteins