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ScienceDirect Novel receptors for bacterial protein toxins Gudula Schmidt1, Panagiotis Papatheodorou1 and Klaus Aktories1,2 While bacterial effectors are often directly introduced into eukaryotic target cells by various types of injection machines, toxins enter the cytosol of host cells from endosomal compartments or after retrograde transport via Golgi from the ER. A first crucial step of toxin–host interaction is receptor binding. Using optimized protocols and new methods novel toxin receptors have been identified, including metalloprotease ADAM 10 for Staphylococcus aureus a-toxin, laminin receptor Lu/ BCAM for Escherichia coli cytotoxic necrotizing factor CNF1, lipolysis stimulated lipoprotein receptor (LSR) for Clostridium difficile transferase CDT and low-density lipoprotein receptorrelated protein (LRP) 1 for Clostridium perfringens TpeL toxin. Addresses 1 Institut fu¨r Experimentelle und Klinische Pharmakologie und Toxikologie der Albert-Ludwigs-Universita¨t Freiburg, Albert-Str. 25, 79104 Freiburg, Germany 2 Centre for Biological Signalling Studies (BIOSS), Germany Corresponding author: Aktories, Klaus ([email protected])

Current Opinion in Microbiology 2015, 23:55–61 This review comes from a themed issue on Host–microbe interactions: bacteria Edited by David Holden and Dana Philpott

http://dx.doi.org/10.1016/j.mib.2014.11.003 1369-5274/# 2014 Elsevier Ltd. All rights reserved.

Introduction During host–pathogen interaction, many pathogenic bacteria produce a cocktail of protein toxins and effectors, which manipulate the eukaryotic host cell behavior for the benefit of the pathogen. Thereby, the pathogens are able to evade host defense mechanisms. This is frequently achieved by covalent modification and/or modulation of regulatory molecules of host cells crucially involved in cell signaling and/or control of innate and acquired immunity defense mechanisms. As most of the host target molecules of toxins and effectors are located inside cells, different mechanisms evolved for entering this cellular compartment.

Direct injection of bacterial effectors into target cells Some Gram-negative bacteria, like Salmonella, Shigella, Pseudomonas or Yersinia directly inject toxic proteins, www.sciencedirect.com

named effectors or outer proteins, into the cytosol of mammalian cells (for review see [1–3]). This process usually requires a direct contact between bacterium and eukaryotic cell. Injection of the proteins is mediated by a syringe-like apparatus, the type III secretion (T3S) system, which is assembled of several proteins by the pathogen. For example the Shigella needle complex with a molecular weight of more than 3 MDa protrudes into the extrabacterial space and forms a hollow structure with an inner diameter of approximately 2–3 nm [2,4]. This allows the passage of partly folded proteins through this needle into the cytosol of mammalian cells. The injectisome of Yersinia is made of 27 Yop secretion (Ysc) proteins, forming a long hollow needle similar to the injectisomes from Salmonella and Shigella [5–7]. Direct injection of the effector proteins enables them to reach the cytosolic target molecules without any exposure to the body fluid or interaction with the outer cell surface. Therefore, the proteins are protected from the attack of several proteases. The type IV secretion (T4S) system, which resembles in some aspects the T3S system consists of 12 (e.g. in Agrobacterium tumefaciens) to 27 essential proteins (e.g. in Legionella), and is used by Agrobacterium, Helicobacter, Brucella, Bordetella and Legionella to inject effectors into host cells or to release toxin (pertussis toxin) into the environment [8,9]. Moreover, some T4S systems participate in conjugative transfer of plasmids between bacteria. Finally, the most recently deciphered system for delivery of effectors is the type VI secretion system, which is comprised of 13 conserved proteins and a variable complement of accessory elements. Initially it was identified as a system to target eukaryotic cells but later turned out to be more important for inter-bacterial injections [10].

Uptake of toxins by receptor-mediated endocytosis Other toxins are secreted by the bacteria into the surrounding body fluid. Some of these toxins directly insert into the plasma membrane of mammalian cells forming a pore (e.g. cholesterol dependent cytolysins [11]). However, most secreted protein toxins act intracellularly and are AB toxins, consisting of a biologically active part (A part) and a part involved in target cell binding and up-take (B part). AB toxins enter the cytosol usually by receptormediated endocytosis. The two main pathways that have been described for the uptake of such toxins into the cytosol are discussed below. Short trip toxins

‘Short trip toxins’ bind to a cellular receptor, are taken up via endocytosis and are released from acidified endosomes Current Opinion in Microbiology 2015, 23:55–61

56 Host–microbe interactions: bacteria

into the cytosol [12]. Acidification is required for insertion of a hydrophobic part of the toxins into the endosomal membrane and to form a pore allowing transport of the unfolded catalytic part of the toxin into the cytosol. However, pore formation could not be proven for all toxins by now. Probably best understood is the pore-formation by the protective antigen (PA), the binding component of anthrax toxin [13], which is a tripartite toxin. PA is proteolytically activated and then forms a heptameric prepore, which binds up to three molecules of edema factor (EF) or lethal factor (LF), the biologically active components of anthrax toxin. The toxin complexes bind to anthrax toxin receptors (ANTXR1 and ANTXR2) and are taken up by endocytosis. In low pH endosomes, the prepore undergoes a conformational change with membrane insertion and formation of a pore by the mushroom-like structure with a 10 nm-long stem that spans the membrane. The pore serves as an active transporter and a charge state-dependent Brownian ratchet mechanism is suggested to be responsible for translocation of unfolded EF and LF through the PA-pore [14]. Cellular chaperones may be required for refolding the toxins. Inhibition of common chaperones like HSP90 by geldanamycin and cyclophilins by cyclosporins has been shown to block the uptake/activity especially of ADP-ribosylating toxins [15–17]. For some toxins it has been shown, that only the catalytic part is released into the cytosol. This requires the cleavage of these single chain toxins. The protease activity can be also part of the toxin as shown for RTX toxins and Clostridium difficile toxins A and B, which harbor a cysteine protease domain for autocleavage [18,19]. The protease is allosterically activated by inositol hexakisphosphate, which is present at high concentrations in the cytosol [20,21].

Long trip toxins

‘Long trip toxins’ also bind to a cellular receptor and are taken up by endocytosis. In contrast to short trip toxins they are not released from the endosome into the cytosol but transported backwards to Golgi and ER from which the proteins are released into the cytosol. A prominent example for a long trip toxin is shiga toxin from Shigella dysenteriae and certain strains of Escherichia coli [22,23]. Shiga toxin is an AB5 toxin, which binds with its pentameric B-subunits to its receptor globotriaosylceramide (Gb3). The toxin complex is taken up by clathrin-dependent and clathrin-independent endocytosis and then retrogradly sorted to the Golgi apparatus. This is a complicated travel, depending on vesicle membrane lipids, and numerous proteins, including p38 and protein kinase Cd, retromer components, clathrin and dynamin, Cdc42, Rab proteins and several others. The intra-Golgi transport depends on various Rab proteins including Rab6, Rab33b and Rab43. Also the transport from Golgi to ER is variable and may occur via COPI-dependent and COPI-independent routes, depending on Cdc42, microtubules and actin. Eventually, the A component of shiga toxin leaves the ER Current Opinion in Microbiology 2015, 23:55–61

and reaches the cytosol using the sec61 translocon of the ER-associated protein degradation (ERAD) system [24]. Considering the above mentioned up-take mechanisms, it is obvious that cell targeting and receptor binding is the first pivotal step for the action of the intracellularly acting toxins. In the following, we will describe new findings about toxin receptors.

Methods to identify receptors for bacterial toxins A crucial task for understanding the pathophysiological action of secreted bacterial toxins is the identification of their cellular receptors. Attempts to identify the toxin receptors by affinity purification from isolated cell membranes often fail, probably, because of miss-orientation of the membrane proteins. However, two of the recently identified receptors for bacterial toxins (ADAM10 for Staphylococcus aureus a-hemolysin and LU/BCAM for E. coli CNF1) were identified by a classical affinity based coprecipitation assay with a simple but crucial modification of the protocol: the toxin was incubated with living cells [25,26]. This guarantees an intact membrane potential and correct folding and functionality of the receptor. The limiting factor of this method is the stability/affinity of the receptor–ligand interaction which has to endure cell lysis and precipitation. Other assays for identification of toxin receptors are based on the fact that many bacterial toxins lead to cell rounding and detachment or killing of cells. Therefore, genetic screens can be performed by selecting attaching/surviving cell clones, following random gene knockout. This survival assay has been developed using haploid cells and virus-based random gene insertion by the group of Brummelkamp [27]. Limiting factor of this method is the requirement of the protein randomly knocked out to be not essential for the viability of the cells. Moreover, expression of functional isoforms or redundancy for toxin binding may limit the success of this assay. However, several receptors for bacterial proteins toxins, including LSR as receptor for the C. difficile transferase CDT and LRP1 as receptor for Clostridium perfringens TpeL have been identified using this method. New methods have been developed, which allow the knockout of genes also in diploid cells, circumventing the restriction to work with haploid cell lines. The clustered regularly interspaced short palindromic repeat (CRISPR) Cas (CRISPR associated) system constitutes the adaptive immune system present in many bacteria and most archaea for their protection against foreign DNA. Short CRISPR-RNA sequences guide effector complexes formed with Cas proteins for the cleavage of the foreign DNA or RNA (for review see [28]). The system was further developed that eukaryotic genes can be targeted. Sequence libraries resembling the eukaryotic genome are www.sciencedirect.com

Toxin receptors Schmidt, Papatheodorou and Aktories 57

commercially available and the identification of several receptors for bacterial toxins with this method is expected in near future.

Examples of ‘novel’ cellular receptors for bacterial protein toxins identified recently ADAM 10, the receptor of S. aureus a-toxin

S. aureus a-toxin (a-hemolysin, Hla) is a cytotoxin that leads to cell injury and death by forming a heptameric pore, spanning the plasma membrane [29,30]. Hla binds to eukaryotic cells by nonspecific adsorption. However, the higher sensitivity of rabbit erythrocytes compared to human erythrocytes for toxin action very early suggested the presence of a specific receptor for Hla [31]. Wilke and Bubeck-Wardenburg identified the proteinanceous receptor interacting with the toxin by using the classic biochemical approach described above [25]. They incubated erythrocyte ghosts with a recombinant tagged toxin mutant unable to form pores but still binding to the cell surface. Cells were lysed and the protein complexes precipitated and analyzed by mass spectrometry. By comparing human and rabbit erythrocyte-derived precipitates the disintegrin and zinc-dependent metalloprotease ADAM 10 could be identified as binding partner for Hla [25] (Table 1). The type-1 transmembrane protein ADAM 10 is expressed on many cells and tissues including erythrocytes and epithelial cells that are targeted in S. aureus infections. Upon toxin-binding the receptor translocates to caveolin-enriched microdomains. This allows clustering of the receptor and initiates intracellular signaling. Moreover, gathering of receptor-bound toxin monomers in microdomains may support the generation of the toxin heptamers required for pore formation, since cholesterol depletion hampers cell lysis [32]. Knockdown experiments showed that binding is specific for ADAM 10, other ADAM types are no binding partners of the toxin (Figure 1). The fact that ADAM10 is a metalloprotease raises the question whether the role of ADAM10-Hla binding goes beyond mere recruitment of the toxin to the cell surface. And indeed, toxin binding to ADAM10 stimulates metalloprotease activity leading to enhanced cleavage of the

adherence junction protein E-cadherin and opening of epithelial barriers [33]. However, it is not clear, whether ADAM10 activation is due to toxin binding or toxininduced changes of intracellular calcium levels or membrane lipid composition that both induce ADAM-mediated protein ectodomain shedding [34]. On the other hand, it is clear that all effects of Hla on target cells depend on toxin assembly and patency of the toxin pore [33]. BCAM, the receptor of E. coli CNF1

E. coli cytotoxic necrotizing factor 1 (CNF1) is a major virulence factor of uropathogenic E. coli and also involved in E. coli-caused meningitis [35]. The toxin acts as a deamidase, which directly activates Rho GTPases [36,37]. CNF1 is a typical short trip toxin, which enters the cytosol following receptor-mediated endocytosis and acidification of the endosomes [38]. Two cellular receptors have been identified as binding partners of CNF1: The N-terminal 342 amino acids of the toxin interact with the 37 kDa laminin receptor precursor (37LRP) in a yeast two-hybrid screen [39]. 37LRP matures to the 67 kDa cell surface-localized laminin receptor (67LR), which interacts with CNF1 on the cell surface. Interestingly, using monoclonal antibodies it has been shown, that a second part of CNF1 is involved in binding to mammalian cells [40]. By affinity based co-precipitation assays, the Lutheran (Lu) adhesion glycoprotein/basal cell adhesion molecule (BCAM) was identified as high affinity binding partner for CNF1 (Table 1). However, although both receptors physiologically interact with laminin, the toxin binds with different parts to 67LR (N-terminus) and Lu/BCAM (C-terminus). Expression of Lu/BCAM is essential for binding and uptake into mammalian cells. Cells which do not express the glycoprotein are not sensitive for CNF1 intoxication [26]. Lu/BCAM consists of 628 amino acids (long isoform), has a large extracellular Ig-like structure and is widely expressed in several cells and tissues [41]. Lu/BCAM is expressed as two isoforms with differences in the length of the cytosolic part of the molecule (59 versus 19 amino acids). The longer isoform Lu contains an SH3 domain for

Table 1 Novel receptors of bacterial toxins identified in recent years Toxin

Receptor

Clostridium difficile Transferase CDT Clostridium perfringens TpeL

LSR

Escherichia coli CNF1 Staphylococcus aureus a-hemolysin

BCAM P37/67 LRP ADAM10

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LRP1

Physiological function of the receptor Lipid metabolism Formation of tricellular tight junctions Scavenger receptor with multiple functions: for example, lipid metabolism, protease scavenging, protease inhibitor scavenging Cell matrix contact (laminin binding) Disintegrin, zinc-dependent metalloprotease

Current Opinion in Microbiology 2015, 23:55–61

58 Host–microbe interactions: bacteria

Figure 1

(a)

Hla

CNF1

CDT

TpeL N

N N Zn

ADAM 10

LU/BCAM

LSR

N

LRP1

E-cadherin and others

Furin

P C

C

C

PKA C

Toxin-induced intracellular signaling?

1 20

(b)

672 694

748

ADAM10 220-456 peptidase

457-551 555-673 disintegrin Cys rich

SH3 SH3

547 569

1 32

628

BCAM 32-142

147-257

274-355 363-441 448-541 lg-like 649

259 281

1

LSR 86-234 lg-like

LRP1

280-304 Cys rich

extracellular

membrane intracellular

1

4445 I

II

25-110 EGF 852-1182 2 x LDL-BD YWTD 8 x LDL-BD

III EGF YWTD

2522-2940 10 x LDL-BD

4544

IV EGF YWTD

3332-3778 11 x LDL-BD

EGF YWTD

EGF

NPXY motif Current Opinion in Microbiology

Receptors identified recently. (a) Toxin receptors are essential for the interaction and up-take of toxins and may also play signaling roles in effects induced by the toxins. ADAM10 is the receptor for S. aureus a-toxin (hla), the proteins is a zinc metalloprotease with many targets and is probably involved in cleavage (shedding) of cell surface proteins (e.g. different types of cadherins, Hb-EGF or TNF). The Rho protein-activating E. coli toxin CNF1 binds to the adhesion molecule Lu/BCAM. The receptor of the C. difficile toxin CDT is LSR, which is suggested to be involved in lipid metabolism but also in regulation of tricellular tight junctions. The clostridial glycosylating toxin TpeL from C. perfringens is LRP1. Multiple ligands are known for this scavenger receptor including Pseudomonas exotoxin A. (b) Domain structures of ADAM10, Lu/BCAM, LSR and LRP1. ADAM10 (Uniprot. Acc. Nr. O14672) possesses an extracellular peptidase, disintegrin and a cysteine rich domain. The intracellular part has two SH3 domains. Lu/BCAM (Uniprot. Acc. Nr. P50895) harbors five Ig-like extracellular domains. LSR (Uniprot. Acc. Nr. Q86X29) possesses one extracellular Ig-like domain and an intracellular cysteine rich region near the plasma membrane. The intracellular part is rather long, suggesting functions not known so far. LRP1 (Uniprot. Acc Nr. Q07954) is a large protein of multiple domains (e.g. 22 EGF-like domains, 31 LDL-binding domain and others). The LDL-binding domains (LDL-BD) form binding clusters (I–IV), which are important for ligand interaction. For example, TPEL binds to cluster IV. Only regions of the clusters are indicated by amino acid numbering. EGF domains, including domains with YWTD (Tyr-Trp-ThrAsp) repeats, which form b-propeller structures, are also shown. The intracellular part contains two NPxY motifs, which are involved in receptor endocytosis and signaling. The receptor is cleaved by a furin like protease (arrow) but both parts remain associated. (The numbering gives signal sequences, transmembrane regions and well defined functional important domains).

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Toxin receptors Schmidt, Papatheodorou and Aktories 59

protein–protein interaction and several phosphorylation sites, indicating involvement of the receptor in signaling processes [42]. Moreover, Lu/BCAM directly interacts with spectrin, which is a cortical actin-binding protein [43]. Notably, Lu/BCAM plays a role in some pathophysiological aspects of sickle cell anemia. Lu/BCAM is overexpressed in erythrocytes of sickle disease patients, leading to enhanced interaction of the blood cells with endothelia inducing thrombosis. This adhesion is activated by the phosphorylation of Lu in a protein kinase A-dependent manner [44]. LSR, the receptor of C. difficile transferase CDT, C. perfringens iota toxin and C. spiroforme toxin

toxins (CGTs) [58]. TpeL GlcNAcylates Ras/Rho proteins at threonine-35 thereby inducing apoptosis of host cells [59,60]. Like other clostridial glycosylating toxins [46,61], TpeL is a single-chain protein that can be subdivided into four functional domains, an N-terminal glycosyltransferase domain, which is followed by a cysteine protease domain and a translocation domain, and a receptor-binding domain at its C-terminus [59,62]. However, unlike other clostridial glycosylating toxins, TpeL entirely lacks the CROP (combined repetitive oligopeptides) domain that represents the common receptor-binding domain of all other CGT family members.

C. difficile is a bacterial pathogen of the human intestine causing diarrhea and pseudomembranous colitis. Two exotoxins, toxin A and B, which glucosylate Rho GTPases [45], are the main virulence factors of the pathogen [46]. However, hyper virulent C. difficile strains have been described that produce a third toxin termed CDT (C. difficile transferase) [47]. CDT is a binary toxin that consists of two separated components, an A component that harbors the toxic enzyme activity and a B component that mediates binding of the toxin to the host cell and translocation of the A component into the host cell cytosol [48]. The toxin covalently attaches the ADP-ribose moiety from NAD to arginine-177 of monomeric actin [49], resulting in actin depolymerization and cell death [50]. At low doses, CDT leads to the formation of microtubule-based cellular protrusions and re-routes vesicle traffic that both enhance adherence and colonization of the bacteria [51,52].

Using a haploid genetic screen, the low-density lipoprotein receptor-related protein 1 (LRP1) was recently identified as a host cell receptor of the TpeL toxin [62] (Table 1). LRP1 belongs to the LDL receptor gene family and participates in a wide range of biological processes, including lipid metabolism, cell communication, signal transduction, and various scavenger functions [63]. The LRP1 protein is a large type-I single-pass transmembrane protein with the size of 600 kDa. The N-terminal, extracellular part (denoted as heavy chain) of LRP1 has a size of 515 kDa and contains four ligand binding clusters. It is processed by the furin protease and remains non-covalently attached to the 85 kDa membrane-integrated intracellular part (light chain) [64]. LRP1 mediates the endocytosis of a variety of ligands (e.g. apolipoprotein E, chylomicron remnants, a2macroglobulin, several proteases and protease inhibitors, etc.). It acts also as the cell entry receptor for Pseudomonas exotoxin A and the minor-group common cold virus [65,66].

A genetic screen based on haploid cells that carry singlegene knockouts via retroviral insertional mutagenesis identified the lipolysis-stimulated lipoprotein receptor (LSR) as the host receptor for CDT (Table 1). Moreover, LSR acts as the cell entry receptor for the C. spiroforme toxin (CST) and C. perfringens iota-toxin that are highly homologous to CDT [53,54].

The finding that LRP1 is the receptor for TpeL is important for the whole family of CGTs. Up to recently, it has been suggested that CGT-host cell interaction depends exclusively on the CROP domain, which is not present in TpeL. Because the C-terminal receptor binding region of TpeL is also conserved in other CGTs, a two-receptor model is proposed for these toxins [62].

LSR is a type I single-pass transmembrane protein that is mainly expressed in the liver, but also in the intestine and in other tissues [55]. In the extracellular part of LSR, an immunoglobuline-like, V-type domain is present. An extracellular receptor fragment inhibits CDT-caused cell intoxication by toxin sequestration. Initially, LSR has been suggested to act as a lipoprotein receptor that contributes to the hepatic clearance of chylomicron remnants from blood [56]. More recently, Furuse and coworkers described a role of LSR in the formation of tricellular tight junctions at the convergence of three adjacent cells in epithelia by recruiting the protein tricellulin [57].

Concluding remarks

LRP1, the receptor for C. perfringens TpeL toxin

C. perfringens TpeL toxin represents the most recently described member of the family of clostridial glycosylating www.sciencedirect.com

Membrane receptors are crucial for the action of bacterial protein toxins. However, receptor identification is difficult, because many toxins are highly active and the up-take of only few toxin molecules may be sufficient for toxin actions. With the development of new methods the identification of the cellular receptors of several bacterial protein toxins could be expected. This is not only important for the analysis of toxins’ action per se. The knowledge of the molecules responsible for toxin-binding is instrumental for blocking entrance of the toxins into mammalian cells. Moreover, high affinity peptides of the toxins may be able to block the physiological action of the receptors or, vice versa, receptor binding domains may be employed to sequester toxins thereby blocking their actions. Since most toxins are composed of a modular structure, exchange of receptor binding Current Opinion in Microbiology 2015, 23:55–61

60 Host–microbe interactions: bacteria

domains between toxins or with physiological receptor ligands may allow to exploit the high efficiency of many toxins as selective and potent tools to target specifically cells and tissues in critical diseases like cancer.

Acknowledgements Studies reported were financially supported by the Deutsche Forschungsgemeinschaft (projects AK6/16-4, AK6/23-1 and Schm1385/4-1). We thank Gerhard Wetterer for excellent help in figure preparation.

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Toxin receptors Schmidt, Papatheodorou and Aktories 61

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vesicle traffic to increase pathogen adherence. Proc Natl Acad Sci USA 2014, 111:2313-2318. 53. Papatheodorou P, Carette JE, Bell GW, Schwan C, Guttenberg G,  Brummelkamp TR, Aktories K: Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc Natl Acad Sci USA 2011, 108:16422-16427. Identification of LSR as the receptor for C. difficile transferase and C. perfringens iota toxin. Successful application of the haploid cell screening for receptor analysis. 54. Papatheodorou P, Wilczek C, Nolke T, Guttenberg G, Hornuss D, Schwan C, Aktories K: Identification of the cellular receptor of Clostridium spiroforme toxin. Infect Immun 2012, 80:1418-1423. 55. Mesli S, Javorschi S, Berard AM, Landry M, Priddle H, Kivlichan D, Smith AJ, Yen FT, Bihain BE, Darmon M: Distribution of the lipolysis stimulated receptor in adult and embryonic murine tissues and lethality of LSRS/S embryos at 12.5 to 14.5 days of gestation. Eur J Biochem 2004, 271:3103-3114. 56. Yen FT, Mann CJ, Guermani LM, Hannouche NF, Hubert N, Hornick CA, Bordeau VN, Agnani G, Bihain BE: Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein. Biochemistry 1994, 33:1172-1180. 57. Masuda S, Oda Y, Sasaki H, Ikenouchi J, Higashi T, Akashi M,  Nishi E, Furuse M: LSR defines cell corners for tricellular tight junction formation in epithelial cells. J Cell Sci 2011, 124:548-555. This study showed that LSR has important functions in regulation of tight junctions. These findings opened a new perspective in research about LSR and largely extended the previous view of LSR as an receptor involved in lipid meatbolism. 58. Amimoto K, Noro T, Oishi E, Shimizu M: A novel toxin homologous to large clostridial cytotoxins found in culture supernatant of Clostridium perfringens type C. Microbiology 2007, 153:1198-1206. 59. Guttenberg G, Hornei S, Jank T, Schwan C, Lu W, Einsle O, Papatheodorou P, Aktories K: Molecular characteristics of Clostridium perfringens TpeL toxin and consequences of mono-O-GlcNAcylation of Ras in living cells. J Biol Chem 2012, 287:24929-24940. 60. Nagahama M, Ohkubo A, Oda M, Kobayashi K, Amimoto K, Miyamoto K, Sakurai J: Clostridium perfringens TpeL glycosylates the Rac and Ras subfamily proteins. Infect Immun 2010, 79:905-910. 61. Jank T, Aktories K: Structure and mode of action of clostridial glucosylating toxins: the ABCD model. Trends Microbiol 2008, 16:222-229. 62. Schorch B, Song S, van Diemen FR, Bock HH, May P, Herz J,  Brummelkamp TR, Papatheodorou P, Aktories K: LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins. Proc Natl Acad Sci USA 2014, 111:6431-6436. Describes the first receptor for a clostridial glycosylating toxin. Points into a new direction concerning receptor studies of this typ of toxins. 63. Herz J, Strickland DK: LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 2001, 108:779-784. 64. Willnow TE, Moehring JM, Inocencio NM, Moehring TJ, Herz J: The low-density-lipoprotein receptor-related protein (LRP) is processed by furin in vivo and in vitro. Biochem J 1996, 313:71-76. 65. Kounnas MZ, Morris RE, Thompson MR, FitzGerald DJ, Strickland DK, Saelinger CB: The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem 1992, 267:12420-12423. 66. Hofer F, Gruenberger M, Kowalski H, Machat H, Huettinger M, Kuechler E, Blaas D: Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Proc Natl Acad Sci USA 1994, 91:1839-1842.

Current Opinion in Microbiology 2015, 23:55–61

Novel receptors for bacterial protein toxins.

While bacterial effectors are often directly introduced into eukaryotic target cells by various types of injection machines, toxins enter the cytosol ...
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