Cellular Entry of Clostridium perfringens Iota-Toxin and Clostridium botulinum C2 Toxin

Takehara, Masaya; Takagishi, Teruhisa; Seike, Soshi; Oda, Masataka; Sakaguchi, Yoshihiko; Hisatsune, Junzo; Ochi, Sadayuki; Kobayashi, Kazuo; Nagahama, Masahiro

doi:10.3390/toxins9080247

Cited by 28 publications

(77 citation statements)

References 51 publications

(129 reference statements)

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“…Clostridium perfringens iota toxin consists of two distinct protein components, one being the cell-binding protein (Ib) and other the enzymatic protein (Ia) [ 1 , 2 , 3 , 4 , 5 , 6 ]. Ia possesses actin-ADP-ribosyltransferase activity, blocking the formation of F-actin in the cytosol and then disrupting the actin cytoskeleton [ 2 , 6 , 7 , 8 ]. It has been reported that lipolysis-stimulated lipoprotein receptor (LSR) is a cellular receptor for Ib, promoting Ia internalization into a target cell [ 6 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Ia possesses actin-ADP-ribosyltransferase activity, blocking the formation of F-actin in the cytosol and then disrupting the actin cytoskeleton [ 2 , 6 , 7 , 8 ]. It has been reported that lipolysis-stimulated lipoprotein receptor (LSR) is a cellular receptor for Ib, promoting Ia internalization into a target cell [ 6 , 9 ]. Iota toxin is a clostridial binary actin-ADP-ribosylating toxin, which family encompasses Clostridium botulinum C2 toxin (C2I and C2II), Clostridium difficile transferase (CDTa and CDTb), and Clostridium spiroforme toxin (CSTa and CSTb) [ 1 , 2 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Interaction of Clostridium perfringens Iota Toxin and Lipolysis-Stimulated Lipoprotein Receptor (LSR)

Nagahama

Takehara

Kobayashi

2018

Toxins

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Iota toxin produced by Clostridium perfringens is a binary, actin ADP-ribosylating toxin that is organized into the enzymatically active component Ia and the binding component Ib. Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a cellular receptor of Ib. Here, we investigated the functional interaction between Ib and LSR, where siRNA for LSR blocked the toxin-mediated cytotoxicity and the binding of Ib. The addition of Ib to LSR-green fluorescence protein (GFP)-transfected cells at 4 °C resulted in colocalization with LSR and Ib on the cell surface. Upon transfer of the cells from 4 °C to 37 °C, LSR and Ib were internalized and observed in cytoplasmic vesicles. When the cells were incubated with Ib at 37 °C and fractionated using the Triton-insoluble membrane, Ib oligomer was localized in insoluble factions that fulfilled the criteria of lipid rafts, and LSR was clustered in lipid rafts. To examine the interaction between N-terminal extracellular region of LSR and Ib, we constructed a series of LSR N-terminal deletions. Ten amino acids residues can be deleted from this end without any reduction of Ib binding. However, deletion of 15 N-terminal residues drastically reduces its ability to bind Ib. These results demonstrate that Ib binds to the LSR N-terminal 10 to 15 residues and endocytoses into trafficking endosomes together with LSR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interaction of Clostridium perfringens Iota Toxin and Lipolysis-Stimulated Lipoprotein Receptor (LSR)

Nagahama

Takehara

Kobayashi

2018

Toxins

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“…The contributions to this Special Issue include several experimental articles, employing sophisticated techniques to gain important insights into the mechanism of cellular entry [1-6]; a thought-provoking perspective comment [7]; and two conceptual reviews, one on apicomplexan pore-forming toxins [8] and one on clostridial binary toxins [9]. What have we learned about the field from this collection?…”

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confidence: 99%

“…Cellular entry of bacterial toxins utilizes a complex mechanism [8,9] that involves multiple protein partners interacting with each other [3,9] and with a lipid bilayer [1,2,6]. Key players often undergo profound conformational changes, both in aqueous [5] and membranous environments [1,2].…”

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confidence: 99%

Cellular Entry of Binary and Pore-Forming Bacterial Toxins

2018

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This Special Issue of Toxins, entitled "Cellular Entry of Binary and Pore-Forming Bacterial Toxins," gives a sense of the recent advances in characterizing the functional and structural aspects of this broad scientific problem that goes beyond the classical field of toxinology and microbiology and spills into the general areas of biochemistry, biophysics, and molecular and cell biology. The contributions to this Special Issue include several experimental articles, employing sophisticated techniques to gain important insights into the mechanism of cellular entry [1-6]; a thought-provoking perspective comment [7]; and two conceptual reviews, one on apicomplexan pore-forming toxins [8] and one on clostridial binary toxins [9]. What have we learned about the field from this collection? Despite the limited selection, some general features can be identified.Deciphering complex pathways requires integration of various approaches. Cellular entry of bacterial toxins utilizes a complex mechanism [8,9] that involves multiple protein partners interacting with each other [3,9] and with a lipid bilayer [1,2,6]. Key players often undergo profound conformational changes, both in aqueous [5] and membranous environments [1,2]. Characterizing these functionally important conformational changes is a prerequisite for deciphering the mechanisms of cellular entry on a molecular level. One of the biggest challenges in establishing the structure-function relationships for bacterial toxins lies in their environment-dependent conformational lability. Consequently, even if a high-resolution structure of the soluble conformation is well-characterized, the mechanism might remain elusive, due to conformational rearrangements triggered by environment acidification and membrane insertion, common for the endosome-dependent pathways. These challenges could be met, for example, by careful examination of site-directed mutagenesis with a variety of functional assays (e.g., for diphtheria toxin [6]), complemented with molecular modeling (e.g., for perfringolysin O [1]). In another example, a sophisticated combination of cryo-electron microscopy, performed on elaborately prepared nanodisc samples, and computer simulations is used to resolve the structure of the pore of the anthrax toxin protective antigen in a lipid environment and in a complex with the toxin's lethal factor [2].Structured vs. unstructured passageways through the membrane. Bridging cellular membranes is a key step in the pathogenic action of both binary and pore-forming toxins. The former use their translocation domains, containing various structural motifs, to ensure efficient delivery of the toxic component into the host cell, while the latter act on the cellular membrane itself. In either case, the integrity of the membrane is compromised via targeted protein-lipid and protein-protein interactions triggered by specific signals, such as proteolytic cleavage and/or endosomal acidification. Several studies presented in this Special Issue either explicitly describe the formation of the...

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“…Cellular uptake of nanoparticles is a thermodynamic phenomenon that occurs from nanoparticle adsorption on the cell membrane followed by membrane wrapping and invagination in order to minimize the chemical binding energy (114)(115)(116)(117)(118)(119). The distinct organization of MENs around glioblastoma and brain endothelial cells was further verified by fluorescence images of these cells incubated with fluorescein isothiocyanate loaded MENs.…”

Section: Discussionmentioning

confidence: 93%

Technobiology Paradigm in Nanomedicine: Treating Cancer with MagnetoElectric Nanoparticles

Stimphil¹

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Cellular Entry of Clostridium perfringens Iota-Toxin and Clostridium botulinum C2 Toxin

Cited by 28 publications

References 51 publications

Interaction of Clostridium perfringens Iota Toxin and Lipolysis-Stimulated Lipoprotein Receptor (LSR)

Interaction of Clostridium perfringens Iota Toxin and Lipolysis-Stimulated Lipoprotein Receptor (LSR)

Cellular Entry of Binary and Pore-Forming Bacterial Toxins

Technobiology Paradigm in Nanomedicine: Treating Cancer with MagnetoElectric Nanoparticles

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