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11 pages, 670 KiB

Open AccessReview

Cellular Uptake and Cytotoxicity of Clostridium perfringens Iota-Toxin

by Masahiro Nagahama, Masaya Takehara, Soshi Seike and Yoshihiko Sakaguchi

Toxins 2023, 15(12), 695; https://doi.org/10.3390/toxins15120695 - 11 Dec 2023

Cited by 5 | Viewed by 3009

Clostridium perfringens iota-toxin is composed of two separate proteins: a binding protein (Ib) that recognizes a host cell receptor and promotes the cellular uptake of a catalytic protein and (Ia) possessing ADP-ribosyltransferase activity that induces actin cytoskeleton disorganization. Ib exhibits the overall structure of bacterial pore-forming toxins (PFTs). Lipolysis-stimulated lipoprotein receptor (LSR) is defined as a host cell receptor for Ib. The binding of Ib to LSR causes an oligomer formation of Ib in lipid rafts of plasma membranes, mediating the entry of Ia into the cytoplasm. Ia induces actin cytoskeleton disruption via the ADP-ribosylation of G-actin and causes cell rounding and death. The binding protein alone disrupts the cell membrane and induces cytotoxicity in sensitive cells. Host cells permeabilized by the pore formation of Ib are repaired by a Ca²⁺-dependent plasma repair pathway. This review shows that the cellular uptake of iota-toxin utilizes a pathway of plasma membrane repair and that Ib alone induces cytotoxicity. Full article

(This article belongs to the Special Issue ADP-Ribosylation and Beyond)

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8 pages, 9084 KiB

Open AccessArticle

Cathepsin Release from Lysosomes Promotes Endocytosis of Clostridium perfringens Iota-Toxin

by Masahiro Nagahama, Keiko Kobayashi and Masaya Takehara

Toxins 2021, 13(10), 721; https://doi.org/10.3390/toxins13100721 - 12 Oct 2021

Cited by 4 | Viewed by 2669

Abstract

Iota-toxin from Clostridium perfringens type E is a binary toxin composed of two independent proteins: actin-ADP-ribosylating enzyme component, iota-a (Ia), and binding component, iota-b (Ib). Ib binds to target cell receptors and mediates the internalization of Ia into the cytoplasm. Extracellular lysosomal enzyme acid sphingomyelinase (ASMase) was previously shown to facilitate the internalization of iota-toxin. In this study, we investigated how lysosomal cathepsin promotes the internalization of iota-toxin into target cells. Cysteine protease inhibitor E64 prevented the cytotoxicity caused by iota-toxin, but aspartate protease inhibitor pepstatin-A and serine protease inhibitor AEBSF did not. Knockdown of lysosomal cysteine protease cathepsins B and L decreased the toxin-induced cytotoxicity. E64 suppressed the Ib-induced ASMase activity in extracellular fluid, showing that the proteases play a role in ASMase activation. These results indicate that cathepsin B and L facilitate entry of iota-toxin via activation of ASMase. Full article

(This article belongs to the Special Issue A-B Type of Toxins: Mode of Transport and Interaction with Lipid Bilayers)

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19 pages, 1839 KiB

Open AccessReview

Tight Junction Modulating Bioprobes for Drug Delivery System to the Brain: A Review

by Keisuke Tachibana, Yumi Iwashita, Erika Wakayama, Itsuki Nishino, Taiki Nishikaji and Masuo Kondoh

Pharmaceutics 2020, 12(12), 1236; https://doi.org/10.3390/pharmaceutics12121236 - 19 Dec 2020

Cited by 19 | Viewed by 4691

Abstract

The blood-brain barrier (BBB), which is composed of endothelial cells, pericytes, astrocytes, and neurons, separates the brain extracellular fluid from the circulating blood, and maintains the homeostasis of the central nervous system (CNS). The BBB endothelial cells have well-developed tight junctions (TJs) and express specific polarized transport systems to tightly control the paracellular movements of solutes, ions, and water. There are two types of TJs: bicellular TJs (bTJs), which is a structure at the contact of two cells, and tricellular TJs (tTJs), which is a structure at the contact of three cells. Claudin-5 and angulin-1 are important components of bTJs and tTJs in the brain, respectively. Here, we review TJ-modulating bioprobes that enable drug delivery to the brain across the BBB, focusing on claudin-5 and angulin-1. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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10 pages, 1414 KiB

Open AccessArticle

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

by Masahiro Nagahama, Masaya Takehara and Keiko Kobayashi

Toxins 2018, 10(10), 405; https://doi.org/10.3390/toxins10100405 - 8 Oct 2018

Cited by 13 | Viewed by 4094

Abstract

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. Full article

(This article belongs to the Special Issue ADP-Ribosylating Toxin)

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11 pages, 1676 KiB

Open AccessArticle

Acid Sphingomyelinase Promotes Cellular Internalization of Clostridium perfringens Iota-Toxin

by Masahiro Nagahama, Masaya Takehara, Kazuaki Miyamoto, Kazumi Ishidoh and Keiko Kobayashi

Toxins 2018, 10(5), 209; https://doi.org/10.3390/toxins10050209 - 20 May 2018

Cited by 7 | Viewed by 4545

Abstract

Clostridium perfringens iota-toxin is a binary actin-ADP-ribosylating toxin composed of the enzymatic component Ia and receptor binding component Ib. Ib binds to a cell surface receptor, forms Ib oligomer in lipid rafts, and associates with Ia. The Ia-Ib complex then internalizes by endocytosis. Here, we showed that acid sphingomyelinase (ASMase) facilitates the cellular uptake of iota-toxin. Inhibitions of ASMase and lysosomal exocytosis by respective blockers depressed cell rounding induced by iota-toxin. The cytotoxicity of the toxin increased in the presence of Ca²⁺ in extracellular fluids. Ib entered target cells in the presence but not the absence of Ca²⁺. Ib induced the extracellular release of ASMase in the presence of Ca²⁺. ASMase siRNA prevented the cell rounding induced by iota-toxin. Furthermore, treatment of the cells with Ib resulted in the production of ceramide in cytoplasmic vesicles. These observations showed that ASMase promotes the internalization of iota-toxin into target cells. Full article

(This article belongs to the Special Issue Bacterial Pore-Forming Toxins)

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21 pages, 2256 KiB

Open AccessReview

Clostridium perfringens Iota-Toxin: Structure and Function

by Jun Sakurai, Masahiro Nagahama, Masataka Oda, Hideaki Tsuge and Keiko Kobayashi

Toxins 2009, 1(2), 208-228; https://doi.org/10.3390/toxins1020208 - 23 Dec 2009

Cited by 62 | Viewed by 18858

Abstract

Clostridium perfringens iota-toxin is composed of the enzyme component (Ia) and the binding component (Ib). Ib binds to receptor on targeted cells and translocates Ia into the cytosol of the cells. Ia ADP-ribosylates actin, resulting in cell rounding and death. Comparisons of the deduced amino acid sequence from the gene and three-dimensional structure of Ia with those of ADP-ribosylating toxins (ARTs) suggests that there is striking structural similarity among these toxins. Our objectives are to review the recent advances in the character, structure-function, and the mode of action of iota-toxin by consideration of the findings about ARTs. Full article

(This article belongs to the Special Issue Bacterial Protein Toxins)

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