title: Clostridial C3 Toxins Target Monocytes/Macrophages and Modulate Their Functions.
abstract: The C3 enzymes from Clostridium (C.) botulinum (C3bot) and Clostridium limosum (C3lim) are single chain protein toxins of about 25 kDa that mono-ADP-ribosylate Rho-A, -B, and -C in the cytosol of mammalian cells. We discovered that both C3 proteins are selectively internalized into the cytosol of monocytes and macrophages by an endocytotic mechanism, comparable to bacterial AB-type toxins, while they are not efficiently taken up into the cytosol of other cell types including epithelial cells and fibroblasts. C3-treatment results in disturbed macrophage functions, such as migration and phagocytosis, suggesting a novel function of clostridial C3 toxins as virulence factors, which selectively interfere with these immune cells. Moreover, enzymatic inactive C3 protein serves as a transport system to selectively deliver pharmacologically active molecules into the cytosol of monocytes/macrophages without damaging these cells. This review addresses also the generation of C3-based molecular tools for experimental macrophage pharmacology and cell biology as well as the exploitation of C3 for development of novel therapeutic strategies against monocyte/macrophage-associated diseases.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center , Ulm , Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center , Ulm , Germany ; Institute of Organic Chemistry III, University of Ulm , Ulm , Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center , Ulm , Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Möglich
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center , Ulm , Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Förtsch
keywords: C3; Rho; cellular uptake; macrophage; targeted drug delivery