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Open AccessArticle

Clostridial C3 Toxins Enter and Intoxicate Human Dendritic Cells

1
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, 89081 Ulm, Germany
2
Institute of Biophysics, Ulm University, 89081 Ulm, Germany
3
Institute for Medical Microbiology and Hygiene, University of Ulm Medical Center, 89081 Ulm, Germany
4
Institute of Pathology, University of Ulm Medical Center, 89081 Ulm, Germany
*
Authors to whom correspondence should be addressed.
Toxins 2020, 12(9), 563; https://doi.org/10.3390/toxins12090563
Received: 30 July 2020 / Revised: 27 August 2020 / Accepted: 28 August 2020 / Published: 1 September 2020
C3 protein toxins produced by Clostridium (C.) botulinum and C. limosum are mono-ADP-ribosyltransferases, which specifically modify the GTPases Rho A/B/C in the cytosol of monocytic cells, thereby inhibiting Rho-mediated signal transduction in monocytes, macrophages, and osteoclasts. C3 toxins are selectively taken up into the cytosol of monocytic cells by endocytosis and translocate from acidic endosomes into the cytosol. The C3-catalyzed ADP-ribosylation of Rho proteins inhibits essential functions of these immune cells, such as migration and phagocytosis. Here, we demonstrate that C3 toxins enter and intoxicate dendritic cells in a time- and concentration-dependent manner. Both immature and mature human dendritic cells efficiently internalize C3 exoenzymes. These findings could also be extended to the chimeric fusion toxin C2IN-C3lim. Moreover, stimulated emission depletion (STED) microscopy revealed the localization of the internalized C3 protein in endosomes and emphasized its potential use as a carrier to deliver foreign proteins into dendritic cells. In contrast, the enzyme C2I from the binary C. botulinum C2 toxin was not taken up into dendritic cells, indicating the specific uptake of C3 toxins. Taken together, we identified human dendritic cells as novel target cells for clostridial C3 toxins and demonstrated the specific uptake of these toxins via endosomal vesicles. View Full-Text
Keywords: dendritic cells; clostridial C3 toxins; cellular uptake; C3botE174Q; fusion toxin C2IN-C3lim; stimulated emission depletion (STED); super-resolution microscopy dendritic cells; clostridial C3 toxins; cellular uptake; C3botE174Q; fusion toxin C2IN-C3lim; stimulated emission depletion (STED); super-resolution microscopy
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Fellermann, M.; Huchler, C.; Fechter, L.; Kolb, T.; Wondany, F.; Mayer, D.; Michaelis, J.; Stenger, S.; Mellert, K.; Möller, P.; Barth, T.F.E.; Fischer, S.; Barth, H. Clostridial C3 Toxins Enter and Intoxicate Human Dendritic Cells. Toxins 2020, 12, 563.

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