Document Detail


Selective and specific internalization of clostridial C3 ADP-ribosyltransferases into macrophages and monocytes.
MedLine Citation:
PMID:  19840027     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The C3 transferases from Clostridium botulinum (C3bot) and Clostridium limosum (C3lim) mono-ADP-ribosylate and thereby inactivate RhoA, -B and -C of eukaryotic cells. Due to their extremely poor cellular uptake, C3 transferases were supposed to be exoenzymes rather than exotoxins, challenging their role in pathogenesis. Here, we report for the first time that low concentrations of both C3lim and C3bot are selectively internalized into macrophages/monocytes in less than 3 h, inducing the reorganization of the actin cytoskeleton by ADP-ribosylation of Rho. We demonstrate that C3 transferases are internalized into the cytosol of macrophages/monocytes via acidified early endosomes. Bafilomycin A1, an inhibitor of endosomal acidification, protected J774A.1 macrophages and human promyelotic leukaemia cells (HL-60) from intoxication by C3. Moreover, confocal laser scanning microscopy revealed colocalization of C3 with early endosomes. An extracellular acidic pulse enabled direct translocation of cell surface-bound C3 across the cytoplasmic membrane to the cytosol. In line with this finding, both C3 proteins exhibited membrane activity in lipid bilayer membranes only under acidic conditions (pH < 5.5). In conclusion, we identified macrophages/monocytes as target cells for clostridial C3 transferases and shed light on their selective uptake mechanism, which might contribute to understand the role of C3 transferases in pathogenesis.
Authors:
J?rg Fahrer; Jasmin Kuban; Karin Heine; Gabriel Rupps; Eva Kaiser; Edward Felder; Roland Benz; Holger Barth
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-10-13
Journal Detail:
Title:  Cellular microbiology     Volume:  12     ISSN:  1462-5822     ISO Abbreviation:  Cell. Microbiol.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-01-18     Completed Date:  2010-03-04     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100883691     Medline TA:  Cell Microbiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  233-47     Citation Subset:  IM    
Affiliation:
Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, Ulm, Germany.
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MeSH Terms
Descriptor/Qualifier:
ADP Ribose Transferases / metabolism*
Animals
Cell Line
Chromatography, Gel
Clostridium / enzymology*
Cytoskeleton / metabolism
Electrophoresis, Polyacrylamide Gel
Endocytosis / drug effects,  physiology*
Fluorescent Antibody Technique
HL-60 Cells
Humans
Immunoblotting
Lipid Bilayers / metabolism
Macrolides / pharmacology
Macrophages / metabolism*
Mice
Microscopy, Confocal
Monocytes / metabolism*
Protein Binding
Protein Transport / drug effects,  physiology*
Chemical
Reg. No./Substance:
0/Lipid Bilayers; 0/Macrolides; 88899-55-2/bafilomycin A1; EC 2.4.2.-/ADP Ribose Transferases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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