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The entry of diphtheria toxin into the mammalian cell cytoplasm: evidence for lysosomal involvement.
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MedLine Citation:
PMID:  7462326     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Lysosomotropic amines, such as ammonium chloride, are known to protect cells from the cytotoxic effects of diphtheria toxin. These drugs are believed to inhibit the transport of the toxin from a receptor at the cell exterior into the cytoplasm where a fragment of the toxin arrests protein synthesis. We studied the effects of lysosomotropic agents on the cytotoxic process to better understand how the toxin enters the cytoplasm. The cytotoxic effects of diphtheria toxin were not inhibited by antitoxin when cells were preincubated at 37 degrees C with toxin and ammonium chloride, exposed to antitoxin at 4 degrees C, washed to relieve the ammonium chloride inhibition, and finally warmed to 37 degrees C. The antigenic determinants of the toxin were, therefore, either altered or sheltered. It is likely that the combination of ammonium chloride and a low temperature trapped the toxin in an intracellular vesicle from which the toxin could proceed to the cytoplasm. Because lysosomotropic amines raise the pH within acidic intracellular vesicles, such as lysosomes, they could trap the toxin within such a vesicle if an acidic environment were necessary for the toxin to penetrate into the cytoplasm. We simulated acidic conditions which the toxin might encounter by exposing cells with toxin bound to their surface to acidic medium. We then measured the effects of lysosomotropic amines on the activity of the toxin to see if the acidic environment substituted for the function normally inhibited by the drugs. The drugs no longer protected the cells. This suggests that exposing the toxin to an acidic environment, such as that found within lysosomes, is an important step in the penetration of diphtheria toxin into the cytoplasm.
Authors:
R K Draper; M I Simon
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of cell biology     Volume:  87     ISSN:  0021-9525     ISO Abbreviation:  J. Cell Biol.     Publication Date:  1980 Dec 
Date Detail:
Created Date:  1981-04-24     Completed Date:  1981-04-24     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0375356     Medline TA:  J Cell Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  849-54     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Ammonium Chloride / pharmacology
Animals
Cell Line
Cell Membrane / metabolism
Cercopithecus aethiops
Cricetinae
Cytoplasm / metabolism*
Diphtheria Toxin / metabolism*
Hydrogen-Ion Concentration
Lysosomes / metabolism*
Protein Biosynthesis
Chemical
Reg. No./Substance:
0/Diphtheria Toxin; 12125-02-9/Ammonium Chloride
Comments/Corrections

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

Full Text
Journal Information
Journal ID (nlm-ta): J Cell Biol
ISSN: 0021-9525
ISSN: 1540-8140
Publisher: The Rockefeller University Press
Article Information
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Print publication date: Day: 1 Month: 12 Year: 1980
Volume: 87 Issue: 3
First Page: 849 Last Page: 854
ID: 2110783
Publisher Id: 81117502
PubMed Id: 7462326

The entry of diphtheria toxin into the mammalian cell cytoplasm: evidence for lysosomal involvement


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