Effects of dynamin inactivation on pathways of anthrax toxin uptake.
Internalization and traffic to acidic endosomes of anthrax lethal factor (LF) and protective antigen (PA), bound to the anthrax toxin receptor (ATR), is required for LF translocation into the cytosol, where it can elicit its toxic effects. Dynamin is required for clathrin-mediated endocytosis, and long-term disruption of dynamin function blocks internalization of PA. We have used LFn-DTA, a surrogate of LF consisting of the N-terminal domain of LF fused to the catalytic subunit of diphtheria toxin, to differentiate the effects of acute and long-term block of dynamin function on LFn-DTA toxicity. Both forms of interference reduce LFn-DTA toxicity only partially, consistent with alternative routes for LFn-DTA endocytosis. In contrast, a long-term block of dynamin activity results in a further interference with LFn-DTA toxicity that is consistent with an altered endosomal environment, probably an increase in endosomal pH.
Boll
Werner
W
Department of Cell Biology, The CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
Ehrlich
Marcelo
M
Collier
R John
RJ
Kirchhausen
Tomas
T
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D016466:CHO Cells; D002966:Clathrin / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000378:metabolism; D004167:Diphtheria Toxin / Q000633:toxicity; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018000:Receptors, Peptide / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002966:Clathrin; D004167:Diphtheria Toxin; D018000:Receptors, Peptide; D011993:Recombinant Fusion Proteins; C030325:anthrax toxin; C070309:anthrax toxin receptors; D034281:Dynamins