NDLI: Trojan horse or proton force: Finding the right partner(s) for toxin translocation

Content Provider	Springer Nature Link
Author	Trujillo, Carolina Ratts, Ryan Tamayo, Alfred Harrison, Robert Murphy, John R.
Copyright Year	2006
Abstract	Much is known about the structure function relationships of a large number of bacterial protein toxins, the nature of their cell surface receptors, and their enzymatic activities which lead to the inactivation of their respective cytosolic targets. Despite this wealth of knowledge a detailed understanding of the mechanisms which underlie translocation of the catalytic domain across the eukaryotic cell membrane to the cytosol, the penultimate event in the intoxication process, have been slow in developing. In the case of diphtheria toxin, two prominent hypotheses have been advanced to explain how the catalytic domain is translocated from the lumen of endocytic vesicles to the target cell cytosol. We discuss each of these hypotheses and provide an overview of recent observations that tend to favor a mechanism employing a Cytosolic Translocation Factor complex in the entry process. This facilitated mechanism of translocation appears to rely upon protein-protein interactions between conserved domains within the transmembrane domain of diphtheria toxin and host cell factors to effect delivery of the enzymatic moiety. We have recently identified a 10 amino acid motif in the transmembrane domain of diphtheria toxin that is conserved in anthrax Lethal and Edema Factors, as well as in botulinum neurotoxins A, C and D. Stable eukaryotic cell transfectants that express a peptide containing this motif become resistant to the toxin, and sensitivity is completely restored by co-expression of siRNA which inhibits peptide expression. Data obtained from use of the protein fusion toxin DAB$_{389}$IL-2 in cytotoxicity assays using susceptible Hut 102/6TG and resistant transfectant Hut102/6TG-T1 cells, as well as pull down assays have led to the formulation of a working model of facilitated delivery of the diphtheria toxin catalytic domain to the cytosol of target cells which is discussed in detail.
Starting Page	63
Ending Page	71
Page Count	9
File Format	PDF
ISSN	10298428
Journal	Neurotoxicity Research
Volume Number	9
Issue Number	2-3
e-ISSN	14763524
Language	English
Publisher	Springer New York
Publisher Date	2009-03-07
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Bacterial protein toxins Botulinum neurotoxin Diphtheria toxin Anthrax DAB$_{389}$IL-2 Vesicles Cytosolic translocation factor complex Neurosciences Neurology Neurochemistry Pharmacology/Toxicology Neurobiology Cell Biology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Toxicology

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