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Dislocation of ricin toxin A chains in human cells utilizes selective cellular factors
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Redmann, V., Oresic, K., Tortorella, L. L., Cook, Jonathan P., Lord, Mike and Tortorella, D. (2011) Dislocation of ricin toxin A chains in human cells utilizes selective cellular factors. Journal of Biological Chemistry, Vol.286 (No.24). pp. 21231-21238. doi:10.1074/jbc.M111.234708 ISSN 0021-9258.
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Official URL: http://dx.doi.org/10.1074/jbc.M111.234708
Abstract
Ricin is a potent A-B toxin that is transported from the cell surface to the cytosol, where it inactivates ribosomes, leading to cell death. Ricin enters cells via endocytosis, where only a minute number of ricin molecules reach the endoplasmic reticulum (ER) lumen. Subsequently, the ricin A chain traverses the ER bilayer by a process referred to as dislocation or retrograde translocation to gain access to the cytosol. To study the molecular processes of ricin A chain dislocation, we have established, for the first time, a human cell system in which enzymatically attenuated ricin toxin A chains (RTA(E177D) and RTA(Delta 177-181)) are expressed in the cell and directed to the ER. Using this human cell-based system, we found that ricin A chains underwent a rapid dislocation event that was quite distinct from the dislocation of a canonical ER soluble misfolded protein, null Hong Kong variant of alpha(1)-antitrypsin. Remarkably, ricin A chain dislocation occurred via a membrane-integrated intermediate and utilized the ER protein SEL1L for transport across the ER bilayer to inhibit protein synthesis. The data support a model in which ricin A chain dislocation occurs via a novel strategy of utilizing the hydrophobic nature of the ER membrane and selective ER components to gain access to the cytosol.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QH Natural history > QH301 Biology | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
| Library of Congress Subject Headings (LCSH): | Endoplasmic reticulum, Saccharomyces cerevisiae, Ricin, Toxins, Golgi apparatus, Cytosol | ||||
| Journal or Publication Title: | Journal of Biological Chemistry | ||||
| Publisher: | American Society for Biochemistry and Molecular Biology | ||||
| ISSN: | 0021-9258 | ||||
| Official Date: | 17 June 2011 | ||||
| Dates: |
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| Volume: | Vol.286 | ||||
| Number: | No.24 | ||||
| Page Range: | pp. 21231-21238 | ||||
| DOI: | 10.1074/jbc.M111.234708 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Funder: | National Institutes of Health (U.S.) (NIH), United States. Defense Threat Reduction Agency (DTRA), Irma T. Hirschl Trust | ||||
| Grant number: | AI060905 (NIH), W81XWH-10-2-0048 (DTRA) |
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