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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 (J. 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. 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 > 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:

Date	Event
17 June 2011	Published

Volume:

Vol.286

Number:

No.24

Page Range:

pp. 21231-21238

Identifier:

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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