This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, M. Articles by Haslam, D. B. Search for Related Content PubMed PubMed Citation Articles by Yu, M. Articles by Haslam, D. B.

 Previous Article  |  Next Article 

Infection and Immunity, April 2005, p. 2524-2532, Vol. 73, No. 4
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.4.2524-2532.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Shiga Toxin Is Transported from the Endoplasmic Reticulum following Interaction with the Luminal Chaperone HEDJ/ERdj3

Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri

Received 23 July 2004/ Returned for modification 14 September 2004/ Accepted 9 November 2004

Shiga toxin (Stx) follows a complex intracellular pathway in order to kill susceptible cells. After binding to cell surface glycolipids, the toxin is internalized and trafficked in retrograde fashion to the endoplasmic reticulum (ER). From the ER lumen, the toxin must gain access to the cytoplasm, where it enzymatically inactivates the 28S rRNA, inhibiting protein synthesis. The host molecules involved in this pathway and the mechanisms utilized by the toxin to access the cytoplasm from the ER are largely unknown. We found that Stx is capable of energy-dependent transport across the ER lumen, as has recently been demonstrated for the cholera and ricin toxins. Genetic screening for molecules involved in Shiga toxin trafficking yielded a cDNA encoding a prematurely truncated protein. Characterization of this cDNA revealed that it encodes a novel Hsp40 chaperone, designated HEDJ or ERdj3, localized to the ER lumen, where it interacts with BiP, a molecule known to be involved in protein retrotranslocation out of the ER. We demonstrated that within the ER lumen Stx interacts with HEDJ and other chaperones known to be involved in retrotranslocation of proteins across the ER membrane. Moreover, sequential immunoprecipitation revealed that Shiga toxin was present in a complex that included HEDJ and Sec61, the translocon through which proteins are retrotranslocated to the cytoplasm. These findings suggest that HEDJ is a component of the ER quality control system and that Stx utilizes HEDJ and other ER-localized chaperones for transport from the ER lumen to the cytosol.

Editor: A. D. O'Brien

This article has been cited by other articles:

• Saenz, J. B., Doggett, T. A., Haslam, D. B. (2007). Identification and Characterization of Small Molecules That Inhibit Intracellular Toxin Transport. Infect. Immun. 75: 4552-4561 [Abstract] [Full Text]  
• Tam, P. J., Lingwood, C. A. (2007). Membrane cytosolic translocation of verotoxin A1 subunit in target cells. Microbiology 153: 2700-2710 [Abstract] [Full Text]  
• Wen, S. X., Teel, L. D., Judge, N. A., O'Brien, A. D. (2006). A plant-based oral vaccine to protect against systemic intoxication by Shiga toxin type 2. Proc. Natl. Acad. Sci. USA 103: 7082-7087 [Abstract] [Full Text]  
• Smith, D. C., Sillence, D. J., Falguieres, T., Jarvis, R. M., Johannes, L., Lord, J. M., Platt, F. M., Roberts, L. M. (2006). The Association of Shiga-like Toxin with Detergent-resistant Membranes Is Modulated by Glucosylceramide and Is an Essential Requirement in the Endoplasmic Reticulum for a Cytotoxic Effect. Mol. Biol. Cell 17: 1375-1387 [Abstract] [Full Text]  
• Zhao, L., Haslam, D. B (2005). A quantitative and highly sensitive luciferase-based assay for bacterial toxins that inhibit protein synthesis. J Med Microbiol 54: 1023-1030 [Abstract] [Full Text]