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A more recent version of this article appeared on April 1, 2006
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Submitted on October 18, 2005
Revised on January 17, 2006
Accepted on January 19, 2006
*Department of Biochemistry, Institute for Cancer Research, Faculty Division The Norwegian Radium Hospital, University of Oslo, Montebello, N-0310 Oslo, Norway; Department of Molecular Biosciences, University of Oslo, N-0316 Oslo, Norway
Monitoring Editor: Jeffrey Brodsky
The plant toxin ricin is transported retrogradely from the cell surface to the endoplasmatic reticulum (ER) from where the enzymatically active part is retrotranslocated to the cytosol, presumably by the same mechanism as used by misfolded proteins. The ER degradation enhancing 
-mannosidase I like protein, EDEM, is responsible for directing aberrant proteins for ER-associated protein degradation (ERAD). In this study we have investigated whether EDEM is involved in ricin retrotranslocation. Overexpression of EDEM strongly protects against ricin. However, when the interaction between EDEM and misfolded proteins is inhibited by kifunensin, EDEM promotes retrotranslocation of ricin from the ER to the cytosol. Furthermore, puromycin, which inhibits synthesis and thereby transport of proteins into the ER, counteracted the protection seen in EDEM-transfected cells. Coimmunoprecipitation studies reveald that ricin can interact with EDEM and with Sec61, and both kifunensin and puromycin increase these interactions. Importantly, vector-based RNAi against EDEM, which leads to reduction of the cellular level of EDEM, decreased retrotranslocation of ricin A-chain to the cytosol. In conclusion, our results indicate that EDEM is involved in retrotranslocation of ricin from the ER to the cytosol.
These authors contributed equally to this work.
Address correspondence to:
Kirsten Sandvig (sandvig{at}labmed.uio.no)
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