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MBC in Press, published online ahead of print December 19, 2007
Mol. Biol. Cell 10.1091/mbc.E07-08-0755

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Submitted on August 6, 2007
Revised on December 5, 2007
Accepted on December 12, 2007

Derlin-1 Facilitates the Retro-Translocation of Cholera Toxin

Kaleena M. Bernardi,* Michele L. Forster,* Wayne I. Lencer,{dagger} and Billy Tsai*

*Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109; {dagger}GI Cell Biology, Children’s Hospital, Harvard Medical School, Boston, MA 02115

Monitoring Editor: Jeffrey Brodsky

Cholera toxin (CT) intoxicates cells by using its receptor-binding B subunit (CTB) to traffic from the plasma membrane to the endoplasmic reticulum (ER). In this compartment, the catalytic A1 subunit (CTA1) is unfolded by protein disulfide isomerase (PDI) and retro-translocated to the cytosol where it triggers a signaling cascade leading to secretory diarrhea. How CT is targeted to the site of retro-translocation in the ER membrane to initiate translocation is unclear. Using a semipermeabilized-cell retro-translocation assay, we demonstrate that a dominant-negative Derlin-1-YFP fusion protein attenuates the ER-to-cytosol transport of CTA1. Derlin-1 interacts with CTB and the ER chaperone PDI as assessed by coimmunoprecipitation experiments. An in vitro membrane-binding assay showed that CTB stimulated the unfolded CTA1 chain to bind to the ER membrane. Moreover, intoxication of intact cells with CTB stabilized the degradation of a Derlin-1-dependent substrate, suggesting that CT uses the Derlin-1 pathway. These findings indicate that Derlin-1 facilitates the retro-translocation of CT. CTB may play a role in this process by targeting the holotoxin to Derlin-1, enabling the Derlin-1-bound PDI to unfold the A1 subunit and prepare it for transport.

Address correspondence to: Billy Tsai (btsai{at}umich.edu)




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A. Ashok and R. S. Hegde
Retrotranslocation of Prion Proteins from the Endoplasmic Reticulum by Preventing GPI Signal Transamidation
Mol. Biol. Cell, August 1, 2008; 19(8): 3463 - 3476.
[Abstract] [Full Text] [PDF]


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