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Experimental Biology and Medicine 233:163-175 (2008)
doi: 10.3181/0705-RM-132
© 2008 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Cholera Toxin Up-Regulates Endoplasmic Reticulum Proteins That Correlate with Sensitivity to the Toxin

Garima Dixit, Carole Mikoryak, Tyler Hayslett, Amritha Bhat and Rockford K. Draper1

The Molecular and Cell Biology Department, FO31, The University of Texas at Dallas, Richardson, Texas 75083-0688

To whom requests for reprints should be addressed at 1 The Molecular and Cell Biology Department, FO31, The University of Texas at Dallas, Box 830688, Richardson, TX 75083–0688. E-mail: draper{at}utdallas.edu

Cholera toxin (CT) contains one A chain and five B chains. The A chain is an enzyme that covalently modifies a trimeric G protein in the cytoplasm, resulting in the overproduction of cAMP. The B chain binds the glycosphingolipid GM1, the cell surface receptor for CT, which initiates receptor-mediated endocytosis of the toxin. After endocytosis, CT enters the endoplasmic reticulum (ER) via retrograde vesicular traffic where the A chain retro-translocates through the ER membrane to reach the cytoplasm. The retro-translocation mechanism is poorly understood, but may involve proteins of the ER stress response, including the ER associated degradation (ERAD) pathway. We report here that treating cells with CT or CTB quickly up-regulates the levels of BiP, Derlin-1, and Derlin-2, known participants in the ER stress response and ERAD. CT did not induce calnexin, another known responder to ER stress, indicating that the CT-mediated induction of ER proteins is selective in this time frame. These data suggest that CT may promote retro-translocation of the A chain to the cytoplasm by rapidly up-regulating a set of ER proteins involved in the retro-translocation process. In support of this idea, a variety of conditions that induced BiP, Derlin-1, and Derlin-2 sensitized cells to CT and conditions that inhibited their induction de-sensitized cells to CT. Moreover, specifically suppressing Derlin-1 with siRNA protected cells from CT. In addition, Derlin-1 co-immunoprecipitated with CTA or CTB from CT-treated cells using anti-CTA or anti-CTB antibodies. Altogether, the results are consistent with the hypothesis that the B chain of CT up-regulates ER proteins that may assist in the retro-translocation of the A chain across the ER membrane.

Key Words: cholera toxin • Derlin-1 • endoplasmic reticulum associated degradation • Shiga toxin • endoplasmic reticulum stress






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