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J. Biol. Chem., Vol. 280, Issue 16, 15865-15871, April 22, 2005

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p97 Is in a Complex with Cholera Toxin and Influences the Transport of Cholera Toxin and Related Toxins to the Cytoplasm^*

Ramzey J. AbuJarour, Seema Dalal¶, Phyllis I. Hanson¶, and Rockford K. Draper||

From the Molecular and Cell Biology Department, The University of Texas at Dallas, Richardson, Texas 75083-0688 and the ^¶Washington University School of Medicine, Department of Cell Biology and Physiology, St. Louis, Missouri 63110

Certain protein toxins, including cholera toxin, ricin, and Pseudomonas aeruginosa exotoxin A, are transported to the lumen of the endoplasmic reticulum where they retro-translocate across the endoplasmic reticulum membrane to enter the cytoplasm. The mechanism of retrotranslocation is poorly understood but may involve the endoplasmic reticulum-associated degradation pathway. The AAA ATPase p97 (also called valosin-containing protein) participates in the retro-translocation of cellular endoplasmic reticulum-associated degradation substrates and is therefore a candidate to participate in the retrotranslocation of protein toxins. To investigate whether p97 functions in toxin delivery to the cytoplasm, we measured the sensitivity to toxins of cells expressing either wild-type p97 or a dominant ATPase-defective p97 mutant under control of a tetracycline-inducible promoter. The rate at which cholera toxin and related toxins entered the cytoplasm was reduced in cells expressing the ATPase-defective p97, suggesting that the toxins might interact with p97. To detect interaction, the cholera toxin A chain was immunoprecipitated from cholera toxin-treated Vero cells, and co-immunoprecipitation of p97 was assessed by immunoblotting. The immunoprecipitates contained both cholera toxin A chain and p97, evidence that the two proteins are in a complex. Altogether, these results provide functional and structural evidence that p97 participates in the transport of cholera toxin to the cytoplasm.

Received for publication, June 7, 2004 , and in revised form, January 10, 2005.

^* This work was supported in part by Grant 0150713Y from the American Heart Association, Texas Affiliate. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work was completed in partial fulfillment of the requirement for a Ph.D. degree.

^|| To whom correspondence should be addressed: Molecular and Cell Biology Dept., FO31, University of Texas at Dallas, Box 830688, Richardson, TX 75083-0688. Tel.: 972-883-2512; Fax: 972-883-2409; E-mail: draper{at}utdallas.edu.

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