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J. Biol. Chem., Vol. 280, Issue 10, 9467-9473, March 11, 2005

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Deficiency of ATP2C1, a Golgi Ion Pump, Induces Secretory Pathway Defects in Endoplasmic Reticulum (ER)-associated Degradation and Sensitivity to ER Stress^*

Jose Ramos-Castañeda, Young-nam Park, Ming Liu, Karin Hauser¶, Hans Rudolph¶, Gary E. Shull||, Marcel F. Jonkman**, Kazutoshi Mori, Shigaku Ikeda, Hideoki Ogawa, and Peter Arvan¶¶

From the Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor Michigan 48109, Centro de Investigaciones sobre Enfermedades Infecciosas, Cuernavaca Morelos 62508, Mexico, ^¶Institute of Biochemistry, University of Stuttgart, Stuttgart, D-70569, Germany, ^||Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, ^**Department of Dermatology, Groningen University Hospital, 9700 RB Groningen, The Netherlands, Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, 606-8304, Japan and Department of Dermatology, Juntendo University School of Medicine, Tokyo 113-8421, Japan

Relatively few clues have been uncovered to elucidate the cell biological role(s) of mammalian ATP2C1 encoding an inwardly directed secretory pathway Ca²⁺/Mn²⁺ pump that is ubiquitously expressed. Deficiency of ATP2C1 results in a human disease (Hailey-Hailey), which primarily affects keratinocytes. ATP2C1-encoded protein is detected in the Golgi complex in a calcium-dependent manner. A small interfering RNA causes knockdown of ATP2C1 expression, resulting in defects in both post-translational processing of wild-type thyroglobulin (a secretory glycoprotein) as well as endoplasmic reticulum-associated protein degradation of mutant thyroglobulin, whereas degradation of a nonglycosylated misfolded secretory protein substrate appears unaffected. Knockdown of ATP2C1 is not associated with elevated steady state levels of ER chaperone proteins, nor does it block cellular activation of either the PERK, ATF6, or Ire1/XBP1 portions of the ER stress response. However, deficiency of ATP2C1 renders cells hypersensitive to ER stress. These data point to the important contributions of the Golgi-localized ATP2C1 protein in homeostatic maintenance throughout the secretory pathway.

Received for publication, November 23, 2004 , and in revised form, December 20, 2004.

^* This work was supported in part by National Institutes of Health Grants DK40344 and DK48280 (to P. A.) and a research grant from the AlphaOne Foundation (to P. A.), as well as a mentor-based postdoctoral award from the American Diabetes Association (to P. A.). 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.

^¶¶ To whom correspondence should be addressed: Division of Metabolism, Endocrinology, and Diabetes, 5560 MSRB2, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Tel.: 734-936-5505; Fax: 718-936-6684; E-mail: parvan{at}umich.edu.

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