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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

Posted by on in 2005
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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‡¶¶J. Biol Chem. 2005 March 11; 280(10): 9467–9473.

‡ 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
§§ Department of Dermatology, Juntendo University School of Medicine, Tokyo 113-8421, Japan

¶¶ 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:


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.

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