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

• DOI: 10.1074/jbc.m413243200
• Publication Date: 2004-12-29T05:13:19Z
• Authors: Jose Ramos-Castañeda; Young-nam Park; Ming Liu; Karin Hauser; Hans Rudolph; Gary E. Shull; Marcel F. Jonkman; Kazutoshi Mori; Shigaku Ikeda; Hideoki Ogawa; Peter Arvan
• Keywords: Keratinocytes; Pemphigus, Benign Familial; Golgi Apparatus; Calcium-Transporting ATPases; Saccharomyces cerevisiae; Endoplasmic Reticulum; Cell Line; SACCHAROMYCES-CEREVISIAE; 03 medical and health sciences; HAILEY-HAILEY-DISEASE; PMR1; QUALITY-CONTROL; Cell Line, Tumor; Animals; Humans; YEAST; Codon; DNA Primers; 0303 health sciences; MUTATIONS; Reverse Transcriptase Polymerase Chain Reaction; Recombinant Proteins; UNFOLDED-PROTEIN RESPONSE; Oxidative Stress; CELLS; CALCIUM-PUMP; CA2+ HOMEOSTASIS; Gene Deletion

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.