title: Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress.
abstract: 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.
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor Michigan 48109, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Ramos-Castañeda
authors.forename: Young-nam
authors.initials: YN
authors.lastname: Park
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Karin
authors.initials: K
authors.lastname: Hauser
authors.forename: Hans
authors.initials: H
authors.lastname: Rudolph
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
mesh_terms: D000818:Animals; D000252:Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D003062:Codon / Q000235:genetics; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000502:physiology; D017353:Gene Deletion; D006056:Golgi Apparatus / Q000235:genetics / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D018384:Oxidative Stress; D016506:Pemphigus, Benign Familial / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D003062:Codon; D017931:DNA Primers; D011994:Recombinant Proteins; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases