Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress.
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.
Ramos-Castañeda
Jose
J
Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor Michigan 48109, USA.
Park
Young-nam
YN
Liu
Ming
M
Hauser
Karin
K
Rudolph
Hans
H
Shull
Gary E
GE
Jonkman
Marcel F
MF
Mori
Kazutoshi
K
Ikeda
Shigaku
S
Ogawa
Hideoki
H
Arvan
Peter
P
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
D003062:Codon; D017931:DNA Primers; D011994:Recombinant Proteins; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases