Luminal Ca2+ depletion during the unfolded protein response in Xenopus oocytes: Cause and consequence

R. Madelaine Paredes, Mariana Bollo, Deborah Holstein, James D. Lechleiter

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The endoplasmic reticulum (ER) is a Ca2+ storing organelle that plays a critical role in the synthesis, folding and post-translational modifications of many proteins. The ER enters into a condition of stress when the load of newly synthesized proteins exceeds its folding and processing capacity. This activates a signal transduction pathway called the unfolded protein response (UPR) that attempts to restore homeostasis. The precise role of ER Ca2+ in the initiation of the UPR has not been defined. Specifically, it has not been established whether ER Ca2+ dysregulation is a cause or consequence of ER stress. Here, we report that partial depletion of ER Ca2+ stores induces a significant induction of the UPR, and leads to the retention of a normally secreted protein Carboxypeptidase Y. Moreover, inhibition of protein glycosylation by tunicamycin rapidly induced an ER Ca2+ leak into the cytosol. However, blockade of the translocon with emetine inhibited the tunicamycin-induced Ca2+ release. Furthermore, emetine treatment blocked elF2α phosphorylation and reduced expression of the chaperone BiP. These findings suggest that Ca2+ may be both a cause and a consequence of ER protein misfolding. Thus, it appears that ER Ca2+ leak is a significant co-factor for the initiation of the UPR.

Original languageEnglish (US)
Pages (from-to)286-296
Number of pages11
JournalCell Calcium
Volume53
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • Calcium signaling
  • Endoplasmic reticulum stress (ER stress)
  • Protein misfolding
  • Thapsigargin (Tg)
  • Tunicamycin (Tn)
  • Unfolded protein response (UPR)
  • α Subunit of eukaryotic translation initiation factor 2 (eIF2 α)

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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