title: Luminal Ca2+ depletion during the unfolded protein response in Xenopus oocytes: cause and consequence.
abstract: The endoplasmic reticulum (ER) is a Ca(2+) 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 Ca(2+) in the initiation of the UPR has not been defined. Specifically, it has not been established whether ER Ca(2+) dysregulation is a cause or consequence of ER stress. Here, we report that partial depletion of ER Ca(2+) 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 Ca(2+) leak into the cytosol. However, blockade of the translocon with emetine inhibited the tunicamycin-induced Ca(2+) release. Furthermore, emetine treatment blocked elF2α phosphorylation and reduced expression of the chaperone BiP. These findings suggest that Ca(2+) may be both a cause and a consequence of ER protein misfolding. Thus, it appears that ER Ca(2+) leak is a significant co-factor for the initiation of the UPR.
authors: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX 78229-3900, USA.
authors: R Madelaine
authors: RM
authors: Paredes
authors: Mariana
authors: M
authors: Bollo
authors: Deborah
authors: D
authors: Holstein
authors: James D
authors: JD
authors: Lechleiter
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D043402:Cathepsin A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058767:Protein Unfolding; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response; D014982:Xenopus laevis
chemical_list: D014415:Tunicamycin; D043402:Cathepsin A; D002118:Calcium