TY - JOUR
T1 - Luminal Ca2+ depletion during the unfolded protein response in Xenopus oocytes
T2 - Cause and consequence
AU - Paredes, R. Madelaine
AU - Bollo, Mariana
AU - Holstein, Deborah
AU - Lechleiter, James D.
N1 - Funding Information:
This work was funded in part by the National Institutes of Health (NIH) grants [ R01 AG029461 ] and [ P01 AG19316 ].
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - Calcium signaling
KW - Endoplasmic reticulum stress (ER stress)
KW - Protein misfolding
KW - Thapsigargin (Tg)
KW - Tunicamycin (Tn)
KW - Unfolded protein response (UPR)
KW - α Subunit of eukaryotic translation initiation factor 2 (eIF2 α)
UR - http://www.scopus.com/inward/record.url?scp=84875251847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875251847&partnerID=8YFLogxK
U2 - 10.1016/j.ceca.2013.01.002
DO - 10.1016/j.ceca.2013.01.002
M3 - Article
C2 - 23415071
AN - SCOPUS:84875251847
VL - 53
SP - 286
EP - 296
JO - Cell Calcium
JF - Cell Calcium
SN - 0143-4160
IS - 4
ER -