TY - JOUR
T1 - Control of Macroautophagy by Calcium, Calmodulin-Dependent Kinase Kinase-β, and Bcl-2
AU - Høyer-Hansen, Maria
AU - Bastholm, Lone
AU - Szyniarowski, Piotr
AU - Campanella, Michelangelo
AU - Szabadkai, György
AU - Farkas, Thomas
AU - Bianchi, Katiuscia
AU - Fehrenbacher, Nicole
AU - Elling, Folmer
AU - Rizzuto, Rosario
AU - Mathiasen, Ida Stenfeldt
AU - Jäättelä, Marja
PY - 2007/1/26
Y1 - 2007/1/26
N2 - Macroautophagy is an evolutionary conserved lysosomal pathway involved in the turnover of cellular macromolecules and organelles. In spite of its essential role in tissue homeostasis, the molecular mechanisms regulating mammalian macroautophagy are poorly understood. Here, we demonstrate that a rise in the free cytosolic calcium ([Ca2+]c) is a potent inducer of macroautophagy. Various Ca2+ mobilizing agents (vitamin D3 compounds, ionomycin, ATP, and thapsigargin) inhibit the activity of mammalian target of rapamycin, a negative regulator of macroautophagy, and induce massive accumulation of autophagosomes in a Beclin 1- and Atg7-dependent manner. This process is mediated by Ca2+/calmodulin-dependent kinase kinase-β and AMP-activated protein kinase and inhibited by ectopic Bcl-2 located in the endoplasmatic reticulum (ER), where it lowers the [Ca2+]ER and attenuates agonist-induced Ca2+ fluxes. Thus, an increase in the [Ca2+]c serves as a potent inducer of macroautophagy and as a target for the antiautophagy action of ER-located Bcl-2.
AB - Macroautophagy is an evolutionary conserved lysosomal pathway involved in the turnover of cellular macromolecules and organelles. In spite of its essential role in tissue homeostasis, the molecular mechanisms regulating mammalian macroautophagy are poorly understood. Here, we demonstrate that a rise in the free cytosolic calcium ([Ca2+]c) is a potent inducer of macroautophagy. Various Ca2+ mobilizing agents (vitamin D3 compounds, ionomycin, ATP, and thapsigargin) inhibit the activity of mammalian target of rapamycin, a negative regulator of macroautophagy, and induce massive accumulation of autophagosomes in a Beclin 1- and Atg7-dependent manner. This process is mediated by Ca2+/calmodulin-dependent kinase kinase-β and AMP-activated protein kinase and inhibited by ectopic Bcl-2 located in the endoplasmatic reticulum (ER), where it lowers the [Ca2+]ER and attenuates agonist-induced Ca2+ fluxes. Thus, an increase in the [Ca2+]c serves as a potent inducer of macroautophagy and as a target for the antiautophagy action of ER-located Bcl-2.
KW - CELLBIO
KW - CELLCYCLE
KW - SIGNALING
UR - http://www.scopus.com/inward/record.url?scp=33846189759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846189759&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2006.12.009
DO - 10.1016/j.molcel.2006.12.009
M3 - Article
C2 - 17244528
AN - SCOPUS:33846189759
VL - 25
SP - 193
EP - 205
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 2
ER -