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 ([Ca(2+)](c)) is a potent inducer of macroautophagy. Various Ca(2+) mobilizing agents (vitamin D(3) 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 Ca(2+)/calmodulin-dependent kinase kinase-beta and AMP-activated protein kinase and inhibited by ectopic Bcl-2 located in the endoplasmatic reticulum (ER), where it lowers the [Ca(2+)](ER) and attenuates agonist-induced Ca(2+) fluxes. Thus, an increase in the [Ca(2+)](c) serves as a potent inducer of macroautophagy and as a target for the antiautophagy action of ER-located Bcl-2.

Høyer-Hansen, M., Bastholm, L., Szyniarowski, P., Campanella, M., Szabadkai, G., Farkas, T., et al. (2007). Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. MOLECULAR CELL, 25(2), 193-205 [10.1016/j.molcel.2006.12.009].

Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2

Campanella, Michelangelo
;
2007-01-26

Abstract

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 ([Ca(2+)](c)) is a potent inducer of macroautophagy. Various Ca(2+) mobilizing agents (vitamin D(3) 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 Ca(2+)/calmodulin-dependent kinase kinase-beta and AMP-activated protein kinase and inhibited by ectopic Bcl-2 located in the endoplasmatic reticulum (ER), where it lowers the [Ca(2+)](ER) and attenuates agonist-induced Ca(2+) fluxes. Thus, an increase in the [Ca(2+)](c) serves as a potent inducer of macroautophagy and as a target for the antiautophagy action of ER-located Bcl-2.
26-gen-2007
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/06 - ANATOMIA COMPARATA E CITOLOGIA
English
Con Impact Factor ISI
AMP-Activated Protein Kinases
Adenosine Triphosphate
Autophagy
Autophagy-Related Protein 7
Base Sequence
Calcitriol
Calcium
Calcium Signaling
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Cell Line
Endoplasmic Reticulum
HeLa Cells
Humans
Ionomycin
Microscopy, Electron
Models, Biological
Multienzyme Complexes
Protein Kinases
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins c-bcl-2
RNA, Small Interfering
Signal Transduction
TOR Serine-Threonine Kinases
Ubiquitin-Activating Enzymes
Høyer-Hansen, M., Bastholm, L., Szyniarowski, P., Campanella, M., Szabadkai, G., Farkas, T., et al. (2007). Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. MOLECULAR CELL, 25(2), 193-205 [10.1016/j.molcel.2006.12.009].
Høyer-Hansen, M; Bastholm, L; Szyniarowski, P; Campanella, M; Szabadkai, G; Farkas, T; Bianchi, K; Fehrenbacher, N; Elling, F; Rizzuto, R; Mathiasen, Is; Jäättelä, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/265753
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