Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy.
Macroautophagy is a vacuolar lysosomal catabolic pathway that is stimulated during periods of nutrient starvation to preserve cell integrity. Ceramide is a bioactive sphingolipid associated with a large range of cell processes. Here we show that short-chain ceramides (C(2)-ceramide and C(6)-ceramide) and stimulation of the de novo ceramide synthesis by tamoxifen induce the dissociation of the complex formed between the autophagy protein Beclin 1 and the anti-apoptotic protein Bcl-2. This dissociation is required for macroautophagy to be induced either in response to ceramide or to starvation. Three potential phosphorylation sites, Thr(69), Ser(70), and Ser(87), located in the non-structural N-terminal loop of Bcl-2, play major roles in the dissociation of Bcl-2 from Beclin 1. We further show that activation of c-Jun N-terminal protein kinase 1 by ceramide is required both to phosphorylate Bcl-2 and to stimulate macroautophagy. These findings reveal a new aspect of sphingolipid signaling in up-regulating a major cell process involved in cell adaptation to stress.
Pattingre
Sophie
S
INSERM U756, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France; Université Paris Sud 11, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
Bauvy
Chantal
C
INSERM U756, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France; Université Paris Sud 11, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France.
Carpentier
Stéphane
S
INSERM U858, Université Toulouse III, 31000 Toulouse, France; Institut de Médecine Moléculaire de Rangueil, Université Toulouse III, 31000 Toulouse, France.
Levade
Thierry
T
INSERM U858, Université Toulouse III, 31000 Toulouse, France; Institut de Médecine Moléculaire de Rangueil, Université Toulouse III, 31000 Toulouse, France.
Levine
Beth
B
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Codogno
Patrice
P
INSERM U756, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France; Université Paris Sud 11, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France. Electronic address: patrice.codogno@u-psud.fr.
D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
D002518:Ceramides; D019253:Proto-Oncogene Proteins c-bcl-2; D048055:Mitogen-Activated Protein Kinase 8