Role of JNK1-dependent Bcl-2 Phosphorylation in Ceramide-induced Macroautophagy
Role of JNK1-dependent Bcl-2 Phosphorylation in Ceramide-induced Macroautophagy
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DOI：
10.1074/jbc.m805920200
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发表时间：
2009-01-30
影响因子：
4.8
通讯作者：
Codogno, Patrice
中科院分区：
文献类型：
--
作者：
Pattingre, Sophie;Bauvy, Chantal;Codogno, Patrice
大自噬是一种空泡溶酶体分解代谢途径，在营养饥饿期间被刺激以保持细胞完整性。神经酰胺是一种生物活性鞘脂，与多种细胞过程相关。在这里，我们表明，短链神经酰胺（C-2-神经酰胺和C-6-神经酰胺）和他莫昔芬从头神经酰胺合成的刺激诱导自噬蛋白Beclin 1和抗凋亡蛋白Bcl-2之间形成的复合物的解离。这种解离是诱导巨自噬所必需的，无论是对神经酰胺还是对饥饿的反应。三个潜在的磷酸化位点，Thr（69），Ser（70）和Ser（87），位于Bcl-2的非结构N-末端环中，在Bcl-2与Beclin 1的解离中起主要作用。我们进一步表明，c-Jun N-末端蛋白激酶1的神经酰胺激活所需的磷酸化Bcl-2和刺激大自噬。这些发现揭示了一个新的方面，鞘脂信号在上调一个主要的细胞过程中参与细胞适应压力。
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.