Pin1 mediates neural-specific activation of the mitochondrial apoptotic machinery
Pin1 mediates neural-specific activation of the mitochondrial apoptotic machinery
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DOI：
10.1016/j.neuron.2006.01.034
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发表时间：
2006-03-02
期刊：
影响因子：
16.2
通讯作者：
Bonni, A
中科院分区：
文献类型：
--
作者：
Becker, EBE;Bonni, A
神经元凋亡在脑发育和疾病中起着重要作用。尽管神经元与其他细胞类型共享线粒体凋亡机制的组成部分，但这种机制如何在神经元中特异性激活仍然知之甚少。值得注意的是，BH 3-only蛋白质BIMEL在Ser 65处的磷酸化引发神经元中的凋亡，但抑制非神经细胞中的细胞死亡。在这里，我们报告脯氨酰异构酶Pin 1与Ser 65-磷酸化的BIMEL在神经元中相互作用。Pinl在神经元的线粒体膜上富集，在那里它与神经元特异性JNK支架蛋白JIP 3形成物理复合物。JNK信号传导的激活诱导Pin 1从JIP 3解离，并伴随促进Pin 1与磷酸化的BIMEL结合。Pin 1与磷酸化的BIMEL的相互作用稳定BIMEL，从而激活神经元凋亡。这些发现定义了细胞死亡的神经特异性机制，其中Pinl将仅BH 3蛋白的磷酸化与线粒体凋亡机制的激活偶联。
Apoptosis of neurons plays fundamental roles in brain development and disease. Although neurons share with other cell types components of the mitochondrial apoptotic machinery, how this machinery is specifically activated in neurons remains poorly understood. Remarkably, phosphorylation of the BH3-only protein BIMEL at Ser65 triggers apoptosis in neurons but suppresses cell death in non-neural cells. Here, we report that the prolyl isomerase Pin1 interacts with Ser65-phosphorylated BIMEL in neurons. Pinl is enriched at the mitochondrial membrane in neurons, where it forms a physical complex with the neuron-specific JNK scaffold protein JIP3. Activation of JNK signaling induces the dissociation of Pin1 from JIP3 and concomitantly promotes Pinl binding to phosphorylated BIMEL. The interaction of Pin1 with phosphorylated BIMEL stabilizes BIMEL and thereby activates neuronal apoptosis. These findings define a neural-specific mechanism of cell death whereby Pinl couples phosphorylation of BH3-only proteins to activation of the mitochondrial apoptotic machinery.