Becker Esther B E, Bonni Azad
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Neuron. 2006 Mar 2;49(5):655-62. doi: 10.1016/j.neuron.2006.01.034.
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. Pin1 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 Pin1 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 Pin1 couples phosphorylation of BH3-only proteins to activation of the mitochondrial apoptotic machinery.
神经元凋亡在大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，但该机制在神经元中如何被特异性激活仍知之甚少。值得注意的是，仅含BH3结构域的蛋白BIMEL在Ser65位点的磷酸化会触发神经元凋亡，但会抑制非神经细胞的细胞死亡。在此，我们报道脯氨酰异构酶Pin1在神经元中与Ser65磷酸化的BIMEL相互作用。Pin1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JIP3形成物理复合物。JNK信号的激活诱导Pin1从JIP3上解离，并同时促进Pin1与磷酸化的BIMEL结合。Pin1与磷酸化的BIMEL相互作用使BIMEL稳定，从而激活神经元凋亡。这些发现定义了一种神经特异性的细胞死亡机制，即Pin1将仅含BH3结构域蛋白的磷酸化与线粒体凋亡机制的激活联系起来。
