Pin1 mediates neural-specific activation of the mitochondrial apoptotic machinery.

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.