Characterization of the c-Jun N-Terminal Kinase-BimELSignaling Pathway in Neuronal Apoptosis

The c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in mediating apoptosis in the nervous system; however, the mechanisms by which JNK triggers neuronal apoptosis remain incompletely understood. Recent studies suggest that in addition to inducing transcription of pro-apoptotic genes, JNK also directly activates the cell death machinery. Here, we report that JNK catalyzed the phosphorylation of the BH3-only protein Bcl-2 interacting mediator of cell death (BimEL) at serine 65, bothin vitroandin vivo. The JNK-induced phosphorylation of BimELat serine 65 promoted the apoptotic effect of BimELin primary cerebellar granule neurons. We also characterized the role of the JNK-BimELsignaling pathway in apoptosis that was triggered by overexpression of the p75 neurotrophin receptor (p75NTR). We found that activation of p75NTRinduced the JNK-dependent phosphorylation of endogenous BimELat serine 65 in cells. The genetic knockdown of BimELby RNA interference or the expression of a dominant interfering form of BimELsignificantly impaired the ability of activated p75NTRto induce apoptosis. Together, these results suggest that JNK-induced phosphorylation of BimELat serine 65 mediates p75NTR-induced apoptosis. Our findings define a novel mechanism by which a death-receptor pathway directly activates the mitochondrial apoptotic machinery.