ATF2 phosphorylation is essential for neuronal apoptosis, linking the DLK/LZK kinase cascade to JUN upregulation

Apoptotic neuron death is a common feature of many neurodegenerative diseases. Perhaps surprisingly, the exact mechanisms by which neurons undergo apoptosis have yet to be elucidated. We conducted an unbiased whole genome screen in human neurons to discover genes required for apoptotic neuron death, and found ATF2, MAP3K12 and JUN among top hits. We demonstrate that ATF2 is a previously unappreciated master regulator of neuron death. ATF2 is phosphorylated downstream of MAP3K12 (dual leucine zipper kinase) and MAP3K13 (leucine zipper kinase) and its phosphorylation is essential for transcriptional upregulation of JUN. We show that JUN upregulation is essential for apoptosis – but not its phosphorylation. Contrary to previous assumptions, cJun phosphorylation is therefore simply a correlate of JUN upregulation. In this study, we identify phosphorylation of ATF2 as a key event in the mechanism of neuronal apoptosis, linking the MAP3K12/13 kinase cascade to transcriptional upregulation of JUN. Since targeting members of this signaling pathway to block neuronal death has proved difficult, ATF2 offers a novel and promising alternative.