ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis

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 the kinase MAP3K12 and transcription factors JUN and ATF2 among top hits. JUN is a known downstream target of the injury signaling cascade controlled by the MAP3K12 kinase (dual leucine zipper kinase or DLK), presumably via phosphorylation. Here, we show that JUN upregulation, but not its phosphorylation, is necessary for apoptosis, raising the question of how its upregulation is controlled. We demonstrate that phosphorylation of ATF2 by the kinases MAP3K12 and MAP3K13 is in fact the essential step for transcriptional upregulation of JUN. We identify phospho-ATF2 as the core driver of the pro-apoptotic transcriptional response in neurons and the factor responsible for converting the DLK/LZK kinase signaling cascade into a pro-degenerative transcriptional response. We validate this role of ATF2 in cultured human neurons and in injury models in vivo. Since targeting members of this signaling pathway to block neuronal death has proved difficult, ATF2 offers a promising alternative.