An Sp1 transcription factor coordinates caspase-dependent and -independent apoptotic pathways

During animal development, the proper regulation of apoptosis requires the precise spatial and temporal execution of cell-death programs, which can include both caspase-dependent and caspase-independent pathways(1, 2). While the mechanisms of caspase-dependent and caspase-independent cell killing have been examined extensively, how these pathways are coordinated within a single cell that is fated to die is unknown. Here we show that the C. elegans Sp1 transcription factor SPTF-3 specifies the programmed cell deaths of at least two cells, the sisters of the pharyngeal M4 motor neuron and of the AQR sensory neuron, by transcriptionally activating both caspase-dependent and caspase-independent apoptotic pathways. SPTF-3 directly drives the transcription of the gene egl-1, which encodes a BH3-only protein that promotes apoptosis through the activation of the CED-3 caspase(3). In addition, SPTF-3 directly drives the transcription of the AMPK-related gene pig-1, which encodes a protein kinase and functions in apoptosis of the M4 sister and AQR sister independently of the pathway that activates CED-3(4, 5). Thus, a single transcription factor controls two distinct cell-killing programs that act in parallel to drive apoptosis. Our findings reveal a bivalent regulatory node for caspase-dependent and caspase-independent pathways in the regulation of cell-type specific apoptosis. We propose that such nodes might act in a general mechanism for regulating cell-type specific apoptosis and could define therapeutic targets for diseases involving the dysregulation of apoptosis through multiple cell-killing mechanisms.