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

Abstract

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 pathways1,2. Although the mechanisms of caspase-dependent and -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 Caenorhabditis 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 the AQR sensory neuron—by transcriptionally activating both caspase-dependent and -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 caspase3. In addition, SPTF-3 directly drives the transcription of the AMP-activated protein kinase-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 (refs 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 -independent pathways in the regulation of cell-type-specific apoptosis. We propose that such nodes might act as features of a general mechanism for regulating cell-type-specific apoptosis and could be therapeutic targets for diseases involving the dysregulation of apoptosis through multiple cell-killing mechanisms.

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Figure 1: sptf-3 and pig-1 promote the death of the M4 sister cell.
Figure 2: pig-1 is a direct transcriptional target of SPTF-3 in the regulation of the death of the M4 sister cell.
Figure 3: sptf-3 directly drives egl-1 expression in the M4 sister.
Figure 4: SPTF-3 functions cell autonomously to promote apoptosis of the M4 sister and the AQR sister.

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Acknowledgements

We thank A. Fire, J. Gaudet, C. Barbara and Y. Iino for reporter constructs used to observe cell-type-specific apoptosis; G. Garriga for pig-1 strains; the Caenorhabditis Genetic Center, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440) and the National BioResource project for strains; D. Denning, K. Boulias, A. Corrionero and H. Johnsen for comments about the manuscript; and members of the Horvitz laboratory for technical support and discussions. This work was supported by the Howard Hughes Medical Institute. T.H. was supported in part by the Ministry of Education, Science, Technology, Sports and Culture of Japan. H.R.H. is the David H. Koch Professor of Biology at the Massachusetts Institute of Technology and an Investigator of the Howard Hughes Medical Institute.

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T.H. and H.R.H. designed the experiments, analysed the data and wrote the manuscript. T.H. performed the experiments.

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Correspondence to H. Robert Horvitz.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12 and Supplementary Tables 3-4 (see separate files for Supplementary-Tables 1-2). (PDF 4109 kb)

Supplementary Table 1

A list of SPTF-3-bound regions obtained from ChIP-seq experiments using the anti- SPTF-3 antibody N81. (XLSX 281 kb)

Supplementary Table 2

A list of SPTF-3-bound regions obtained from ChIP-seq experiments using the anti-SPTF-3 antibody M82. (XLSX 210 kb)

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Hirose, T., Horvitz, H. An Sp1 transcription factor coordinates caspase-dependent and -independent apoptotic pathways. Nature 500, 354–358 (2013). https://doi.org/10.1038/nature12329

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