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Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc.

Publication ,  Journal Article
Yang, C-S; Thomenius, MJ; Gan, EC; Tang, W; Freel, CD; Merritt, TJS; Nutt, LK; Kornbluth, S
Published in: The EMBO journal
September 2010

Apoptosis ensures tissue homeostasis in response to developmental cues or cellular damage. Recently reported genome-wide RNAi screens have suggested that several metabolic regulators can modulate caspase activation in Drosophila. Here, we establish a previously unrecognized link between metabolism and Drosophila apoptosis by showing that cellular NADPH levels modulate the initiator caspase Dronc through its phosphorylation at S130. Depletion of NADPH removed this inhibitory phosphorylation, resulting in the activation of Dronc and subsequent cell death. Conversely, upregulation of NADPH prevented Dronc-mediated apoptosis upon DIAP1 RNAi or cycloheximide treatment. Furthermore, this CaMKII-mediated phosphorylation of Dronc hindered Dronc activation, but not its catalytic activity. Blockade of NADPH production aggravated the death-inducing activity of Dronc in specific neurons, but not in the photoreceptor cells of the eyes of transgenic flies; similarly, non-phosphorylatable Dronc was more potent than wild type in triggering specific neuronal apoptosis. Our observations reveal a novel regulatory circuitry in Drosophila apoptosis, and, as NADPH levels are elevated in cancer cells, also provide a genetic model to understand aberrations in cancer cell apoptosis resulting from metabolic alterations.

Duke Scholars

Published In

The EMBO journal

DOI

EISSN

1460-2075

ISSN

0261-4189

Publication Date

September 2010

Volume

29

Issue

18

Start / End Page

3196 / 3207

Related Subject Headings

  • RNA, Small Interfering
  • Neurons
  • NADP
  • Malates
  • Inhibitor of Apoptosis Proteins
  • Immunoprecipitation
  • Enzyme Activation
  • Drosophila melanogaster
  • Drosophila Proteins
  • Developmental Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Yang, C.-S., Thomenius, M. J., Gan, E. C., Tang, W., Freel, C. D., Merritt, T. J. S., … Kornbluth, S. (2010). Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc. The EMBO Journal, 29(18), 3196–3207. https://doi.org/10.1038/emboj.2010.191
Yang, Chih-Sheng, Michael J. Thomenius, Eugene C. Gan, Wanli Tang, Christopher D. Freel, Thomas J. S. Merritt, Leta K. Nutt, and Sally Kornbluth. “Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc.The EMBO Journal 29, no. 18 (September 2010): 3196–3207. https://doi.org/10.1038/emboj.2010.191.
Yang C-S, Thomenius MJ, Gan EC, Tang W, Freel CD, Merritt TJS, et al. Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc. The EMBO journal. 2010 Sep;29(18):3196–207.
Yang, Chih-Sheng, et al. “Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc.The EMBO Journal, vol. 29, no. 18, Sept. 2010, pp. 3196–207. Epmc, doi:10.1038/emboj.2010.191.
Yang C-S, Thomenius MJ, Gan EC, Tang W, Freel CD, Merritt TJS, Nutt LK, Kornbluth S. Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc. The EMBO journal. 2010 Sep;29(18):3196–3207.

Published In

The EMBO journal

DOI

EISSN

1460-2075

ISSN

0261-4189

Publication Date

September 2010

Volume

29

Issue

18

Start / End Page

3196 / 3207

Related Subject Headings

  • RNA, Small Interfering
  • Neurons
  • NADP
  • Malates
  • Inhibitor of Apoptosis Proteins
  • Immunoprecipitation
  • Enzyme Activation
  • Drosophila melanogaster
  • Drosophila Proteins
  • Developmental Biology