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Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc
Author(s) -
Yang ChihSheng,
Thomenius Michael J,
Gan Eugene C,
Tang Wanli,
Freel Christopher D,
Merritt Thomas J S,
Nutt Leta K,
Kornbluth Sally
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.191
Subject(s) - biology , phosphorylation , apoptosis , microbiology and biotechnology , drosophila (subgenus) , inhibitory postsynaptic potential , drosophila melanogaster , drosophilidae , genetics , kinase , gene , neuroscience
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.