Abstract SY31-03: Global signaling mechanisms that regulate autophagy

Abstract

Abstract Apoptosis is an evolutionally conserved cellular suicide mechanism that can be activated in response to a variety of stressful stimuli. Increasing evidence suggests that apoptotic regulation relies on specialized cell death signaling pathways and also integrates diverse signals from additional regulatory circuits, including those of cellular metabolism. Cell metabolism is exquisitely linked to multiple aspects of cell physiology relevant for cancer development, including cell proliferation, growth, and death. However, the mechanism by which cellular metabolism controls apoptotic sensitivity is unknown. We conducted a genome-wide RNA interference screen to systematically identify regulators of apoptosis induced by DNA damage in Drosophila melanogaster cells. This screen identified 47 double- stranded RNAs that target a functionally diverse set of genes, including several with a known function in promoting cell death. Further characterization uncovers 10 genes that influence caspase activation upon the removal of Drosophila inhibitor of apoptosis 1 (DIAP1). This set includes the Drosophila initiator caspase Dronc and, surprisingly, several metabolic regulators, and an N-acetyltransferase, ARD1. Importantly, several of these genes show functional conservation in regulating apoptosis in mammalian cells. Our data suggest a previously unappreciated fundamental connection between various cellular processes and caspase-dependent cell death. We have further explored the functional role and the mechanism by which ARD1 regulates apoptotic sensitivity in mammalian cells. We found that a reduction of N-alpha-acetylation mediated by ARD1 leads to inhibit apoptosis by blocking the interaction of a caspase with its activating complex. We further demonstrate the levels of protein N-alpha-acetylation is controlled by the availability of acetyl-CoA, a key intermediate metabolite. Our study provides a mechanistic link between cellular metabolism and apoptotic sensitivity and suggests that targeting the mechanism of protein N-alpha-acetylation may provide a new therapeutic approach for anti-cancer drug development. Citation Format: Caroline Yi, Junying Yuan. Global signaling mechanisms that regulate autophagy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY31-03