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Mar. Drugs 2018, 16(3), 77; https://doi.org/10.3390/md16030077

ATG5 Promotes Death Signaling in Response to the Cyclic Depsipeptides Coibamide A and Apratoxin A

1
Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
2
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
*
Author to whom correspondence should be addressed.
Received: 14 December 2017 / Revised: 17 February 2018 / Accepted: 23 February 2018 / Published: 1 March 2018
(This article belongs to the Special Issue Marine Compounds as Modulators of Autophagy and Lysosomal Activity)
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Abstract

Our understanding of autophagy and lysosomal function has been greatly enhanced by the discovery of natural product structures that can serve as chemical probes to reveal new patterns of signal transduction in cells. Coibamide A is a cytotoxic marine natural product that induces mTOR-independent autophagy as an adaptive stress response that precedes cell death. Autophagy-related (ATG) protein 5 (ATG5) is required for coibamide-induced autophagy but not required for coibamide-induced apoptosis. Using wild-type and autophagy-deficient mouse embryonic fibroblasts (MEFs) we demonstrate that coibamide-induced toxicity is delayed in ATG5−/− cells relative to ATG5+/+ cells. Time-dependent changes in annexin V staining, membrane integrity, metabolic capacity and caspase activation indicated that MEFs with a functional autophagy pathway are more sensitive to coibamide A. This pattern could be distinguished from autophagy modulators that induce acute ER stress (thapsigargin, tunicamycin), ATP depletion (oligomycin A) or mTORC1 inhibition (rapamycin), but was shared with the Sec61 inhibitor apratoxin A. Coibamide- or apratoxin-induced cell stress was further distinguished from the action of thapsigargin by a pattern of early LC3-II accumulation in the absence of CHOP or BiP expression. Time-dependent changes in ATG5-ATG12, PARP1 and caspase-3 expression patterns were consistent with the conversion of ATG5 to a pro-death signal in response to both compounds. View Full-Text
Keywords: mTOR-independent autophagy; apoptosis; coibamide A; apratoxin A; ER stress; Sec61; BiP; GRP78 mTOR-independent autophagy; apoptosis; coibamide A; apratoxin A; ER stress; Sec61; BiP; GRP78
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Wan, X.; Serrill, J.D.; Humphreys, I.R.; Tan, M.; McPhail, K.L.; Ganley, I.G.; Ishmael, J.E. ATG5 Promotes Death Signaling in Response to the Cyclic Depsipeptides Coibamide A and Apratoxin A. Mar. Drugs 2018, 16, 77.

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