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SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia
Article first published online: 22 MAR 2013
Copyright © 2013 European Molecular Biology Organization
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
The EMBO Journal
Volume 32, Issue 11, pages 1514–1528, May 29, 2013
How to Cite
Guo, C., Hildick, K. L., Luo, J., Dearden, L., Wilkinson, K. A. and Henley, J. M. (2013), SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia. The EMBO Journal, 32: 1514–1528. doi: 10.1038/emboj.2013.65
- Issue published online: 29 MAY 2013
- Article first published online: 22 MAR 2013
- Manuscript Accepted: 27 FEB 2013
- Manuscript Received: 9 JAN 2013
Global increases in small ubiquitin-like modifier (SUMO)-2/3 conjugation are a neuroprotective response to severe stress but the mechanisms and specific target proteins that determine cell survival have not been identified. Here, we demonstrate that the SUMO-2/3-specific protease SENP3 is degraded during oxygen/glucose deprivation (OGD), an in vitro model of ischaemia, via a pathway involving the unfolded protein response (UPR) kinase PERK and the lysosomal enzyme cathepsin B. A key target for SENP3-mediated deSUMOylation is the GTPase Drp1, which plays a major role in regulating mitochondrial fission. We show that depletion of SENP3 prolongs Drp1 SUMOylation, which suppresses Drp1-mediated cytochrome c release and caspase-mediated cell death. SENP3 levels recover following reoxygenation after OGD allowing deSUMOylation of Drp1, which facilitates Drp1 localization at mitochondria and promotes fragmentation and cytochrome c release. RNAi knockdown of SENP3 protects cells from reoxygenation-induced cell death via a mechanism that requires Drp1 SUMOylation. Thus, we identify a novel adaptive pathway to extreme cell stress in which dynamic changes in SENP3 stability and regulation of Drp1 SUMOylation are crucial determinants of cell fate.