SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia

• Published in: The EMBO journal Vol. 32; no. 11; pp. 1514 - 1528
• Main Authors: Guo, Chun, Hildick, Keri L, Luo, Jia, Dearden, Laura, Wilkinson, Kevin A, Henley, Jeremy M
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 29.05.2013; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Apoptosis; Cell Death; Cell Line; Cells; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Cytochrome; Cytochromes c - metabolism; Cytosol - metabolism; Drp1; Dynamins; eIF-2 Kinase - metabolism; EMBO27; EMBO31; Embryo, Mammalian; Gene Expression Regulation; Glucose - metabolism; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Heart attacks; Humans; Ischemia; Mice; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; mitochondria; Mitochondria - metabolism; Mitochondrial Dynamics; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Models, Biological; Mortality; Mutation; Neurons; Neurons - metabolism; Oxygen - metabolism; Proteins; Rats; SENP3; Small Ubiquitin-Related Modifier Proteins - genetics; Small Ubiquitin-Related Modifier Proteins - metabolism; SUMO; Sumoylation; apoptosis; SUMO; SENP3; mitochondria; Drp1
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2013.65

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. The SUMO‐2/3‐specific deSUMOylating enzyme SENP3 induces apoptosis by targeting the GTPase Drp1 to mitochondria, causing cytochrome c release.