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

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.
Mesh Terms:
Animals, Apoptosis, Cell Death, Cell Line, Cysteine Endopeptidases, Cytochromes c, Cytosol, Embryo, Mammalian, GTP Phosphohydrolases, Gene Expression Regulation, Glucose, Humans, Ischemia, Mice, Microtubule-Associated Proteins, Mitochondria, Mitochondrial Dynamics, Mitochondrial Proteins, Models, Biological, Mutation, Neurons, Oxygen, Rats, Small Ubiquitin-Related Modifier Proteins, Sumoylation, eIF-2 Kinase
EMBO J.
Date: May. 29, 2013
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