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

• Chun Guo ^[1] ; Keri L Hildick ^[1] ; Jia Luo ^[1] ; Laura Dearden ^[1] ; Kevin A Wilkinson ^[1] ; Jeremy M Henley ^[1]
  1. [1] University of Bristol

     University of Bristol

     Reino Unido

     
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 32, Nº. 11, 2013, págs. 1514-1528
• Idioma: inglés
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• Resumen

  • 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.