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Author (up) Guo, C.; Hildick, K.L.; Luo, J.; Dearden, L.; Wilkinson, K.A.; Henley, J.M.
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  Title SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia Type Journal Article
  Year 2013 Publication The EMBO Journal Abbreviated Journal Embo J  
  Volume Issue Pages  
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  Abstract 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.  
  Address School of Biochemistry, University of Bristol, University Walk, Bristol, UK  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0261-4189 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23524851 Approved no  
  Call Number @ @ Serial 38635  
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