title: SENP3-mediated deSUMOylation of dynamin-related protein 1 promotes cell death following ischaemia.
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.
authors.affiliation: School of Biochemistry, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.forename: Keri L
authors.initials: KL
authors.lastname: Hildick
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.forename: Laura
authors.initials: L
authors.lastname: Dearden
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Wilkinson
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Henley
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D034281:Dynamins; D004622:Embryo, Mammalian; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007511:Ischemia; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D045304:Cytochromes c; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D005947:Glucose; D010100:Oxygen