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

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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.

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          Most cited references 59

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          The unfolded protein response: controlling cell fate decisions under ER stress and beyond.

           Claudio Hetz (2012)
          Protein-folding stress at the endoplasmic reticulum (ER) is a salient feature of specialized secretory cells and is also involved in the pathogenesis of many human diseases. ER stress is buffered by the activation of the unfolded protein response (UPR), a homeostatic signalling network that orchestrates the recovery of ER function, and failure to adapt to ER stress results in apoptosis. Progress in the field has provided insight into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6). In addition, novel physiological outcomes of the UPR that are not directly related to protein-folding stress, such as innate immunity, metabolism and cell differentiation, have been revealed.
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            Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.

            Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
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              Mitochondrial fission, fusion, and stress.

              Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson's.
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                Author and article information

                Journal
                EMBO J
                EMBO J
                The EMBO Journal
                Nature Publishing Group
                0261-4189
                1460-2075
                29 May 2013
                22 March 2013
                22 March 2013
                : 32
                : 11
                : 1514-1528
                Affiliations
                [1 ]School of Biochemistry, University of Bristol, University Walk , Bristol, UK
                Author notes
                [a ]School of Biochemistry, University of Bristol, University Walk , Medical Sciences Building, Bristol BS8 1TD, UK. Tel.:+44 (0)117 331 1945; Fax:+44 (0)117 331 2168; E-mail: j.m.henley@ 123456bristol.ac.uk
                Article
                emboj201365
                10.1038/emboj.2013.65
                3671254
                23524851
                Copyright © 2013, European Molecular Biology Organization

                This article is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported Licence. To view a copy of this licence visit http://creativecommons.org/licenses/by-nc-nd/3.0/.

                Categories
                Article

                Molecular biology

                apoptosis, drp1, mitochondria, senp3, sumo

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