SENP3-mediated DeSUMOylation of Dynamin-related Protein 1 Promotes Cell Death Following Ischaemia

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2013 Mar 26

PMID 23524851

Citations 117

Authors

Chun Guo

Keri L Hildick

Jia Luo

Laura Dearden

Kevin A Wilkinson

Jeremy M Henley

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Cassidy-Stone A, Chipuk J, Ingerman E, Song C, Yoo C, Kuwana T . Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008; 14(2):193-204. PMC: 2267902. DOI: 10.1016/j.devcel.2007.11.019. View

Cimarosti H, Lindberg C, Bomholt S, Ronn L, Henley J . Increased protein SUMOylation following focal cerebral ischemia. Neuropharmacology. 2007; 54(2):280-9. DOI: 10.1016/j.neuropharm.2007.09.010. View

Cimarosti H, Ashikaga E, Jaafari N, Dearden L, Rubin P, Wilkinson K . Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurones. J Cereb Blood Flow Metab. 2011; 32(1):17-22. PMC: 3308141. DOI: 10.1038/jcbfm.2011.146. View

Cribbs J, Strack S . Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 2007; 8(10):939-44. PMC: 2002551. DOI: 10.1038/sj.embor.7401062. View

Jourdain A, Martinou J . Mitochondrial outer-membrane permeabilization and remodelling in apoptosis. Int J Biochem Cell Biol. 2009; 41(10):1884-9. DOI: 10.1016/j.biocel.2009.05.001. View

Chang C, Blackstone C . Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007; 282(30):21583-7. DOI: 10.1074/jbc.C700083200. View

Figueroa-Romero C, Iniguez-Lluhi J, Stadler J, Chang C, Arnoult D, Keller P . SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle. FASEB J. 2009; 23(11):3917-27. PMC: 2775011. DOI: 10.1096/fj.09-136630. View

Konopacki F, Jaafari N, Rocca D, Wilkinson K, Chamberlain S, Rubin P . Agonist-induced PKC phosphorylation regulates GluK2 SUMOylation and kainate receptor endocytosis. Proc Natl Acad Sci U S A. 2011; 108(49):19772-7. PMC: 3241814. DOI: 10.1073/pnas.1111575108. View

Van der Kelen K, Beyaert R, Inze D, De Veylder L . Translational control of eukaryotic gene expression. Crit Rev Biochem Mol Biol. 2009; 44(4):143-68. DOI: 10.1080/10409230902882090. View

10.

Harding H, Zhang Y, Ron D . Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999; 397(6716):271-4. DOI: 10.1038/16729. View

11.

Yang W, Sheng H, Warner D, Paschen W . Transient focal cerebral ischemia induces a dramatic activation of small ubiquitin-like modifier conjugation. J Cereb Blood Flow Metab. 2008; 28(5):892-6. DOI: 10.1038/sj.jcbfm.9600601. View

12.

Li T, Santockyte R, Shen R, Tekle E, Wang G, Yang D . Expression of SUMO-2/3 induced senescence through p53- and pRB-mediated pathways. J Biol Chem. 2006; 281(47):36221-7. DOI: 10.1074/jbc.M608236200. View

13.

Lee Y, Mou Y, Maric D, Klimanis D, Auh S, Hallenbeck J . Elevated global SUMOylation in Ubc9 transgenic mice protects their brains against focal cerebral ischemic damage. PLoS One. 2011; 6(10):e25852. PMC: 3189225. DOI: 10.1371/journal.pone.0025852. View

14.

Frank S, Gaume B, Bergmann-Leitner E, Leitner W, Robert E, Catez F . The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001; 1(4):515-25. DOI: 10.1016/s1534-5807(01)00055-7. View

15.

Kim R, Emi M, Tanabe K . Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol. 2005; 57(5):545-53. DOI: 10.1007/s00280-005-0111-7. View

16.

Hetz C . The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012; 13(2):89-102. DOI: 10.1038/nrm3270. View

17.

Saito A, Maier C, Narasimhan P, Nishi T, Song Y, Yu F . Oxidative stress and neuronal death/survival signaling in cerebral ischemia. Mol Neurobiol. 2005; 31(1-3):105-16. DOI: 10.1385/MN:31:1-3:105. View

18.

Lee Y, Jeong S, Karbowski M, Smith C, Youle R . Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004; 15(11):5001-11. PMC: 524759. DOI: 10.1091/mbc.e04-04-0294. View

19.

Renner F, Moreno R, Schmitz M . SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death. Mol Cell. 2010; 37(4):503-15. DOI: 10.1016/j.molcel.2010.01.018. View

20.

Yang W, Sheng H, Warner D, Paschen W . Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab. 2007; 28(2):269-79. DOI: 10.1038/sj.jcbfm.9600523. View