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.

Increased SUMO-2/3-ylation mediated by SENP3 degradation is protective against cadmium-induced caspase 3–dependent cytotoxicity

“…There is an increasing body of evidence suggesting that SENP3 is a key regulator of stress responses (Huang et al, 2009;Han et al, 2010;Yan et al, 2010;Wang et al, 2012;Wei et al, 2012;Guo et al, 2013Guo et al, , 2017Yang et al, 2015aYang et al, , 2015bYu et al, 2015;Lee et al, 2016;Guo and Henley, 2014). This study adds to previous reports by demonstrating that loss of SENP3 and the consequent increase in SUMOylation plays a protective role in cadmium-induced toxicity, but that this effect is cell-type specific.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…However, other groups did not observe increased Drp1 S-nitrosylation but, instead, proposed increased phosphorylation of S616 and the subsequent recruitment of Drp1 to mitochondria as a mechanism to trigger the mitochondrial fragmentation found in neurodegenerative diseases (Bossy et al, 2010;Zhang et al, 2016). In addition, Drp1 is SUMOylated at multiple lysine residues, which has been suggested to stabilize Drp1 oligomers at the OMM in order to promote mitochondrial fission and initiate apoptosis (Wasiak et al, 2007;Harder et al, 2004;Guo et al, 2013a;Figueroa-Romero et al, 2009). Drp1 is also subject to alternative splicing and can include up to three alternative exons that give rise to eight different protein isoforms in mammals (Fig.…”

Mitochondrial fission and fusion in secondary brain damage after CNS insults

“…However, following reoxygenation, recovery of SENP3 deSUMOylates Drp1 to reverse this process, thereby allowing Drp1 mitochondrial localization and subsequent mitochondrial fragmentation and cyto C release. 64 Thus, both ubiquitination and SUMOylation modulate Drp1-mediated mitochondrial fragmentation, cyto C release, and cell death.…”