E2-25K SUMOylation inhibits proteasome for cell death during cerebral ischemia/reperfusion

• Published in: Cell death & disease 2016-12, Vol.7 (12), p.e2573-e2573
• Main Authors: Jeong, Eun Il, Chung, Hae Won, Lee, Won Jea, Kim, Seo-Hyun, Kim, Hyunjoo, Choi, Seon-Guk, Jung, Yong-Keun
• Format: Article
• Language: English
• Subjects: 13/1; 631/45/474/2085; 631/45/474/538; 631/80/82; 64/60; 692/699/75/593/1370; 82/16; 96; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Brain; Brain Ischemia - complications; Brain Ischemia - enzymology; Brain Ischemia - pathology; Carrier Proteins - metabolism; Cell Biology; Cell Culture; Cell Death; Down-Regulation; Glucose - deficiency; Immunology; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - enzymology; Infarction, Middle Cerebral Artery - pathology; Ischemia; Life Sciences; Lysine - metabolism; Male; Mice, Knockout; Neurons - metabolism; Neurons - pathology; Original; original-article; Oxidative Stress; Oxygen; Proteases; Proteasome Endopeptidase Complex - metabolism; Reperfusion Injury - complications; Reperfusion Injury - enzymology; Reperfusion Injury - pathology; Sumoylation; Ubiquitin-Conjugating Enzymes - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.428

Cerebral ischemia/reperfusion (I/R) causes brain damage accompanied by ubiquitin accumulation and impairment of proteasome activity. In this study, we report that E2-25K, an E2-conjugating enzyme, is SUMOylated during oxidative stress and regulates cerebral I/R-induced damage. Knockdown of E2-25K expression protects against oxygen/glucose deprivation and reoxygenation (OGD/R)-induced neuronal cell death, whereas ectopic expression of E2-25K stimulates it. Compared with the control mice, cerebral infarction lesions and behavioral/neurological disorders are ameliorated in E2-25K knockout mice during middle cerebral artery occlusion and reperfusion. In particular, E2-25K is SUMOylated at Lys14 under oxidative stress, OGD/R and I/R to prompt cell death. Further, E2-25K downregulates the proteasome subunit S5a to impair proteasome complex and thus restrain proteasome activity under oxidative stress. This proteasome inhibitory activity of E2-25K is dependent on its SUMOylation. These results suggest that E2-25K has a crucial role in oxidative stress and cerebral I/R-induced damage through inhibiting proteasome via its SUMOylation.