Abstract
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.
Highlights
Stroke is a major cause of mortality and disability in humans
To characterize the role of E2-25K in I/R, we first examined the contribution of E2-25K to oxygen/glucose deprivation and reoxygenation (OGD/R)-induced neuronal cell death by targeting E2-25K expression with shRNA
The appearance of 38 kDa E2-25K was proportional to the treated H2O2 concentration (100–300 μM; Figures 1e and h), whereas 24 kDa E2-25K was concomitantly reduced
Summary
Stroke is a major cause of mortality and disability in humans. Because of the intricate pathological characteristics of ischemic neuronal cell death, diverse mechanisms and molecules associated with cerebral ischemia/reperfusion (I/R) have been reported. Evidence from a number of studies suggests that the proteasome might have an important role in I/R21,22 and cerebral I/R results in reduced proteasomal activity.[23] Besides, I/R is involved in immoderate production of various abnormal proteins due to oxidative stress and other mechanisms.[24] These proteins are reflected in the prolonged accumulation of polyubiquitinated proteins that can be attributable to impaired proteasome and are observed in dying neurons but not in the remaining neurons that survive.[25] the mechanism of inhibition of proteasome activity in neurons after I/R remains unknown. We observed that E2-25K was SUMOylated under oxidative stress and I/R to mediate neuronal cell death and brain injury In this process, SUMOylated E2-25K was crucial for regulating proteasome activity through S5a
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