• Nan Chen, Yushuang Liu, Hongyi Yu, Sihan Liu, Peng Xiao, Zhongyi Jia, and Zhongling Zhang.
• Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
• Neuroscience. 2023 Mar 15; 514: 142414-24.

AbstractCullin 3 (CUL3), a member of Cullin-RING ubiquitin ligase family, regulates multiple intracellular pathways. CUL3 expression in peripheral immune cells is highly associated with the development of stroke, while little is known about the mechanism of how CUL3 participates in cerebral ischemia/reperfusion (I/R) injury. In this study, we showed that CUL3 was obviously upregulated in brain tissues of male rats received middle cerebral artery occlusion (MCAO) and reperfusion and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neurons. We firstly confirmed that CUL3 interacted with WNK3, a protein that has been proved to be associated with brain damage after ischemic stroke. CUL3 knockdown inhibited the ubiquitination of WNK3 and accelerated the phosphorylation of OSR1 in OGD/R-stimulated neurons. CUL3 silencing did not further aggravate cerebral I/R injury and played a neuroprotective role in vitro and in vivo. CUL3 knockdown attenuated the impairment of cell viability caused by OGD/R. CUL3 silencing reduced TUNEL-positive cells, down-regulated pro-apoptotic factor (Bax and Cleaved caspase 3) levels and increased the anti-apoptotic factor (Bcl-2) level in vitro and in vivo, suggesting that CUL3 repression alleviated neuronal apoptosis. Interestingly, rescue experiments revealed that WNK3 downregulation did not block the neuroprotection of CUL3 inhibition. These findings suggested that CUL3-mediated cerebral I/R injury might be not achieved through WNK3 signaling but other pathways. Furthermore, CUL3 inhibition suppressed ubiquitin-mediated degradation of Nrf2 and activated Nrf2 signaling by increasing the nuclear translocation of Nrf2 and expression levels of HO-1 and NQO-1. Taken together, CUL3 exacerbates cerebral I/R injury potentially due to its negative regulation of Nrf2 activation.Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.

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