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- Title
The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Racl.
- Authors
Tao Li; Juan-Juan Qin; Xia Yang; Yan-Xiao Ji; Fangliang Guo; Wen-Lin Cheng; Xiaolin Wu; Fu-Han Gong; Ying Hong; Xue-Yong Zhu; Jun Gong; Zhihua Wang; Zan Huang; Zhi-Gang She; Hongliang Li
- Abstract
Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflanunatory signaling, oxidative stress, and neuronal death after cerebral 1/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Racl activation and consequently promoted I/R injury by directly binding and ubiquitinating Racl. Either functionally mutating the TRAF6 ubiquitination site on Racl or inactivating Racl with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. 1 n conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Racl pathway might be a promising target to attenuate cerebral I/R injury.
- Subjects
UBIQUITIN; LIGASES; STROKE; TUMOR necrosis factor receptors; MOLECULAR biology; CEREBRAL ischemia; REPERFUSION injury; LABORATORY mice
- Publication
Journal of Neuroscience, 2017, Vol 37, Issue 50, p12123
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1751-17.2017