Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 50, Pages 12123-12140Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1751-17.2017
Keywords
ischemic stroke; molecular mechanism; Rac1; therapy; TRAF6; ubiquitinating
Categories
Funding
- National Science Fund for Distinguished Young Scholars [81425005]
- National Natural Science Foundation [81330005, 91639304]
- National Natural Science Foundation of China [81370209, 81370365, 81270184, 31371481, 81271364]
- National Science and Technology Support Project [2013YQ030923-05, 2014BAI02B01, 2015BAI08B01, 2016YFF0101500]
- China Postdoctoral Science Foundation [2016M600617]
- Wuhan Science and Technique Foundation [201306062010270]
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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 proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In 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/Rac1 pathway might be a promising target to attenuate cerebral I/R injury.
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