ClC-3 induction protects against cerebral ischemia/reperfusion injury through promoting Beclin1/Vps34-mediated autophagy
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RESEARCH ARTICLE
ClC‑3 induction protects against cerebral ischemia/reperfusion injury through promoting Beclin1/Vps34‑mediated autophagy Beilin Zhang1 · Fang Deng1 · Chunkui Zhou1 · Shaokuan Fang1 Received: 15 April 2020 / Accepted: 28 July 2020 © Japan Human Cell Society 2020
Abstract Acute ischemic stroke is a devastating disease with very limited therapeutics. Growing appreciation of dysregulated autophagy contributes to the progression of brain ischemic injury, making it to be an appealing intervention target. In terms of its well-characterized consequences, the signal molecules required for autophagy activation are rather poorly defined. Here, we found the induction of chloride channel-3 (ClC-3) directly activated autophagy, which played an important role in limiting cerebral ischemia/reperfusion (I/R) injury. Further mechanism exploration discovered that the up-regulation of ClC-3 was critical for the interaction of Beclin1 and Vps34. After ClC-3 knockdown using adeno-associated virus vectors in vivo, the autophagy activation was partially inhibited through disrupting the formation of Beclin1 and Vps34 complex. Consistent with these observations, ClC-3 knockdown could also significantly aggravated cerebral I/R injury through suppressing autophagy in vivo, which further confirmed the neuroprotective roles of ClC-3. Collectively, we provided an novel evidence for ClC-3 serving as a crucial regulator of autophagy; and our results indicated that the induction of ClC-3 may serve as a self-protective mechanism against cerebral I/R injury. Keywords ClC-3 · Acute ischemic stroke · Beclin1 · Autophagy
Introduction Acute ischemic stroke (AIS) is a serious neurological disease caused by the abrupt cerebrovascular occlusion, resulting in temporary or permanent damage to the affected brain tissues owing to the diminished supply of oxygen and glucose [1, 2]. AIS is the second leading cause of death from cardiovascular diseases in people over 60 years old, accounting for an estimated 6.7 million deaths per year worldwide [3]. Meanwhile, it is a common cause of adult disability, will bring a heavy burden to the caregivers and society [4]. Despite of ample bench researches about AIS have been made, the translational results are unsatisfying or discouraging [5]. Therefore, a thorough and deeper understanding of the pathophysiology of AIS can provide an opportunity
* Shaokuan Fang [email protected] 1
Department of Neurology, The First Teaching Hospital of Jilin University, No. 71 Xinmin Street, Chaoyang District, Changchun 130021, Jilin Province, People’s Republic of China
for identifying promising targets and developing novel therapeutics. The roles of autophagy in AIS have been established but with controversy. Autophagy is an evolutionally conversed mechanism across species for degradation or recycling misfolded proteins and injured organelles in lysosomes under physiological conditions [6–8]. The obstruction of lysosome acidification can directly suppress autophagy [9]. Under pathological conditions suc
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