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.
Hum Cell. 2020 Oct;33(4):1046-1055. doi: 10.1007/s13577-020-00406-x. Epub 2020 Aug 9.
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.
急性缺血性脑卒中是一种具有非常有限治疗方法的破坏性疾病。对调节失常的自噬作用促进脑缺血损伤的进展的日益认识，使其成为一个有吸引力的干预靶点。就其特征明显的后果而言，对于自噬激活所需的信号分子还没有很好的定义。在这里，我们发现氯离子通道 3（ClC-3）的诱导可直接激活自噬，这在限制脑缺血/再灌注（I / R）损伤中起重要作用。进一步的机制探索发现，ClC-3 的上调对于 Beclin1 和 Vps34 的相互作用至关重要。在体内使用腺相关病毒载体敲低 ClC-3 后，通过破坏 Beclin1 和 Vps34 复合物的形成，自噬激活被部分抑制。与这些观察结果一致，ClC-3 的敲低也可以通过体内抑制自噬来显著加重脑 I / R 损伤，这进一步证实了 ClC-3 的神经保护作用。总的来说，我们为 ClC-3 作为自噬的关键调节因子提供了新的证据；我们的结果表明，ClC-3 的诱导可能是针对脑 I / R 损伤的一种自我保护机制。
