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ClC-3 induction protects against cerebral ischemia/reperfusion injury through promoting Beclin1/Vps34-mediated autophagy

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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.

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Acknowledgements

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81873794).

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Authors and Affiliations

  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

    Beilin Zhang, Fang Deng, Chunkui Zhou & Shaokuan Fang

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  1. Beilin Zhang
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  2. Fang Deng
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  3. Chunkui Zhou
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  4. Shaokuan Fang
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Contributions

Beilin Zhang carried out the study and drafted the manuscript. Shaokuan Fang participated in the study design and the data statistics. Fang Deng and Chunkui Zhou participated in scientific discussion of the data.

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Correspondence to Shaokuan Fang.

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All animal experiments were approved and performed according to the guidelines of the institutional animal care and use committee of the Jilin University.

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Zhang, B., Deng, F., Zhou, C. et al. ClC-3 induction protects against cerebral ischemia/reperfusion injury through promoting Beclin1/Vps34-mediated autophagy. Human Cell 33, 1046–1055 (2020). https://doi.org/10.1007/s13577-020-00406-x

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