自噬
细胞生物学
神经炎症
缺血
连接蛋白
程序性细胞死亡
泛素
蛋白质降解
生物
细胞凋亡
缝隙连接
医学
炎症
免疫学
生物化学
内科学
基因
细胞内
作者
Xinyu Wang,Liangshu Feng,Meiying Xin,Yulei Hao,Xu Wang,Pei Shang,Mingming Zhao,Shuai Hou,Yunhai Zhang,Yun Xiao,Di Ma,Jiachun Feng
标识
DOI:10.1016/j.biopha.2020.110125
摘要
• Inhibiting Cx43 degradation transitioned astrocytes to anti-inflammatory status. • Knockdown or accelerated degradation of Cx43 protected astrocytes from apoptosis. • Cx43 degradation during ischemia injury is mediated by selective autophagy. Connexin-43 (Cx43) is the most abundant gap junction protein in the nervous system. It enables cell communication and has important physiological roles including ion transport and substrate exchange, all of which have been implicated in cerebral ischemia injury. Our previous in vitro and in vivo studies have demonstrated that Cx43 is internalized and degraded during ischemia stress. However, the significance of ischemia-induced degradation of Cx43 remains unclear. Herein, we demonstrated that Cx43 degradation during ischemia injury is mediated by selective autophagy; additionally, we identified two related autophagy receptors—OPTN and NDP52. Cx43 degradation during ischemia requires its phosphorylation and ubiquitination, which are mediated by PKC, Src kinases, and ubiquitin kinase PINK1. Using point mutagenesis, we identified three phosphorylation sites underlying Cx43 autophagy degradation under ischemic stress. Cx43 degradation inhibition promoted the transition of astrocytes from a pro-inflammatory to an anti-inflammatory status, based on the levels of IL-10 and TNF in ischemia. Knockdown or accelerated degradation of Cx43 protected astrocytes from apoptosis under ischemic stress. These findings elucidate the underlying mechanism of astrocytic Cx43 autophagic degradation during ischemia. The study has identified potentially novel therapeutic strategies against ischemic stroke and evidence of crosstalk between autophagic degradation of Cx43, astrocytic apoptosis, and neuroinflammation.
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