Selective 14-3-3 Upregulation Promotes Beclin-1-LC3-Autophagic Influx via -Catenin Interaction in Starved Neurons In Vitro and In Vivo
Selective 14-3-3 Upregulation Promotes Beclin-1-LC3-Autophagic Influx via -Catenin Interaction in Starved Neurons In Vitro and In Vivo
复制标题
体外和体内饥饿神经元中选择性 14-3-3 上调通过 -Catenin 相互作用促进 Beclin-1-LC3 自噬流入
DOI：
10.1007/s11064-019-02717-4
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发表时间：
2019
影响因子：
4.4
通讯作者：
Chen Xiao Qian
中科院分区：
文献类型：
--
作者：
Xiong Xin Xin;Hu Dian Xing;Xu Lu;Lin Huang;Zhang Yu;Li Chun Yang;Chen Xiao Qian
缺乏血液或葡萄糖供应是大脑中最常见的病理因素。为了科普这种能量压力，需要在神经元中启动程序化的自噬过程。然而，在饥饿过程中控制神经元自噬的机制仍然很不清楚。在此，我们报道了14-3-3γ在饥饿激活的神经元自噬内流信号中的重要作用，并阐明了潜在的机制。双荧光免疫染色显示，14-3-3γ蛋白升高与Beclin-1和LC 3升高在缺血脑中的皮质神经元中良好地共定位。饥饿处理激活自噬内流并上调N2 a细胞和培养的皮质神经元中的Beclin-1和仅14-3-3的γ亚型。通过difopein过表达或敲除14-3-3的γ同种型来抑制总体14 - 3 -3功能足以消除饥饿诱导的Beclin-1诱导和LC 3活化，而过表达14-3-3γ但没有其他14-3-3同种型显著上调Beclin-1-LC 3信号传导。饥饿时，14-3-3γ结合更多的β-连环蛋白，但结合更少的Beclin-1。最后，过表达14-3-3γ重新激活神经元细胞中β-连环蛋白抑制的Beclin-1-LC 3信号传导。综上所述，我们的数据揭示了饥饿诱导的14-3-3γ是体外和体内饥饿神经元中β-catenin-Beclin-1-LC 3-自噬所必需的，这可能为治疗神经系统疾病如斯托克提供见解。
Lack of blood or glucose supply is the most common pathological factor in the brain. To cope with such an energy stress, initiating programmed autophagic processes in neurons is required. However, the mechanisms controlling neuronal autophagy during starvation remain far from clear. Here, we report an essential role of 14-3-3γ in starvation-activated neuronal autophagic influx signaling and elucidate the underlying mechanism. Double-fluorescent immunostaining demonstrates that 14-3-3γ protein elevation is well co-localized with Beclin-1 and LC3 elevation in cortical neurons in ischemic brains. Starvation treatment activates autophagic influx and upregulates Beclin-1 and only the γ isoform of 14-3-3 in N2a cells and cultured cortical neurons. Suppressing overall 14-3-3 function by difopein overexpression or knocking-out the γ isoform of 14-3-3 is sufficient to abolish starvation-induced Beclin-1 induction and LC3 activation while overexpressing 14-3-3γ but no other 14-3-3 isoform significantly upregulate Beclin-1-LC3 signaling. Upon starvation, 14-3-3γ binds more p-β-catenin but less Beclin-1. Finally, overexpressing 14-3-3γ reactivates β-catenin-suppressed Beclin-1-LC3 signaling in neuronal cells. Taken together, our data reveal that starvation-induced 14-3-3γ is required for β-catenin-Beclin-1-LC3-autophagy in starved neurons in vitro and in vivo, which may provide insights in the treatment of neurologic diseases such as stoke.