Unique anti-apoptotic activity of EAAC1 in injured motor neurons
Unique anti-apoptotic activity of EAAC1 in injured motor neurons
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DOI：
10.1038/sj.emboj.7601225
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发表时间：
2006-07-26
期刊：
影响因子：
11.4
通讯作者：
Kiyama, Hiroshi
中科院分区：
文献类型：
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作者：
Kiryu-Seo, Sumiko;Gamo, Kazushige;Kiyama, Hiroshi
成年大鼠受损的运动神经元可以存活，而类似的轴突切断会导致成年小鼠运动神经元逐渐死亡。我们报告神经损伤后神经元谷氨酸转运体兴奋性氨基酸载体1（EAAC 1）的表达减少与小鼠运动神经元死亡有关。谷氨酸转运体通过抑制谷氨酸毒性在预防神经元死亡中起着至关重要的作用。然而，与神经胶质谷氨酸转运蛋白如GLT-1相比，EAAC 1在防止神经元死亡中可能的功能作用尚未得到解决。在这里，我们已经揭示了EAAC 1的独特的“救援”功能，这是独立的细胞外谷氨酸的去除。在凋亡刺激期间，线粒体蛋白，全细胞色素c合成酶（HCCS），易位到线粒体外部，结合并抑制X连锁凋亡抑制蛋白（XIAP），导致半胱天冬酶-3的活化。EAAC 1的N端可以与HCCS结合，从而干扰HCCS-XIAP结合，从而维持XIAP活性。EAAC 1的这种独特的抗凋亡机制分别在从NGF剥夺和神经损伤中拯救PC 12细胞和运动神经元中发挥作用。
Injured motor neurons of the adult rat can survive, whereas similar axotomy causes gradual motor neuron death in the adult mouse. We report that the decreased expression of the neuronal glutamate transporter excitatory amino-acid carrier 1 (EAAC1) following nerve injury is associated with motor neuron death in the mouse. Glutamate transporters play a crucial role in prevention of neuronal death by suppressing glutamate toxicity. However, the possible functional role of EAAC1 in preventing neuron death has not been resolved as compared with glial glutamate transporters such as GLT-1. Here, we have revealed a unique 'rescue' function of EAAC1, which is independent of removal of extracellular glutamate. During apoptotic stimuli, a mitochondrial protein, holocytochrome c synthetase (HCCS), translocates to outside the mitochondria, binds to and suppresses the X-linked inhibitor of apoptosis protein ( XIAP), leading to activation of caspase-3. The N-terminus of EAAC1 can bind to HCCS, which interferes with the HCCS-XIAP association, and thereby maintain XIAP activity. This unique anti-apoptotic mechanism of EAAC1 functions in rescuing PC12 cells and motor neurons from NGF deprivation and nerve injury, respectively.