Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4-CHOP-Mediated Induction of the Bcl-2 Homology 3-Only Member PUMA
Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4-CHOP-Mediated Induction of the Bcl-2 Homology 3-Only Member PUMA
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DOI：
10.1523/jneurosci.1598-10.2010
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发表时间：
2010-12-15
影响因子：
5.3
通讯作者：
Cregan, Sean P.
中科院分区：
文献类型：
--
作者：
Galehdar, Zohreh;Swan, Patrick;Cregan, Sean P.
越来越多的证据表明，内质网(ER)应激在急性和慢性神经退行性疾病中起着关键作用。广泛的内质网应激可引发神经细胞凋亡，但调节这种细胞死亡的信号通路尚不清楚。在本研究中，我们证明了PUMA是BH3家族中的唯一成员，在内质网应激诱导的神经元中转录激活，在内质网应激诱导的细胞死亡中起重要作用。已知PUMA是P53的关键转录靶点，但我们发现内质网应激通过内质网应激诱导转录因子ATF4(激活转录因子4)介导的PUMA诱导和细胞死亡的非P53机制。具体地说，我们证明了ATF4的异位表达使小鼠皮质神经元对内质网应激诱导的细胞凋亡敏感，并且ATF4缺失的神经元表现出显著的PUMA表达水平和细胞死亡。然而，染色质免疫沉淀实验表明，ATF4不直接调节PUMA启动子。相反，我们发现ATF4诱导转录因子CHOP(C/EBP同源蛋白)的表达，CHOP反过来激活PUMA诱导。具体地说，我们证明了在内质网应激过程中，CHOP与PUMA启动子结合，并且CHOP基因敲除减弱了PUMA的诱导和神经元的凋亡。综上所述，我们已经确定了内质网应激诱导神经元死亡的一个关键信号通路，该通路涉及ATF4-CHOP介导的促凋亡的Bcl-2家族成员PUMA的反式激活。我们认为，这一途径可能是与许多神经退行性疾病相关的重要治疗靶点。
An increasing body of evidence points to a key role of endoplasmic reticulum (ER) stress in acute and chronic neurodegenerative conditions. Extensive ER stress can trigger neuronal apoptosis, but the signaling pathways that regulate this cell death remain unclear. In the present study, we demonstrate that PUMA, a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family, is transcriptionally activated in cortical neurons by ER stress and is essential for ER-stress-induced cell death. PUMA is known to be a key transcriptional target of p53, but we have found that ER stress triggers PUMA induction and cell death through a p53-independent mechanism mediated by the ER-stress-inducible transcription factor ATF4 (activating transcription factor 4). Specifically, we demonstrate that ectopic expression of ATF4 sensitizes mouse cortical neurons to ER-stress-induced apoptosis and that ATF4-deficient neurons exhibit markedly reduced levels of PUMA expression and cell death. However, chromatin immunoprecipitation experiments suggest that ATF4 does not directly regulate the PUMA promoter. Rather, we found that ATF4 induces expression of the transcription factor CHOP (C/EBP homologous protein) and that CHOP in turn activates PUMA induction. Specifically, we demonstrate that CHOP binds to the PUMA promoter during ER stress and that CHOP knockdown attenuates PUMA induction and neuronal apoptosis. In summary, we have identified a key signaling pathway in ER-stress-induced neuronal death involving ATF4-CHOP-mediated transactivation of the proapoptotic Bcl-2 family member PUMA. We propose that this pathway may be an important therapeutic target relevant to a number of neurodegenerative conditions.