Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington's disease
Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington's disease
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DOI：
10.1073/pnas.1717877115
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发表时间：
2018-01-23
影响因子：
11.1
通讯作者：
Paul, Bindu D.
中科院分区：
文献类型：
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作者：
Sbodio, Juan I.;Snyder, Solomon H.;Paul, Bindu D.
高尔基应激反应是一个与内质网（ER）和线粒体应激反应相当重要的生理过程。然而，与内质网应激不同，参与高尔基应激反应的信号转导途径的身份一直是难以捉摸的。我们发现高尔基应激源莫能菌素通过pkr样ER激酶/激活转录因子4途径起作用。ATF4是氨基酸代谢的主要调节因子，在氨基酸耗竭和其他形式的应激时被诱导。ATF4调控的基因之一是半胱氨酸、半胱甘肽的生物合成酶。-裂解酶（CSE）在维持氧化还原稳态中也起着核心作用。亨廷顿氏病（HD）是一种神经退行性疾病，与半胱氨酸代谢紊乱有关，这是由于CSE的消耗导致异常的氧化还原平衡和应激反应。因此，恢复CSE功能和半胱氨酸配置可能对HD有益。因此，我们利用莫能菌素- atf4信号级联通过莫能菌素预处理细胞来刺激CSE表达，从而恢复HD的半胱氨酸代谢和最佳应激反应。这些发现对HD和其他与氧化还原失衡和ATF4信号失调相关的疾病的治疗具有启示意义。
Golgi stress response is emerging as a physiologic process of comparable importance to endoplasmic reticulum (ER) and mitochondrial stress responses. However, unlike ER stress, the identity of the signal transduction pathway involved in the Golgi stress response has been elusive. We show that the Golgi stressor monensin acts via the PKR-like ER kinase/Activating Transcription Factor 4 pathway. ATF4 is the master regulator of amino acid metabolism, which is induced during amino acid depletion and other forms of stress. One of the genes regulated by ATF4 is the biosynthetic enzyme for cysteine, cystathionine.-lyase (CSE), which also plays central roles in maintenance of redox homeostasis. Huntington's disease (HD), a neurodegenerative disorder, is associated with disrupted cysteine metabolism caused by depletion of CSE leading to abnormal redox balance and stress response. Thus, restoring CSE function and cysteine disposition may be beneficial in HD. Accordingly, we harnessed the monensin-ATF4-signaling cascade to stimulate CSE expression by preconditioning cells with monensin, which restores cysteine metabolism and an optimal stress response in HD. These findings have implications for treatment of HD and other diseases associated with redox imbalance and dysregulated ATF4 signaling.