Department of Pathology and Cell Biology, Columbia University Medical Center, NY 10032, USA.
Cell Death Differ. 2013 Dec;20(12):1719-30. doi: 10.1038/cdd.2013.128.
The mechanisms governing neuron death following NGF deprivation are incompletely understood. Here, we show that Trib3, a protein induced by NGF withdrawal, has a key role in such death via a loop involving the survival kinase Akt and FoxO transcription factors. Trib3 overexpression is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn. Mechanism studies reveal that Trib3 interferes with phosphorylation/activity of Akt and contributes to Akt inactivation after NGF deprivation. FoxO1a, a direct Akt substrate, is dephosphorylated upon NGF withdrawal and consequently undergoes nuclear translocation and activates pro-apoptotic genes. We find that Trib3 is required for FoxO1a dephosphorylation and nuclear translocation after NGF deprivation. Conversely, Trib3 induction requires FoxO transcription factors, which show enhanced occupancy of the Trib3 promoter region following NGF withdrawal. Collectively, these findings support a mechanism in which NGF deprivation, Akt dephosphorylation/inactivation, FoxO dephosphorylation/activation and Trib3 induction are linked in a self-amplifying feed-forward loop that culminates in neuron death.
NGF 剥夺后神经元死亡的机制尚不完全清楚。在这里，我们表明，Trib3 是一种由 NGF 撤出诱导的蛋白质，通过涉及生存激酶 Akt 和 FoxO 转录因子的循环，在这种死亡中起着关键作用。Trib3 的过表达足以诱导神经元死亡，而当 NGF 被撤出时，内源性 Trib3 的沉默强烈地保护神经元免于死亡。机制研究表明，Trib3 干扰 Akt 的磷酸化/活性，并有助于 NGF 剥夺后 Akt 的失活。FoxO1a 是 Akt 的直接底物，在 NGF 撤出后发生去磷酸化，随后发生核转位并激活促凋亡基因。我们发现 Trib3 是 NGF 剥夺后 FoxO1a 去磷酸化和核转位所必需的。相反，Trib3 的诱导需要 FoxO 转录因子，这些转录因子在 NGF 撤出后显示出 Trib3 启动子区域的增强占据。总之，这些发现支持了一种机制，即 NGF 剥夺、Akt 去磷酸化/失活、FoxO 去磷酸化/激活和 Trib3 诱导在一个自我放大的正反馈环中相互关联，最终导致神经元死亡。
