Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, 04023-062, Brazil.
J Biol Chem. 2013 Apr 12;288(15):10860-9. doi: 10.1074/jbc.M113.461970. Epub 2013 Feb 27.
The product of the mouse Imprinted and Ancient gene, IMPACT, is preferentially expressed in neurons. We have previously shown that IMPACT overexpression inhibits the activation of the protein kinase GCN2, which signals amino acid starvation. GCN2 phosphorylates the α-subunit of eukaryotic translation initiation factor 2 (eIF2α), resulting in inhibition of general protein synthesis but increased translation of specific messages, such as ATF4. GCN2 is also involved in the regulation of neuronal functions, controlling synaptic plasticity, memory, and feeding behavior. We show here that IMPACT abundance increases during differentiation of neurons and neuron-like N2a cells, whereas GCN2 displays lowered activation levels. Upon differentiation, IMPACT associates with translating ribosomes, enhances translation initiation, and down-regulates the expression of ATF4. We further show that endogenous IMPACT promotes neurite outgrowth whereas GCN2 is a strong inhibitor of spontaneous neuritogenesis. Together, these results uncover the participation of the GCN2-IMPACT module of translational regulation in a highly controlled step in the development of the nervous system.
鼠印迹基因和远古基因的产物 IMPACT 优先在神经元中表达。我们之前已经表明，IMPACT 的过表达抑制了蛋白激酶 GCN2 的激活，而 GCN2 会发出氨基酸饥饿信号。GCN2 磷酸化真核翻译起始因子 2（eIF2α）的α 亚基，导致一般蛋白质合成受到抑制，但特定消息（如 ATF4）的翻译增加。GCN2 还参与神经元功能的调节，控制突触可塑性、记忆和进食行为。我们在这里表明，IMPACT 的丰度在神经元和神经元样 N2a 细胞的分化过程中增加，而 GCN2 的激活水平降低。在分化过程中，IMPACT 与正在翻译的核糖体结合，增强翻译起始，并下调 ATF4 的表达。我们进一步表明，内源性 IMPACT 促进神经突生长，而 GCN2 是自发神经突发生的强烈抑制剂。总之，这些结果揭示了翻译调节的 GCN2-IMPACT 模块在神经系统发育的一个高度受控步骤中的参与。
