Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Gyeongsangbuk, Republic of Korea.
Int J Mol Sci. 2023 Nov 14;24(22):16319. doi: 10.3390/ijms242216319.
FMRP is a multifunctional protein encoded by the gene (). The inactivation of the gene results in fragile X syndrome (FXS), a serious neurodevelopmental disorder. FMRP deficiency causes abnormal neurite outgrowth, which is likely to lead to abnormal learning and memory capabilities. However, the mechanism of FMRP in modulating neuronal development remains unknown. We found that FMRP enhances the translation of 4EBP2, a neuron-specific form of 4EBPs that inactivates eIF4E by inhibiting the interaction between eIF4E and eIF4G. Depletion of 4EBP2 results in abnormal neurite outgrowth. Moreover, the impairment of neurite outgrowth upon FMRP depletion was overcome by the ectopic expression of 4EBP2. These results suggest that FMRP controls neuronal development by enhancing 4EBP2 expression at the translational level. In addition, treatment with 4EGI-1, a chemical that blocks eIF4E activity, restored neurite length in FMRP-depleted and 4EBP2-depleted cells. In conclusion, we discovered that 4EBP2 functions as a key downstream regulator of FMRP activity in neuronal development and that FMRP represses eIF4E activity by enhancing 4EBP2 translation.
脆性 X 相关蛋白（FMRP）是由 基因编码的一种多功能蛋白。该基因失活会导致脆性 X 综合征（FXS），这是一种严重的神经发育障碍。FMRP 缺乏会导致神经突生长异常，这可能导致学习和记忆能力异常。然而，FMRP 调节神经元发育的机制尚不清楚。我们发现 FMRP 增强了 4EBP2 的翻译，4EBP2 是 4EBP 家族中神经元特异的形式，通过抑制 eIF4E 与 eIF4G 的相互作用来使 eIF4E 失活。4EBP2 的耗竭会导致神经突生长异常。此外，通过异位表达 4EBP2 可以克服 FMRP 耗竭导致的神经突生长受损。这些结果表明，FMRP 通过在翻译水平上增强 4EBP2 的表达来控制神经元发育。此外，用 4EGI-1 处理，一种阻断 eIF4E 活性的化学物质，可以恢复 FMRP 耗竭和 4EBP2 耗竭细胞中的神经突长度。总之，我们发现 4EBP2 是 FMRP 调节神经元发育过程中活性的关键下游调节剂，并且 FMRP 通过增强 4EBP2 的翻译来抑制 eIF4E 的活性。
