Department of Research, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain.
Proteomics Unit, Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain.
Int J Mol Sci. 2023 May 4;24(9):8246. doi: 10.3390/ijms24098246.
Transient cerebral ischemia induces neuronal degeneration, followed in time by secondary delayed neuronal death that is strongly correlated with a permanent inhibition of protein synthesis in vulnerable brain regions, while protein translational rates are recovered in resistant areas. In the translation-regulation initiation step, the eukaryotic initiation factor (eIF) 4E is a key player regulated by its association with eIF4E-binding proteins (4E-BPs), mostly 4E-BP2 in brain tissue. In a previous work, we identified dihydropyrimidinase-related protein 2 (DRP2) as a 4E-BP2-interacting protein. Here, using a proteomic approach in a model of transient cerebral ischemia, a detailed study of DRP2 was performed in order to address the challenge of translation restoration in vulnerable regions. In this report, several DRP2 isoforms that have a specific interaction with both 4E-BP2 and eIF4E were identified, showing significant and opposite differences in this association, and being differentially detected in resistant and vulnerable regions in response to ischemia reperfusion. Our results provide the first evidence of DRP2 isoforms as potential regulators of the 4E-BP2-eIF4E association that would have consequences in the delayed neuronal death under ischemic-reperfusion stress. The new knowledge reported here identifies DRP2 as a new target to promote neuronal survival after cerebral ischemia.
短暂性脑缺血诱导神经元变性，随后是继发性延迟性神经元死亡，这与易损脑区的蛋白质合成永久抑制密切相关，而在抗性区域，蛋白质翻译速率得到恢复。在翻译调控起始步骤中，真核起始因子（eIF）4E 是一个关键的调节因子，通过与 eIF4E 结合蛋白（4E-BP）的结合来调节，在脑组织中主要是 4E-BP2。在之前的一项工作中，我们鉴定出二氢嘧啶酶相关蛋白 2（DRP2）是 4E-BP2 的相互作用蛋白。在这里，我们使用短暂性脑缺血模型中的蛋白质组学方法，对 DRP2 进行了详细研究，以解决易损区域翻译恢复的挑战。在本报告中，鉴定出几种与 4E-BP2 和 eIF4E 都具有特异性相互作用的 DRP2 同工型，它们在这种结合中表现出显著的、相反的差异，并在缺血再灌注后在抗性和易损区域中以不同的方式被检测到。我们的结果首次提供了 DRP2 同工型作为 4E-BP2-eIF4E 结合潜在调节剂的证据，这将对缺血再灌注应激下的延迟性神经元死亡产生影响。这里报道的新知识将 DRP2 确定为脑缺血后促进神经元存活的新靶标。
