Spinal cord injury (SCI) is a devastating neurological trauma that causes losses of motor and sensory function. Sestrin2, also known as hypoxia inducible gene 95, is emerging as a critical determinant of cell homeostasis in response to cellular stress. However, the role of sestrin2 in the neuronal response to endoplasmic reticulum (ER) stress and the potential mechanism remain undefined. In this study, we investigated the effects of sestrin2 on ER stress and delineated an underlying molecular mechanism after SCI. Here, we found that elevated sestrin2 is a protective process in neurons against chemical ER stress induced by tunicamycin (TM) or traumatic invasion, while treatment with PERK inhibitor or knockdown of ATF4 reduces sestrin2 expression upon ER stress. In addition, we demonstrated that overexpression of sestrin2 limits ER stress, promoting neuronal survival and improving functional recovery after SCI, which is associated with activation of autophagy and restoration of autophagic flux mediated by sestrin2. Moreover, we also found that sestrin2 activates autophagy dependent on the AMPK-mTOR signaling pathway. Consistently, inhibition of AMPK abrogates the effect of sestrin2 on the activation of autophagy, and blockage of autophagic flux abolishes the effect of sestrin2 on limiting ER stress and neural death. Together, our data reveal that upregulation of sestrin2 is an important resistance mechanism of neurons to ER stress and the potential role of sestrin2 as a therapeutic target for SCI.

Graphical abstract

脊髓损伤 (SCI) 是一种破坏性的神经系统创伤，会导致运动和感觉功能丧失。Sestrin2，也称为缺氧诱导基因 95，正在成为响应细胞应激的细胞稳态的关键决定因素。然而，sestrin2 在神经元对内质网 (ER) 应激反应中的作用及其潜在机制仍未确定。在这项研究中，我们研究了 sestrin2 对 ER 应激的影响，并描述了 SCI 后潜在的分子机制。在这里，我们发现升高的 sestrin2 是神经元中针对衣霉素 (TM) 或创伤性入侵引起的化学 ER 应激的保护过程，而用 PERK 抑制剂治疗或 ATF4 的敲低会降低 estrin2 在 ER 应激时的表达。此外，我们证明了sestrin2的过表达限制了ER应激，促进神经元存活并改善 SCI 后的功能恢复，这与 sestrin2 介导的自噬激活和自噬通量的恢复有关。此外，我们还发现 sestrin2 激活依赖于 AMPK-mTOR 信号通路的自噬。一致地，AMPK的抑制消除了sestrin2对自噬激活的影响，而自噬通量的阻断消除了sestrin2对限制ER应激和神经死亡的影响。总之，我们的数据表明，sestrin2 的上调是神经元对 ER 应激的重要抵抗机制，也是 sestrin2 作为 SCI 治疗靶点的潜在作用。我们还发现 sestrin2 激活依赖于 AMPK-mTOR 信号通路的自噬。一致地，AMPK的抑制消除了sestrin2对自噬激活的影响，而自噬通量的阻断消除了sestrin2对限制ER应激和神经死亡的影响。总之，我们的数据表明，sestrin2 的上调是神经元对 ER 应激的重要抵抗机制，也是 sestrin2 作为 SCI 治疗靶点的潜在作用。我们还发现 sestrin2 激活依赖于 AMPK-mTOR 信号通路的自噬。一致地，AMPK的抑制消除了sestrin2对自噬激活的影响，而自噬通量的阻断消除了sestrin2对限制ER应激和神经死亡的影响。总之，我们的数据表明，sestrin2 的上调是神经元对 ER 应激的重要抵抗机制，也是 sestrin2 作为 SCI 治疗靶点的潜在作用。

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