Department of Arthroplasty, The First People's Hospital of Wenling, The Affiliated Wenling Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317500, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju, South Korea.
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
Exp Neurol. 2023 Oct;368:114495. doi: 10.1016/j.expneurol.2023.114495. Epub 2023 Jul 24.
Endoplasmic reticulum (ER) stress-induced apoptosis and autophagy flux blockade significantly contribute to neuronal pathology of spinal cord injury (SCI). Yet, the molecular interplay between these two distinctive pathways in mediating the pathology of SCI remains largely unexplored. Currently, we aimed at exploring the crucial role of Stub1 in maintaining ER homeostasis and regulating autophagic flux after SCI. Our results demonstrate that Stub1 reduces ER stress induced neuronal apoptosis, promotes axonal regeneration, inhibits glial scar formation and fosters functional recovery by restoring autophagic flux following SCI. Stub1 enhances autophagic flux following SCI by alleviating the permeabilization of lysosomal membrane through activating TFEB. Importantly, we showed that Stub1 promotes the activation of TFEB by targeting HDAC2 for ubiquitination and degradation. Furthermore, the neuroprotective effect of Stub1 on SCI was abrogated by chloroquine administration, underscoring the essential role of Stub1-mediated enhancement of autophagic flux in its protective effects against SCI. Collectively, our data highlights the vital role of Stub1 in regulating ER stress and autophagy flux after SCI, and propose its potential as a promising target for neuroprotective interventions in SCI.
内质网（ER）应激诱导的细胞凋亡和自噬流阻断显著促进脊髓损伤（SCI）的神经元病理学。然而，这两种不同途径在介导 SCI 病理学中的分子相互作用在很大程度上仍未得到探索。目前，我们旨在探索 Stub1 在维持 ER 稳态和调节 SCI 后自噬流中的关键作用。我们的结果表明，Stub1 通过恢复 SCI 后的自噬流来减少 ER 应激诱导的神经元凋亡、促进轴突再生、抑制神经胶质瘢痕形成并促进功能恢复。Stub1 通过激活 TFEB 减轻溶酶体膜的通透性来增加 SCI 后的自噬流。重要的是，我们表明 Stub1 通过靶向 HDAC2 进行泛素化和降解来促进 TFEB 的激活。此外，氯喹给药削弱了 Stub1 对 SCI 的神经保护作用，突出了 Stub1 介导的自噬流增强在其对 SCI 的保护作用中的重要作用。总之，我们的数据强调了 Stub1 在调节 SCI 后 ER 应激和自噬流中的重要作用，并提出了将其作为 SCI 神经保护干预的有前途的靶点的可能性。
