Wu Kefan, Chen Lili, Qiu Zhen, Zhao Bo, Hou Jiabao, Lei Shaoqin, Jiang Meng, Xia Zhongyuan
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan 430064, China.
Biomedicines. 2023 Apr 24;11(5):1259. doi: 10.3390/biomedicines11051259.
(1) SAH induces cellular stress and endoplasmic reticulum stress, activating the unfolded protein response (UPR) in nerve cells. IRE1 (inositol-requiring enzyme 1) is a protein that plays a critical role in cellular stress response. Its final product, Xbp1s, is essential for adapting to changes in the external environment. This process helps maintain proper cellular function in response to various stressors. O-GlcNAcylation, a means of protein modification, has been found to be involved in SAH pathophysiology. SAH can increase the acute O-GlcNAcylation level of nerve cells, which enhances the stress capacity of nerve cells. The GFAT1 enzyme regulates the level of O-GlcNAc modification in cells, which could be a potential target for neuroprotection in SAH. Investigating the IRE1/XBP1s/GFAT1 axis could offer a promising avenue for future research. (2) Methods: SAH was induced using a suture to perforate an artery in mice. HT22 cells with Xbp1 loss- and gain-of-function in neurons were generated. Thiamet-G was used to increase O-GlcNAcylation; (3) Results: Severe neuroinflammation caused by subarachnoid hemorrhage leads to extensive endoplasmic reticulum stress of nerve cells. Xbp1s, the final product of unfolded proteins induced by endoplasmic reticulum stress, can induce the expression of the hexosamine pathway rate limiting enzyme GFAT1, increase the level of O-GlcNAc modification of cells, and have a protective effect on neural cells; (4) Conclusions: The correlation between Xbp1s displayed by immunohistochemistry and O-GlcNAc modification suggests that the IRE1/XBP1 branch of unfolded protein reaction plays a key role in subarachnoid hemorrhage. IRE1/XBP1 branch is a new idea to regulate protein glycosylation modification, and provides a promising strategy for clinical perioperative prevention and treatment of subarachnoid hemorrhage.
(1) 蛛网膜下腔出血（SAH）会引发细胞应激和内质网应激，从而激活神经细胞中的未折叠蛋白反应（UPR）。肌醇需求酶1（IRE1）是一种在细胞应激反应中起关键作用的蛋白质。其最终产物Xbp1s对于适应外部环境变化至关重要。这一过程有助于维持细胞在应对各种应激源时的正常功能。O-连接N-乙酰葡糖胺化（O-GlcNAcylation）作为一种蛋白质修饰方式，已被发现参与SAH的病理生理过程。SAH可增加神经细胞的急性O-GlcNAcylation水平，进而增强神经细胞的应激能力。谷氨酰胺：果糖-6-磷酸氨基转移酶1（GFAT1）酶调节细胞中O-GlcNAc修饰水平，这可能是SAH神经保护的一个潜在靶点。研究IRE1/XBP1s/GFAT1轴可能为未来研究提供一条有前景的途径。(2) 方法：通过用缝线穿刺小鼠动脉诱导SAH。构建神经元中Xbp1功能缺失和功能获得的HT22细胞。使用噻美司特-G增加O-GlcNAcylation；(3) 结果：蛛网膜下腔出血引起的严重神经炎症导致神经细胞广泛的内质网应激。内质网应激诱导的未折叠蛋白的最终产物Xbp1s可诱导己糖胺途径限速酶GFAT1的表达，增加细胞的O-GlcNAc修饰水平，并对神经细胞具有保护作用；(4) 结论：免疫组织化学显示的Xbp1s与O-GlcNAc修饰之间的相关性表明，未折叠蛋白反应的IRE1/XBP1分支在蛛网膜下腔出血中起关键作用。IRE1/XBP1分支是调节蛋白质糖基化修饰的新思路，为蛛网膜下腔出血的临床围手术期防治提供了有前景的策略。
