Accumulation of misfolded proteins in endoplasmic reticulum (ER) generates a stress condition in the cell. The cell combats ER stress by activating unfolded protein response (UPR) and ERAD (ER stress-associated degradation) pathway. Failure to restore favorable folding environment results in cell dysfunction and apoptosis. Various neurodegenerative disorders are characterized by the accumulation of misfolded protein, protein aggregates, and ER stress. GNE myopathy (GNEM) is a neuromuscular disorder pathologically characterized by rimmed vacuole formation due to the accumulation of protein aggregates. More than 200 mutations in key sialic acid biosynthetic enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) have been identified worldwide in the muscle biopsies of GNE myopathy patients. However, the cellular and molecular pathomechanism leading to the disease ar poorly understood. In the present study, the phenomenon of ER stress has been elucidated in GNE mutant cells overexpressing GNE mutations of Indian origin. The effect of GNE mutations on activation of UPR signaling via inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE-1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6) were deciphered to understand the effect of GNE mutations on these proteins. GRP78 was upregulated with increased X-box-binding protein-1 (XBP-1) splicing and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) upregulation leading to increased apoptosis of GNE mutant cells. Insulin-like growth factor 1 (IGF-1) ligand rescued the cells from apoptotic phenotype by supporting cell survival mechanism. Our study indicates a balance of cell death and survival that decides cell fate and offers potential therapeutic targets to combat ER stress in diseases associated with dysfunctional UPR pathway.

中文翻译：

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唾液酸缺陷细胞中 ER 应激和 UPR 通路的阐明：与 GNEM 的病理相关性

内质网 (ER) 中错误折叠蛋白的积累会在细胞中产生应激状态。细胞通过激活未折叠蛋白反应 (UPR) 和 ERAD（ER 应激相关降解）途径来对抗 ER 应激。未能恢复有利的折叠环境会导致细胞功能障碍和凋亡。各种神经退行性疾病的特征是错误折叠的蛋白质、蛋白质聚集体和 ER 应激的积累。GNE 肌病 (GNEM) 是一种神经肌肉疾病，其病理特征是由于蛋白质聚集体的积累而形成边缘空泡。唾液酸生物合成关键酶 UDP- N-乙酰氨基葡萄糖 2-差向异构酶/ N的 200 多个突变-乙酰甘露糖胺激酶 (GNE) 已在全球范围内对 GNE 肌病患者的肌肉活检进行鉴定。然而，导致该疾病的细胞和分子病理机制知之甚少。在本研究中，ER 应激现象已在过表达印度血统 GNE 突变的 GNE 突变细胞中得到阐明。GNE 突变对通过肌醇需要的跨膜激酶/核糖核酸内切酶 1 (IRE-1)、蛋白激酶 RNA 样内质网激酶 (PERK) 和激活转录因子-6 (ATF6) 激活 UPR 信号传导的影响被破译以了解GNE 突变对这些蛋白质的影响。GRP78 随着 X-box 结合蛋白-1 (XBP-1) 剪接增加和 CCAAT/增强子结合蛋白 (C/EBP) 同源蛋白 (CHOP) 上调而上调，导致 GNE 突变细胞凋亡增加。胰岛素样生长因子 1 (IGF-1) 配体通过支持细胞存活机制将细胞从凋亡表型中拯救出来。我们的研究表明细胞死亡和存活的平衡决定了细胞的命运，并提供了潜在的治疗靶点来对抗与功能失调的 UPR 通路相关的疾病中的 ER 应激。