Proteostasis is essential for cellular survival and particularly important for highly specialised post-mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK-deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Haem-regulated inhibitor (HRI) mediates p-eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back-up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress.

中文翻译：

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神经元特异性翻译控制转变确保 ER 应激期间的蛋白质弹性恢复

蛋白质稳态对于细胞存活至关重要，对于高度特化的有丝分裂后细胞（如神经元）尤其重要。蛋白激酶 R 样内质网 (ER) 激酶 (PERK) 介导的真核翻译起始因子 2α (p-eIF2α) 磷酸化导致蛋白质合成的瞬时减少是 ER 应激期间的主要蛋白质抑制生存反应。矛盾的是，神经元对 PERK 功能障碍具有显着的耐受性，这表明存在细胞类型特异性机制来确保蛋白质稳态压力恢复。在这里，我们证明了 PERK 缺陷神经元与其他细胞类型不同，完全保留了在 E​​R 应激期间控制翻译的能力。我们观察到 ATF4 反应的重新调整，而蛋白质合成的减少被完全保留。我们确定了两种共同驱动 PERK 缺陷神经元的翻译控制的分子途径。血红素调节抑制剂 (HRI) 介导 p-eIF2α 和 ATF4 反应，并辅以 tRNA 切割 RNase 血管生成素 (ANG) 以减少蛋白质合成。总体而言，我们的研究阐明了一种复杂的备份机制，以确定神经元 ER 应激期间的平移控制，这为迄今为止尚未解决的神经元对蛋白质静止应激的恢复力的观察提供了机械解释。