Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Nucleic Acids Res. 2020 Nov 4;48(19):10648-10661. doi: 10.1093/nar/gkaa757.
Cells rely on stress response pathways to uphold cellular homeostasis and limit the negative effects of harmful environmental stimuli. The stress- and mitogen-activated protein (MAP) kinases, p38 and JNK, are at the nexus of numerous stress responses, among these the ribotoxic stress response (RSR). Ribosomal impairment is detrimental to cell function as it disrupts protein synthesis, increase inflammatory signaling and, if unresolved, lead to cell death. In this review, we offer a general overview of the three main translation surveillance pathways; the RSR, Ribosome-associated Quality Control (RQC) and the Integrated Stress Response (ISR). We highlight recent advances made in defining activation mechanisms for these pathways and discuss their commonalities and differences. Finally, we reflect on the physiological role of the RSR and consider the therapeutic potential of targeting the sensing kinase ZAKα for treatment of ribotoxin exposure.
细胞依赖于应激反应途径来维持细胞内稳态并限制有害环境刺激的负面影响。应激和有丝分裂原激活蛋白（MAP）激酶 p38 和 JNK 处于许多应激反应的交汇点，其中包括核糖体毒性应激反应（RSR）。核糖体损伤对细胞功能有害，因为它会破坏蛋白质合成，增加炎症信号，如果得不到解决，会导致细胞死亡。在这篇综述中，我们提供了三种主要的翻译监测途径的概述：RSR、核糖体相关质量控制（RQC）和整体应激反应（ISR）。我们强调了最近在定义这些途径的激活机制方面取得的进展，并讨论了它们的共同点和差异。最后，我们反思了 RSR 的生理作用，并考虑了针对感应激酶 ZAKα 进行靶向治疗以治疗核糖体毒素暴露的治疗潜力。
