Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS Biol. 2021 Mar 11;19(3):e3001096. doi: 10.1371/journal.pbio.3001096. eCollection 2021 Mar.
The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). Here we report the identification of a direct kinase of eIF2α, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2α in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2α kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKCδ), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKCδ are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKCδ-MARK2-eIF2α cascade that may play a critical role in cellular proteotoxic stress responses and human diseases.
蛋白质合成的调控对于维持细胞内环境稳定至关重要，特别是在应激反应期间，其失调可能是人类疾病发展的基础。在翻译调控的关键步骤是真核起始因子 2α（eIF2α）的磷酸化。在这里，我们报告了一种 eIF2α 的直接激酶，微管亲和调节激酶 2（MARK2）的鉴定，该激酶在应对蛋白毒性应激时磷酸化 eIF2α。在缺乏先前已知的 4 种 eIF2α 激酶的细胞中，证实了 MARK2 的活性。MARK2 本身是蛋白激酶 C 三角洲（PKCδ）的底物，PKCδ 通过与热休克蛋白 90（HSP90）的动态相互作用，作为蛋白质错误折叠应激的传感器。MARK2 和 PKCδ 在与蛋白毒性相关的神经退行性小鼠模型和肌萎缩侧索硬化症（ALS）的人类患者中均通过磷酸化激活。这些结果揭示了一个 PKCδ-MARK2-eIF2α 级联反应，它可能在细胞蛋白毒性应激反应和人类疾病中发挥关键作用。
