MARK2 phosphorylates eIF2? in response to proteotoxic stress.
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 (eIF2?). Here we report the identification of a direct kinase ... of eIF2?, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2? in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2? kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKC?), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKC? are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKC?-MARK2-eIF2? cascade that may play a critical role in cellular proteotoxic stress responses and human diseases.
Mesh Terms:
Animals, Cell Line, Disease Models, Animal, Endoplasmic Reticulum, Eukaryotic Initiation Factor-2, HSP90 Heat-Shock Proteins, Homeostasis, Humans, Mice, Mice, Knockout, Microtubules, Phosphorylation, Protein Biosynthesis, Protein Serine-Threonine Kinases, Stress, Physiological, eIF-2 Kinase
Animals, Cell Line, Disease Models, Animal, Endoplasmic Reticulum, Eukaryotic Initiation Factor-2, HSP90 Heat-Shock Proteins, Homeostasis, Humans, Mice, Mice, Knockout, Microtubules, Phosphorylation, Protein Biosynthesis, Protein Serine-Threonine Kinases, Stress, Physiological, eIF-2 Kinase
PLoS Biol
Date: Dec. 01, 2020
PubMed ID: 33705388
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