Open AccessMARK2 phosphorylates eIF2α in response to proteotoxic stress
Author(s) -
Yu Ning Lu,
Sarah Kavianpour,
Tao Zhang,
Xumei Zhang,
Dao K.H. Nguyen,
Ravi Thombre,
Lǚ Hé,
Jiou Wang
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001096
Subject(s) - proteotoxicity , biology , microbiology and biotechnology , integrated stress response , phosphorylation , kinase , hsf1 , eif2 , proteostasis , protein kinase c , unfolded protein response , protein kinase a , signal transduction , translation (biology) , heat shock protein , hsp70 , protein aggregation , biochemistry , endoplasmic reticulum , messenger rna , gene
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.