| First Author | Lu YN | Year | 2021 |
| Journal | PLoS Biol | Volume | 19 |
| Issue | 3 | Pages | e3001096 |
| PubMed ID | 33705388 | Mgi Jnum | J:304551 |
| Mgi Id | MGI:6513021 | Doi | 10.1371/journal.pbio.3001096 |
| Citation | Lu YN, et al. (2021) MARK2 phosphorylates eIF2alpha in response to proteotoxic stress. PLoS Biol 19(3):e3001096 |
| abstractText | 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 (eIF2alpha). Here we report the identification of a direct kinase of eIF2alpha, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2alpha in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2alpha kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKCdelta), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKCdelta are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKCdelta-MARK2-eIF2alpha cascade that may play a critical role in cellular proteotoxic stress responses and human diseases. |
