The eIF2alpha kinases: their structures and functions.
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Donnelly N, Gorman AM, Gupta S, Samali A
The eIF2alpha kinases: their structures and functions.
Cell Mol Life Sci. 2013 Oct;70(19):3493-511. doi: 10.1007/s00018-012-1252-6. Epub 2013 Jan 26.
- PubMed ID
- 23354059 [ View in PubMed]
- Abstract
Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2alpha on serine 51 results in a severe decline in de novo protein synthesis and is an important strategy in the cell's armory against stressful insults including viral infection, the accumulation of misfolded proteins, and starvation. The phosphorylation of eIF2alpha is carried out by a family of four kinases, PERK (PKR-like ER kinase), PKR (protein kinase double-stranded RNA-dependent), GCN2 (general control non-derepressible-2), and HRI (heme-regulated inhibitor). Each primarily responds to a distinct type of stress or stresses. Thus, while significant sequence similarity exists between the eIF2alpha kinases in their kinase domains, underlying their common role in phosphorylating eIF2alpha, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2alpha kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2alpha kinase activation the translation of stress-induced mRNAs, most notably activating transcription factor 4 (ATF4) is enhanced and these set in motion cascades of gene expression constituting the integrated stress response (ISR), which seek to remediate stress and restore homeostasis. Depending on the cellular context and concurrent signaling pathways active, however, translational attenuation can also facilitate apoptosis. Accordingly, the role of the kinases in determining cell fate will also be discussed.