The eIF2α kinases: their structures and functions

Abstract

Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2). Phosphorylation of eIF2α 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 eIF2α 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 eIF2α kinases in their kinase domains, underlying their common role in phosphorylating eIF2α, additional unique features determine the regulation of these four proteins, that is, what signals activate them. This review will describe the structure of each eIF2α kinase and discuss how this is linked to their activation and function. In parallel to the general translational attenuation elicited by eIF2α 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.

mRNP granules

“…106,107 Broad translational control mechanisms that likely act upon most mRNAs include phosphorylation of the initiation factor eIF2a by various stress-responsive kinases, 109 which limits levels of ternary complex, and thus, translation initiation rates. This event facilitates assembly of stress granules under most (but not all) circumstances.…”

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

“…A group of these mechanisms, collectively referred to as the integrated stress response (ISR), share as a common, pivotal element the phosphorylation of the elongation initiation factor 2α (eIF2α) [67,68]. The translation of Atf4 mRNA is controlled by eIF2α phosphorylation, and it is the central component of the ISR and the related unfolded protein response (UPR).…”

“…eIF2α phosphorylation shifts the cell's translation to genes with roles in stress responses thereby reducing the pressure on protein synthesis, folding, and secretion, and conserving limited resources, such as amino acids. Mammals have four different eIF2α kinases that are activated in response to distinct stress situations [68]: protein kinase doubled-stranded RNA-dependent (PKR) is activated in response to endoplasmic reticulum (ER) stress, viral infections, cytokines, and growth factors; PKR-like ER kinase (PERK) is mainly activated in response to accumulation of misfolded proteins in the ER; general control nonderepressible-2 (GCN2) is primarily activated in response to amino acid deprivation; and heme-regulated inhibitor (HRI) is a sensor in erythrocytes for heme and iron levels. The activation of any of the four kinases results in eIF2α phosphorylation, but whether the effect is ultimately pro-or antiapoptotic is heavily dependent on the nature, duration, and level of the stress signal.…”

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

“…eIF2 est phosphorylée sur la sérine 51 par une kinase, qui diffère selon le type de stress. Ces kinases sont au nombre de quatre [16,17] : la protéine kinase R (PKR) intervient lors d'infections virales, la kinase PERK (PKR-like endoplasmic reticulum kinase) lors d'un stress De plus, l'anémie causée par une déficience en fer pourrait être aggravée par la déplétion en HRI via une apoptose accrue des précurseurs érythrocytaires [20,22]. La perte de HRI a également des conséquences délétères dans d'autres modèles murins d'ané-mie, comme dans la protoporphyrie érythropoïétique, causée par une mutation d'une enzyme de la synthèse de l'hème.…”

“…De plus, la phosphorylation d'eIF2 est connue, soit pour activer des signaux pro-apoptotiques (activation de la voie de mort cellulaire ATF4-CHOP [14,47], induction de l'expression du récepteur Fas de mort cellulaire [48]), soit pour empêcher la traduction de protéines de survie telles Bcl-x, inhibant ainsi les voies anti-apoptotiques et favorisant la mort cellulaire [16]. Ce rôle pro-apoptotique de la phosphorylation d'eIF2α suppose que son induction par les kinases eIF2α puisse contrer le développement tumoral en induisant la mort des cellules cancéreuses.…”