EIF2S1

EIF2S1 Background

Eukaryotic translation initiation factor 2 subunit 1, a protein in humans encoded by EIF2S1 ^[1], is the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2). So it is also known as eukaryotic translation initiation factor 2 subunit alpha (eIF2α). Four eIF2α kinases, including protein kinase R (PKR)RNA-dependent protein kinase (PKR), (PKR)-like endoplasmic reticulum kinase (PERK), general control non-derepressible 2 kinase (GCN2), and heme-regulated eIF2α kinase (HRI), can phosphorylate eIF2α on Ser 51, which leads to the inhibition of eIF2α and consequent transient suppression of general protein synthesis, up to its complete blockade, concomitant with the translation of mRNAs that encode for antiviral factors and/or mediate the integrated stress response ^[2]. Such blockade of protein synthesis results in the decrease or prevention of viral replication and may result in apoptosis ^[3]. Consistently, Sri P. Srivastava et al. also identified a novel requirement for PKR in stress-induced apoptosis that is mediated through eIF-2α phosphorylation ^[4]. These four eIF2α kinases share a homologous kinase domain (KD) but possess different regulatory domains that mediate their activation by diverse stress signals, respectively ^[5]. Previous studies suggested that the induction of eIF2α phosphorylation can be either cytoprotective or proapoptotic. The cytoprotective function of transient induction of eIF2α phosphorylation predominantly by activating pathways that promote cell survival such as the phosphatidylinositol-3 kinase (PI3K) ^[6] and nuclear factor-κB (NF-κB) pathways ^[7][8]. Nevertheless, prolonged induction of eIF2α phosphorylation is mainly proapoptotic ^[8][9].

[1] Ernst H, Duncan RF, et al. Cloning and sequencing of complementary DNAs encoding the alpha-subunit of translational initiation factor eIF-2. Characterization of the protein and its messenger RNA [J]. J Biol Chem. 1987, 262 (3): 1206–12.
[2] Hoang, H., Graber, T. E., et al. Battling for ribosomes: translational control at the forefront of the antiviral response [J]. J. Mol. Biol. 2018, 430, 1965–1992.
[3] García, M. A., Meurs, E. F., et al. The dsRNA protein kinase PKR: virus and cell control [J]. Biochimie 2007, 89, 799–811.
[4] Sri P. Srivastava, Kotlo U. Kumar, et al. Phosphorylation of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis in Response to Activation of the Double-stranded RNA-dependent Protein Kinase [J]. The Journal of Biological Chemistry, 1998, 273, 2416-2423.
[5] Wek RC, Jiang HY, et al. Coping with stress: eIF2 kinases and translational control [J]. Biochem Soc Trans. 2006 Feb; 34(Pt 1):7-11.
[6] Kazemi S, Mounir Z, et al. A novel function of eIF2alpha kinases as inducers of the phosphoinositide-3 kinase signaling pathway [J]. Mol Biol Cell. 2007 Sep; 18(9):3635-44.
[7] Deng J, Lu PD, et al. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2 [J]. Mol Cell Biol. 2004 Dec; 24(23):10161-8.
[8] Donzé O, Deng J, et al. The protein kinase PKR: a molecular clock that sequentially activates survival and death programs [J]. EMBO J. 2004 Feb 11; 23(3):564-71.
[9] Kazemi S, Papadopoulou S, et al. Control of alpha subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) phosphorylation by the human papillomavirus type 18 E6 oncoprotein: implications for eIF2 alpha-dependent gene expression and cell death [J]. Mol Cell Biol. 2004 Apr; 24(8):3415-29.