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Gene Review

Eif2s1  -  eukaryotic translation initiation factor 2...

Mus musculus

Synonyms: 0910001O23Rik, 2410026C18Rik, 35kDa, Eif2a, Eukaryotic translation initiation factor 2 subunit 1, ...
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Disease relevance of Eif2s1


High impact information on Eif2s1

  • To understand the basis for substrate recognition by and the regulation of PKR, we determined X-ray crystal structures of the catalytic domain of PKR in complex with eIF2alpha [5].
  • Accumulation of unfolded proteins in the ER activates phosphorylation of eIF2alpha at Ser51 and inhibits translation [6].
  • Here we show that regulation of mRNA translation through phosphorylation of eukaryotic initiation factor 2 (eIF2alpha) is essential to preserve the integrity of the endoplasmic reticulum (ER) and to increase insulin production to meet the demand imposed by a high-fat diet [6].
  • Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER) [7].
  • ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein [7].

Chemical compound and disease context of Eif2s1


Biological context of Eif2s1

  • Together, these studies suggest that eIF2alpha kinases monitor and are activated by a range of stress conditions that affect transcription and protein synthesis and assembly, and the resulting eIFalpha phosphorylation is central to activation of the NF-kappaB [11].
  • The absence of NF-kappaB-mediated transcription and its antiapoptotic function provides an explanation for why eIF2alpha kinase deficiency in diseases such as Wolcott-Rallison syndrome leads to cellular apoptosis and disease [11].
  • Translational control directed by the eukaryotic translation initiation factor 2 alpha-subunit (eIF2alpha) kinase GCN2 is important for coordinating gene expression programs in response to nutritional deprivation [12].
  • Examination of ATF4-/- MEFs revealed an absence of GADD34 induction, prolonged eIF-2 alpha phosphorylation, delayed protein synthesis recovery, and diminished translational up-regulation of BiP during ER stress [13].
  • We show that activating transcription factor-4 (ATF4), which is paradoxically translated during the eIF-2 alpha-mediated translational block, is required for the transactivation of the GADD34 promoter in response to ER stress and amino acid deprivation [13].

Anatomical context of Eif2s1

  • Endoplasmic reticulum (ER) stress is not effectively induced in MEF cells subjected to proteasome inhibition, with minimal activation of the ER stress sensory proteins, eIF2alpha kinase PEK (PERK/EIF2AK3), IRE1 protein kinase and the transcription regulator ATF6 following up to 6 h of proteasome inhibitor treatment [14].
  • Phosphorylation of eIF2alpha in mouse embryo fibroblast (MEF) cells subjected to proteasome inhibition leads to a significant reduction in protein synthesis, concomitant with induced expression of the bZIP transcription regulator, ATF4, and its target gene CHOP/GADD153 [14].
  • In eukaryotic cells, protein synthesis is regulated in response to various environmental stresses by phosphorylating the alpha subunit of the eukaryotic initiation factor 2 (eIF2alpha) [15].
  • Among many differentially expressed genes, eIF2alpha kinase, a heme regulated inhibitor was down-regulated in ovarian epithelium cancer [16].
  • Our data demonstrate that the interaction of CUGBP1 with the eIF2alpha enhances the association of CUGBP1 with ribosomes and correlates with increased translation of LIP in the liver after partial hepatectomy [17].

Associations of Eif2s1 with chemical compounds

  • Furthermore, inhibition of general translation or transcription by cycloheximide and actinomycin D, respectively, elicits the eIF2alpha phosphorylation required for induction of NF-kappaB [11].
  • GADD34 was recently identified as the factor that activates the type 1 protein serine/threonine phosphatase (PP1), which dephosphorylates eIF-2 alpha during cellular stresses [13].
  • Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2alpha by GCN2 under leucine starvation conditions, abolishing expression of its downstream target genes, ATF4 (CREB-2) and CHOP (GADD153) [12].
  • The results demonstrate that regulation of translation through eIF2alpha phosphorylation is essential for the ER stress response and in vivo glucose homeostasis [1].
  • 2-Aminopurine (2-AP), an inhibitor of eIF2alpha kinases, could overcome the apoptotic effect of AICAR, abolishing the reduction of PPARgamma and C/EBPalpha and the lipolytic properties of AMPK [18].
  • Consistent with these findings, long term activation of the phospho-eIF2alpha/ATF4/xCT signaling module by the specific eIF2alpha phosphatase inhibitor, salubrinal, induces resistance against oxidative glutamate toxicity in the hippocampal cell line HT22 and primary cortical neurons [19].

Enzymatic interactions of Eif2s1


Regulatory relationships of Eif2s1

  • The primary eIF2alpha kinase activated by exposure of these fibroblast cells to proteasome inhibition is GCN2 (EIF2AK4), which has a central role in the recognition of cytoplasmic stress signals [14].
  • These studies suggest a direct role for eIF2alpha phosphorylation-dependent translational control in activating NF-kappaB during ER stress [20].
  • Stress-induced activation of GADD34 feeds back negatively on this pathway by promoting eIF2alpha dephosphorylation, however, GADD34 mutant cells retain significant eIF2alpha-directed phosphatase activity [23].
  • Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation [24].
  • Our data indicate that in normal cells, PKR primarily prevents virus replication by inhibiting the translation of viral mRNAs through phosphorylation of eIF2alpha, while concomitantly assisting in the production of autocrine IFN and the establishment of an antiviral state [25].

Other interactions of Eif2s1


Analytical, diagnostic and therapeutic context of Eif2s1


  1. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Scheuner, D., Song, B., McEwen, E., Liu, C., Laybutt, R., Gillespie, P., Saunders, T., Bonner-Weir, S., Kaufman, R.J. Mol. Cell (2001) [Pubmed]
  2. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. Novoa, I., Zeng, H., Harding, H.P., Ron, D. J. Cell Biol. (2001) [Pubmed]
  3. Importance of eIF2alpha phosphorylation and stress granule assembly in alphavirus translation regulation. McInerney, G.M., Kedersha, N.L., Kaufman, R.J., Anderson, P., Liljeström, P. Mol. Biol. Cell (2005) [Pubmed]
  4. PERK is responsible for the increased phosphorylation of eIF2alpha and the severe inhibition of protein synthesis after transient global brain ischemia. Owen, C.R., Kumar, R., Zhang, P., McGrath, B.C., Cavener, D.R., Krause, G.S. J. Neurochem. (2005) [Pubmed]
  5. Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR. Dar, A.C., Dever, T.E., Sicheri, F. Cell (2005) [Pubmed]
  6. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Scheuner, D., Mierde, D.V., Song, B., Flamez, D., Creemers, J.W., Tsukamoto, K., Ribick, M., Schuit, F.C., Kaufman, R.J. Nat. Med. (2005) [Pubmed]
  7. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Harding, H.P., Zhang, Y., Ron, D. Nature (1999) [Pubmed]
  8. Phosphorylation of the alpha subunit of translation initiation factor-2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus. Carnevalli, L.S., Pereira, C.M., Jaqueta, C.B., Alves, V.S., Paiva, V.N., Vattem, K.M., Wek, R.C., Mello, L.E., Castilho, B.A. Biochem. J. (2006) [Pubmed]
  9. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Marciniak, S.J., Yun, C.Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H.P., Ron, D. Genes Dev. (2004) [Pubmed]
  10. Oxidative injury to the endoplasmic reticulum in mouse brains after transient focal ischemia. Hayashi, T., Saito, A., Okuno, S., Ferrand-Drake, M., Dodd, R.L., Chan, P.H. Neurobiol. Dis. (2004) [Pubmed]
  11. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Jiang, H.Y., Wek, S.A., McGrath, B.C., Scheuner, D., Kaufman, R.J., Cavener, D.R., Wek, R.C. Mol. Cell. Biol. (2003) [Pubmed]
  12. IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. Pereira, C.M., Sattlegger, E., Jiang, H.Y., Longo, B.M., Jaqueta, C.B., Hinnebusch, A.G., Wek, R.C., Mello, L.E., Castilho, B.A. J. Biol. Chem. (2005) [Pubmed]
  13. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. Ma, Y., Hendershot, L.M. J. Biol. Chem. (2003) [Pubmed]
  14. Phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) reduces protein synthesis and enhances apoptosis in response to proteasome inhibition. Jiang, H.Y., Wek, R.C. J. Biol. Chem. (2005) [Pubmed]
  15. Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. Berlanga, J.J., Santoyo, J., De Haro, C. Eur. J. Biochem. (1999) [Pubmed]
  16. Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha kinase: down-regulated in epithelial ovarian cancers. Hwang, S.Y., Kim, M.K., Kim, J.C. Mol. Cells (2000) [Pubmed]
  17. RNA CUG-binding protein 1 increases translation of 20-kDa isoform of CCAAT/enhancer-binding protein beta by interacting with the alpha and beta subunits of eukaryotic initiation translation factor 2. Timchenko, N.A., Wang, G.L., Timchenko, L.T. J. Biol. Chem. (2005) [Pubmed]
  18. AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes. Dagon, Y., Avraham, Y., Berry, E.M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  19. Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression. Lewerenz, J., Maher, P. J. Biol. Chem. (2009) [Pubmed]
  20. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Deng, J., Lu, P.D., Zhang, Y., Scheuner, D., Kaufman, R.J., Sonenberg, N., Harding, H.P., Ron, D. Mol. Cell. Biol. (2004) [Pubmed]
  21. A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Sood, R., Porter, A.C., Olsen, D.A., Cavener, D.R., Wek, R.C. Genetics (2000) [Pubmed]
  22. The double-stranded RNA-activated protein kinase PKR is dispensable for regulation of translation initiation in response to either calcium mobilization from the endoplasmic reticulum or essential amino acid starvation. Kimball, S.R., Clemens, M.J., Tilleray, V.J., Wek, R.C., Horetsky, R.L., Jefferson, L.S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  23. Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. Jousse, C., Oyadomari, S., Novoa, I., Lu, P., Zhang, Y., Harding, H.P., Ron, D. J. Cell Biol. (2003) [Pubmed]
  24. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Harding, H.P., Zhang, Y., Zeng, H., Novoa, I., Lu, P.D., Calfon, M., Sadri, N., Yun, C., Popko, B., Paules, R., Stojdl, D.F., Bell, J.C., Hettmann, T., Leiden, J.M., Ron, D. Mol. Cell (2003) [Pubmed]
  25. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Balachandran, S., Roberts, P.C., Brown, L.E., Truong, H., Pattnaik, A.K., Archer, D.R., Barber, G.N. Immunity (2000) [Pubmed]
  26. Double-stranded RNA-dependent protein kinase phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 mediates apoptosis. Scheuner, D., Patel, R., Wang, F., Lee, K., Kumar, K., Wu, J., Nilsson, A., Karin, M., Kaufman, R.J. J. Biol. Chem. (2006) [Pubmed]
  27. Changes in the phosphorylation of initiation factor eIF-2alpha, elongation factor eEF-2 and p70 S6 kinase after transient focal cerebral ischaemia in mice. Althausen, S., Mengesdorf, T., Mies, G., Oláh, L., Nairn, A.C., Proud, C.G., Paschen, W. J. Neurochem. (2001) [Pubmed]
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