EIF2S1 explained

EIF2S1 should not be confused with EIF2A.

Eukaryotic translation initiation factor 2 subunit 1 (eIF2α) is a protein that in humans is encoded by the EIF2S1 gene.^{[1] [2]}

Function

The protein encoded by this gene is the alpha (α) subunit of the translation initiation factor eIF2 protein complex which catalyzes an early regulated step of protein synthesis initiation, promoting the binding of the initiator tRNA (Met-tRNA_i^Met) to 40S ribosomal subunits. Binding occurs as a ternary complex of methionyl-tRNA, eIF2, and GTP. eIF2 is composed of 3 nonidentical subunits, alpha (α, 36 kD, this article), beta (β, 38 kD), and gamma (γ, 52 kD). The rate of formation of the ternary complex is modulated by the phosphorylation state of eIF2α.^[2] Phosphorylation of eIF2α by EIF-2 kinases plays a key role in regulating the integrated stress response.^[3]

Clinical significance

After reperfusion following brain ischemia, there is inhibition of neuron protein synthesis due to phosphorylation of eIF2α. There is colocalization between phosphorylated eIF2α and cytosolic cytochrome c, which is released from mitochondria in apoptosis. Phosphorylated Eif2-alpha appeared before cytochrome c release, suggesting that phosphorylation of eIF2α triggers cytochrome c release during apoptotic cell death.^[4]

Mice heterozygous for the S51A mutation become obese and diabetic on a high-fat diet. Glucose intolerance resulted from reduced insulin secretion, defective transport of proinsulin, and a reduced number of insulin granules in beta cells. Hence proper functioning of eIF2α appears essential for preventing diet-induced type II diabetes.^[5]

Dephosphorylation inhibitors

Salubrinal is a selective inhibitor of enzymes that dephosphorylate eIF2α.^[6] Salubrinal also blocks eIF2α dephosphorylation by a herpes simplex virus protein and inhibits viral replication. eIF2α phosphorylation is cytoprotective during endoplasmic reticulum stress.^{[7] [8]}

See also

• eIF2

References

Further reading

• Hershey JW . Translational control in mammalian cells . Annual Review of Biochemistry . 60 . 717–55 . 1991 . 1883206 . 10.1146/annurev.bi.60.070191.003441 .
• Mao X, Green JM, Safer B, Lindsten T, Frederickson RM, Miyamoto S, Sonenberg N, Thompson CB . 6 . Regulation of translation initiation factor gene expression during human T cell activation . The Journal of Biological Chemistry . 267 . 28 . 20444–50 . October 1992 . 10.1016/S0021-9258(19)88722-7 . 1400363 . free .
• Mellor H, Proud CG . A synthetic peptide substrate for initiation factor-2 kinases . Biochemical and Biophysical Research Communications . 178 . 2 . 430–7 . July 1991 . 1677563 . 10.1016/0006-291X(91)90125-Q .
• Green SR, Spalding A, Ashford T, Proud CG, Tuite MF . Synthesis of human initiation factor-2 alpha in Saccharomyces cerevisiae . Gene . 108 . 2 . 253–8 . December 1991 . 1748310 . 10.1016/0378-1119(91)90441-D .
• Kramer G . Two phosphorylation sites on eIF-2 alpha . FEBS Letters . 267 . 2 . 181–2 . July 1990 . 2116318 . 10.1016/0014-5793(90)80919-A . 85417664 .
• Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T . 6 . Construction of a human full-length cDNA bank . Gene . 150 . 2 . 243–50 . December 1994 . 7821789 . 10.1016/0378-1119(94)90433-2 .
• Ray MK, Chakraborty A, Datta B, Chattopadhyay A, Saha D, Bose A, Kinzy TG, Wu S, Hileman RE, Merrick WC . 6 . Characteristics of the eukaryotic initiation factor 2 associated 67-kDa polypeptide . Biochemistry . 32 . 19 . 5151–9 . May 1993 . 8098621 . 10.1021/bi00070a026 .
• Dever TE, Chen JJ, Barber GN, Cigan AM, Feng L, Donahue TF, London IM, Katze MG, Hinnebusch AG . 6 . Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast . Proceedings of the National Academy of Sciences of the United States of America . 90 . 10 . 4616–20 . May 1993 . 8099443 . 46563 . 10.1073/pnas.90.10.4616 . free . 1993PNAS...90.4616D .
• Barber GN, Wambach M, Wong ML, Dever TE, Hinnebusch AG, Katze MG . Translational regulation by the interferon-induced double-stranded-RNA-activated 68-kDa protein kinase . Proceedings of the National Academy of Sciences of the United States of America . 90 . 10 . 4621–5 . May 1993 . 8099444 . 46564 . 10.1073/pnas.90.10.4621 . 1993PNAS...90.4621B . free .
• Miyamoto S, Chiorini JA, Urcelay E, Safer B . Regulation of gene expression for translation initiation factor eIF-2 alpha: importance of the 3' untranslated region . The Biochemical Journal . 315 (Pt 3) . 3 . 791–8 . May 1996 . 8645159 . 1217276 . 10.1042/bj3150791 .
• Yang W, Hinnebusch AG . Identification of a regulatory subcomplex in the guanine nucleotide exchange factor eIF2B that mediates inhibition by phosphorylated eIF2 . Molecular and Cellular Biology . 16 . 11 . 6603–16 . November 1996 . 8887689 . 231662 . 10.1128/MCB.16.11.6603 .
• Brand SR, Kobayashi R, Mathews MB . The Tat protein of human immunodeficiency virus type 1 is a substrate and inhibitor of the interferon-induced, virally activated protein kinase, PKR . The Journal of Biological Chemistry . 272 . 13 . 8388–95 . March 1997 . 9079663 . 10.1074/jbc.272.13.8388 . free .
• Ting NS, Kao PN, Chan DW, Lintott LG, Lees-Miller SP . DNA-dependent protein kinase interacts with antigen receptor response element binding proteins NF90 and NF45 . The Journal of Biological Chemistry . 273 . 4 . 2136–45 . January 1998 . 9442054 . 10.1074/jbc.273.4.2136 . free .
• Kimball SR, Heinzinger NK, Horetsky RL, Jefferson LS . Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B . The Journal of Biological Chemistry . 273 . 5 . 3039–44 . January 1998 . 9446619 . 10.1074/jbc.273.5.3039 . free .
• Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC . Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control . Molecular and Cellular Biology . 18 . 12 . 7499–509 . December 1998 . 9819435 . 109330 . 10.1128/MCB.18.12.7499 .
• Satoh S, Hijikata M, Handa H, Shimotohno K . Caspase-mediated cleavage of eukaryotic translation initiation factor subunit 2alpha . The Biochemical Journal . 342 (Pt 1) . 1 . 65–70 . August 1999 . 10432301 . 1220437 . 10.1042/0264-6021:3420065 .
• Berlanga JJ, Santoyo J, De Haro C . Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase . European Journal of Biochemistry . 265 . 2 . 754–62 . October 1999 . 10504407 . 10.1046/j.1432-1327.1999.00780.x . free .
• Lu J, O'Hara EB, Trieselmann BA, Romano PR, Dever TE . The interferon-induced double-stranded RNA-activated protein kinase PKR will phosphorylate serine, threonine, or tyrosine at residue 51 in eukaryotic initiation factor 2alpha . The Journal of Biological Chemistry . 274 . 45 . 32198–203 . November 1999 . 10542257 . 10.1074/jbc.274.45.32198 . free .

Notes and References

1. Ernst H, Duncan RF, Hershey JW . Cloning and sequencing of complementary DNAs encoding the alpha-subunit of translational initiation factor eIF-2. Characterization of the protein and its messenger RNA . The Journal of Biological Chemistry . 262 . 3 . 1206–12 . January 1987 . 10.1016/S0021-9258(19)75772-X . 2948954 . free .
2. Web site: Entrez Gene: EIF2S1 eukaryotic translation initiation factor 2, subunit 1 alpha, 35kDa. 2010-10-05. National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM . The integrated stress response . EMBO Reports . 17 . 10 . 1374–1395 . October 2016 . 27629041 . 5048378 . 10.15252/embr.201642195 .
4. Page AB, Owen CR, Kumar R, Miller JM, Rafols JA, White BC, DeGracia DJ, Krause GS . 6 . Persistent eIF2alpha(P) is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal neurons after 4 hours of reperfusion following 10-minute complete brain ischemia . Acta Neuropathologica . 106 . 1 . 8–16 . July 2003 . 12687390 . 10.1007/s00401-003-0693-2 . 11308634 .
5. Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, Ribick M, Schuit FC, Kaufman RJ . 6 . Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis . Nature Medicine . 11 . 7 . 757–64 . July 2005 . 15980866 . 10.1038/nm1259 . 2785104 .
6. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J . 6 . A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress . Science . 307 . 5711 . 935–9 . February 2005 . 15705855 . 10.1126/science.1101902 . 2005Sci...307..935B . 86257684 .
7. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D . Perk is essential for translational regulation and cell survival during the unfolded protein response . Molecular Cell . 5 . 5 . 897–904 . May 2000 . 10882126 . 10.1016/S1097-2765(00)80330-5 . free .
8. Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S, Kaufman RJ . 6 . Translational control is required for the unfolded protein response and in vivo glucose homeostasis . Molecular Cell . 7 . 6 . 1165–76 . June 2001 . 11430820 . 10.1016/S1097-2765(01)00265-9 . free .