Response of EIF2AK4 (GCN2) to amino acid deficiency

Stable Identifier
R-HSA-9633012
Type
Pathway
Species
Homo sapiens
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EIF2AK4 (GCN2) senses amino acid deficiency by binding uncharged tRNAs near the ribosome and responds by phosphorylating EIF2S1, the alpha subunit of the translation initiation factor EIF2 (inferred from yeast homologs and mouse homologs, reviewed in Chaveroux et al. 2010, Castilho et al. 2014, Gallinetti et al. 2013, Bröer and Bröer 2017, Wek 2018). Phosphorylated EIF2S1 reduces translation of most mRNAs but increases translation of downstream ORFs in mRNAs such as ATF4 that contain upstream ORFs (inferred from mouse homologs in Vattem and Wek 2004, reviewed in Hinnebusch et al. 2016, Sonenberg and Hinnebusch 2009). ATF4, in turn, activates expression of genes involved in responding to amino acid deficiency such as DDIT3 (CHOP), ASNS (asparagine synthetase), CEBPB, and ATF3 (reviewed in Kilberg et al. 2012, Wortel et al. 2017). In mice, EIF2AK4 in the brain may responsible for avoidance of diets lacking essential amino acids (Hao et al. 2005, Maurin et al. 2005, see also Leib and Knight 2015, Gietzen et al. 2016, reviewed in Dever and Hinnebusch 2005).
EIF2AK4 is bound to both the ribosome and GCN1, which is required for activation of EIF2AK4 and may act by shuttling uncharged tRNAs from the A site of the ribosome to EIF2AK4. Upon binding tRNA, EIF2AK4 trans-autophosphorylates. Phosphorylated EIF2AK4 then phosphorylates EIF2S1 on serine-52, the same serine residue phosphorylated by other kinases of the integrated stress response: EIF2AK1 (HRI, activated by heme deficiency and other stresses), EIF2AK2 (PKR, activated by double-stranded RNA), and EIF2AK3 (PERK, activated by unfolded proteins) (reviewed in Hinnebusch 1994, Wek et al. 2006, Donnelly et al. 2013, Pakos-Zebrucka et al. 2016, Wek 2018),

Literature References
PubMed ID Title Journal Year
15774759 Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex

Hao, S, Sharp, JW, Ross-Inta, CM, McDaniel, BJ, Anthony, TG, Wek, RC, Cavener, DR, McGrath, BC, Rudell, JB, Koehnle, TJ, Gietzen, DW

Science 2005
27629041 The integrated stress response

Pakos-Zebrucka, K, Koryga, I, Mnich, K, Ljujic, M, Samali, A, Gorman, AM

EMBO Rep. 2016
26526991 Re-examination of Dietary Amino Acid Sensing Reveals a GCN2-Independent Mechanism

Leib, DE, Knight, ZA

Cell Rep 2015
24732012 Keeping the eIF2 alpha kinase Gcn2 in check

Castilho, BA, Shanmugam, R, Silva, RC, Ramesh, R, Himme, BM, Sattlegger, E

Biochim. Biophys. Acta 2014
23216249 Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR

Gallinetti, J, Harputlugil, E, Mitchell, JR

Biochem. J. 2013
28797581 Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells

Wortel, IMN, van der Meer, LT, Kilberg, MS, van Leeuwen, FN

Trends Endocrinol. Metab. 2017
20188139 Molecular mechanisms involved in the adaptation to amino acid limitation in mammals

Chaveroux, C, Lambert-Langlais, S, Cherasse, Y, Averous, J, Parry, L, Carraro, V, Jousse, C, Maurin, AC, Bruhat, A, Fafournoux, P

Biochimie 2010
16246168 Coping with stress: eIF2 kinases and translational control

Wek, RC, Jiang, HY, Anthony, TG

Biochem. Soc. Trans. 2006
27313038 Translational control by 5'-untranslated regions of eukaryotic mRNAs

Hinnebusch, AG, Ivanov, IP, Sonenberg, N

Science 2016
19239892 Regulation of translation initiation in eukaryotes: mechanisms and biological targets

Sonenberg, N, Hinnebusch, AG

Cell 2009
7711290 The eIF-2 alpha kinases: regulators of protein synthesis in starvation and stress

Hinnebusch, AG

Semin. Cell Biol. 1994
27558824 Measuring the Ability of Mice to Sense Dietary Essential Amino Acid Deficiency: The Importance of Amino Acid Status and Timing

Gietzen, DW, Anthony, TG, Fafournoux, P, Maurin, AC, Koehnle, TJ, Hao, S

Cell Rep 2016
23354059 The eIF2α kinases: their structures and functions

Donnelly, N, Gorman, AM, Gupta, S, Samali, A

Cell. Mol. Life Sci. 2013
28546457 Amino acid homeostasis and signalling in mammalian cells and organisms

Broer, S, Bröer, A

Biochem. J. 2017
22585903 The transcription factor network associated with the amino acid response in mammalian cells

Kilberg, MS, Balasubramanian, M, Fu, L, Shan, J

Adv Nutr 2012
15277680 Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells

Vattem, KM, Wek, RC

Proc Natl Acad Sci U S A 2004
16054071 The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores

Maurin, AC, Jousse, C, Averous, J, Parry, L, Bruhat, A, Cherasse, Y, Zeng, H, Zhang, Y, Harding, HP, Ron, D, Fafournoux, P

Cell Metab. 2005
29440070 Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress

Wek, RC

Cold Spring Harb Perspect Biol 2018
15837415 GCN2 whets the appetite for amino acids

Dever, TE, Hinnebusch, AG

Mol. Cell 2005
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