Amino acid response

Amino acid response is the mechanism triggered in mammalian cells by amino acid starvation.^[1]

The amino acid response pathway is triggered by shortage of any essential amino acid, and results in an increase in activating transcription factor ATF4, which in turn affects many processes by sundry pathways to limit or increase the production of other proteins.^[2]

Essential amino acids are crucial to maintain homeostasis within an organism. Diet plays an important role in the health of an organism, as evidence ranging from human epidemiological to model organism experimental data suggests that diet-dependent pathways impact a variety of adult stem cells.^[3]

Amino acid response pathway

Amino acid deficiency detection

At low concentration of amino acid, GCN2 is activated due to the increase level of uncharged tRNA molecules. Uncharged tRNA activates GCN2 due to the displacement of the protein kinase moiety from a bipartite tRNA-binding domain.^[4] Activated GCN2 phosphorylates itself and eIF2α, it triggers a transcriptional and translational response to restore amino acid homeostasis by affecting the utilization, acquisition, and mobilization of amino acid in an organism.^[5]

Increased synthesis of ATF4

In homeostasis, eIF2 combines with guanosine triphosphate (GTP) to activate the mRNA which will start transcription and simultaneously lead to the hydrolysis of GTP so that the process can start again.^[6] However during an essential amino acid shortage, P-eIF2α is phosphorylated and binds tightly to eIF2B preventing GDP from turning back to GTP leading to fewer mRNAs being activated and fewer proteins being synthesized.^[6] This response causes translation to be increased for some mRNAs, including ATF4, which regulates the transcription of other genes.^[7]

Proteins increased by the amino acid response

Some of the proteins whose concentration is increased by the amino acid response include:

• Membrane transporters^[2]
• Transcription factors from the basic region/leucine zipper (bZIP) superfamily^[2][8]
• Growth factors^[2]
• Metabolic enzymes ^[2]

Leucine starvation

Starvation induces the lysosomal retention of leucine such that it requires RAG-GTPases and the lysosomal protein complex regulator.^[9] PCAF is recruited specifically to the CHOP amino acid response element to enhance the ATF4 transcriptional activity.^[10]

References

1. Chaveroux C, Jousse C, Cherasse Y, Maurin AC, Parry L, Carraro V, et al. (December 2009). "Identification of a novel amino acid response pathway triggering ATF2 phosphorylation in mammals". Molecular and Cellular Biology. 29 (24): 6515–6526. doi:10.1128/MCB.00489-09. PMC 2786873. PMID 19822663.
2. Kilberg MS, Pan YX, Chen H, Leung-Pineda V (2005). "Nutritional control of gene expression: how mammalian cells respond to amino acid limitation". Annual Review of Nutrition. 25: 59–85. doi:10.1146/annurev.nutr.24.012003.132145. PMC 3600373. PMID 16011459.
3. Armstrong AR, Laws KM, Drummond-Barbosa D (December 2014). "Adipocyte amino acid sensing controls adult germline stem cell number via the amino acid response pathway and independently of Target of Rapamycin signaling in Drosophila". Development. 141 (23): 4479–4488. doi:10.1242/dev.116467. PMC 4302921. PMID 25359724.
4. Dong J, Qiu H, Garcia-Barrio M, Anderson J, Hinnebusch AG (August 2000). "Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain". Molecular Cell. 6 (2): 269–279. doi:10.1016/S1097-2765(00)00028-9. PMID 10983975.
5. Strakovsky RS, Zhou D, Pan YX (December 2010). "A low-protein diet during gestation in rats activates the placental mammalian amino acid response pathway and programs the growth capacity of offspring". The Journal of Nutrition. 140 (12): 2116–2120. doi:10.3945/jn.110.127803. PMID 20980649.
6. Wek, Ronald C. (2018-07-02). "Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress". Cold Spring Harbor Perspectives in Biology. 10 (7): a032870. doi:10.1101/cshperspect.a032870. ISSN 1943-0264. PMC 6028073. PMID 29440070.
7. B'chir, Wafa; Maurin, Anne-Catherine; Carraro, Valérie; Averous, Julien; Jousse, Céline; Muranishi, Yuki; Parry, Laurent; Stepien, Georges; Fafournoux, Pierre; Bruhat, Alain (September 2013). "The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression". Nucleic Acids Research. 41 (16): 7683–7699. doi:10.1093/nar/gkt563. ISSN 1362-4962. PMC 3763548. PMID 23804767.
8. Chen H, Pan YX, Dudenhausen EE, Kilberg MS (December 2004). "Amino acid deprivation induces the transcription rate of the human asparagine synthetase gene through a timed program of expression and promoter binding of nutrient-responsive basic region/leucine zipper transcription factors as well as localized histone acetylation". The Journal of Biological Chemistry. 279 (49): 50829–39. doi:10.1074/jbc.M409173200. PMID 15385533.
9. Bandyopadhyay U, Todorova P, Pavlova NN, Tada Y, Thompson CB, Finley LW, Overholtzer M (February 2022). "Leucine retention in lysosomes is regulated by starvation". Proceedings of the National Academy of Sciences of the United States of America. 119 (6): e2114912119. Bibcode:2022PNAS..11914912B. doi:10.1073/pnas.2114912119. PMC 8833167. PMID 35105808.
10. Chérasse Y, Maurin AC, Chaveroux C, Jousse C, Carraro V, Parry L, et al. (2007). "The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP". Nucleic Acids Research. 35 (17): 5954–5965. doi:10.1093/nar/gkm642. PMC 2034469. PMID 17726049.