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]

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.[3] Activated GCN2 phosphorylates itself and elF2ɑ, 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.[4] 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.[5]

Proteins increased by the amino acid response

Leucine starvation

Starvation induces the lysosomal retention of leucine such that it requires RAG-GTPases and the lysosomal protein complex regulator.[7] PCAF is recruited specifically to the CHOP amino acid response element to enhance the ATF4 transcriptional activity.[8]

References
  1. Chaveroux, Cédric; Jousse, Céline; Cherasse, Yoan; Maurin, Anne-Catherine; Parry, Laurent; Carraro, Valérie; Derijard, Benoit; Bruhat, Alain; Fafournoux, Pierre (2009-12-15). "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. ISSN 0270-7306. PMC 2786873. PMID 19822663.
  2. Kilberg MS, Pan YX, Chen H, Leung-Pineda V. Nutritional control of gene expression: how mammalian cells respond to amino acid limitation*. Annu. Rev. Nutr. 2005;25:59–85.
  3. Dong, Jinsheng; Qiu, Hongfang; Garcia-Barrio, Minerva; Anderson, James; Hinnebusch, Alan G. (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.
  4. Strakovsky, Rita S.; Zhou, Dan; Pan, Yuan-Xiang (1 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.
  5. Armstrong, Alissa R.; Laws, Kaitlin M.; Drummond-Barbosa, Daniela (1 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.
  6. Chen H, Pan YX, Dudenhausen EE, Kilberg MS. 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. J. Biol. Chem. 2004;279:50829–50839.
  7. Bandyopadhyay, Urmi; Todorova, Pavlina; Pavlova, Natalya N.; Tada, Yuma; Thompson, Craig B.; Finley, Lydia W.S.; Overholtzer, Michael (2022-02-08). "Leucine retention in lysosomes is regulated by starvation". Proceedings of the National Academy of Sciences. 119 (6): e2114912119. doi:10.1073/pnas.2114912119. ISSN 0027-8424. PMC 8833167. PMID 35105808.{{cite journal}}: CS1 maint: PMC format (link)
  8. Chérasse Y, Maurin AC, Chaveroux C, et al. (2007). "The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP". Nucleic Acids Res. 35 (17): 5954–65. doi:10.1093/nar/gkm642. PMC 2034469. PMID 17726049.


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