Amino acid response explained

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.

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.^[2]

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.^[3] 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.^[4]

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.^[5] 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. This response causes translation to be increased for some mRNAs, including ATF4, which regulates the transcription of other genes.^[6]

Proteins increased by the amino acid response

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

• Membrane transporters
• Transcription factors from the basic region/leucine zipper (bZIP) superfamily
• Growth factors
• Metabolic enzymes

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.

Notes and References

1. Chaveroux C, Jousse C, Cherasse Y, Maurin AC, Parry L, Carraro V, Derijard B, Bruhat A, Fafournoux P . 6 . Identification of a novel amino acid response pathway triggering ATF2 phosphorylation in mammals . Molecular and Cellular Biology . 29 . 24 . 6515–6526 . December 2009 . 19822663 . 2786873 . 10.1128/MCB.00489-09 .
2. Armstrong AR, Laws KM, Drummond-Barbosa D . 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 . December 2014 . 25359724 . 4302921 . 10.1242/dev.116467 . Daniela Drummond-Barbosa .
3. 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 . 10.1016/S1097-2765(00)00028-9 . 10983975. free .
4. 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 . 10.3945/jn.110.127803 . 20980649 . free.
5. 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 . 10.1101/cshperspect.a032870 . 1943-0264 . 6028073 . 29440070.
6. 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 . 10.1093/nar/gkt563 . 1362-4962 . 3763548 . 23804767.
7. Bandyopadhyay U, Todorova P, Pavlova NN, Tada Y, Thompson CB, Finley LW, Overholtzer M . Leucine retention in lysosomes is regulated by starvation . Proceedings of the National Academy of Sciences of the United States of America . 119 . 6 . e2114912119 . February 2022 . 35105808 . 8833167 . 10.1073/pnas.2114912119 . free . 2022PNAS..11914912B .