Amino acid response is the mechanism triggered in mammalian cells by

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

starvation. The amino acid response pathway is triggered by shortage of any

essential amino acid An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life form ...

, and results in an increase in

activating transcription factor Activating transcription factor, ATF, is a group of bZIP transcription factors, which act as homodimers or heterodimers with a range of other bZIP factors. First, they have been described as members of the CREB/ATF family, whereas it turned out la ...

ATF4 Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ''ATF4'' gene. Function This gene encodes a transcription factor that was originally identified as a wi ...

, 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.

Amino acid response pathway

Amino acid deficiency detection

At low concentration of amino acid,

GCN2 GCN2 (general control nonderepressible 2) is a serine/threonine-protein kinase that senses amino acid deficiency through binding to uncharged transfer RNA (tRNA). It plays a key role in modulating amino acid metabolism as a response to nutrient d ...

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. 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.

Increased synthesis of ATF4

In homeostasis, elF2 combines with

guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only diffe ...

(GTP) to activate the

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

which will start transcription and simultaneously lead to the hydrolysis of GTP so that the process can start again. However during an essential amino acid shortage, P-elF2α is phosphorylated and binds tightly to elF2B 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.

Proteins increased by the amino acid response

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

Transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

s from the basic region/

leucine zipper A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...

(bZIP) superfamily *

Growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...

s * Metabolic enzymes

Leucine starvation

Starvation induces the lysosomal retention of leucine such that it requires RAG-GTPases and the lysosomal protein complex regulator.

PCAF P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53. Structure Several domains of PCAF can act independently or in unison to enable its funct ...

is recruited specifically to the CHOP amino acid response element to enhance the ATF4 transcriptional activity.

References

{{Reflist, refs= {{cite journal , vauthors = Kilberg MS, Pan YX, Chen H, Leung-Pineda V , title = Nutritional control of gene expression: how mammalian cells respond to amino acid limitation , journal = Annual Review of Nutrition , volume = 25 , issue = , pages = 59–85 , date = 2005 , pmid = 16011459 , pmc = 3600373 , doi = 10.1146/annurev.nutr.24.012003.132145 {{cite journal , vauthors = Chen H, Pan YX, Dudenhausen EE, Kilberg MS , title = 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 , journal = The Journal of Biological Chemistry , volume = 279 , issue = 49 , pages = 50829–39 , date = December 2004 , pmid = 15385533 , doi = 10.1074/jbc.M409173200 , doi-access = free {{cite journal , vauthors = Chérasse Y, Maurin AC, Chaveroux C, Jousse C, Carraro V, Parry L, Deval C, Chambon C, Fafournoux P, Bruhat A , display-authors = 6 , title = The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP , journal = Nucleic Acids Research , volume = 35 , issue = 17 , pages = 5954–5965 , year = 2007 , pmid = 17726049 , pmc = 2034469 , doi = 10.1093/nar/gkm642 Transcription factors