Amino acid response

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

Contents

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:

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]

Related Research Articles

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<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

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<span class="mw-page-title-main">Protein kinase R</span> Human protein and coding gene

Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long.

<span class="mw-page-title-main">Microphthalmia-associated transcription factor</span> Mammalian protein found in humans

Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the MITF gene.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

<span class="mw-page-title-main">PCAF</span> Protein-coding gene in humans

P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.

<span class="mw-page-title-main">Protein inhibitor of activated STAT</span>

Protein inhibitor of activated STAT (PIAS), also known as E3 SUMO-protein ligase PIAS, is a protein that regulates transcription in mammals. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins in order to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with.

<span class="mw-page-title-main">Jun dimerization protein</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">HSF1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ATF4</span> Mammalian protein found in Homo sapiens

Activating transcription factor 4 , also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.

<span class="mw-page-title-main">DNA damage-inducible transcript 3</span> Human protein and coding gene

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

<span class="mw-page-title-main">EIF2S1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 2 subunit 1 (eIF2α) is a protein that in humans is encoded by the EIF2S1 gene.

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Eukaryotic Initiation Factor 2 (eIF2) is an eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha, a beta, and a gamma subunit.

<span class="mw-page-title-main">Gcn2</span>

GCN2 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 deprivation.

The integrated stress response is a cellular stress response conserved in eukaryotic cells that downregulates protein synthesis and upregulates specific genes in response to internal or environmental stresses.

mTORC1 Protein complex

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.

The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms. DNA is normally found in the nucleus of the cell. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and invasion by some intracellular bacteria. The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response.

<span class="mw-page-title-main">CCDC188</span> Protein found in humans

CCDC188 or coiled-coil domain containing protein is a protein that in humans is encoded by the CCDC188 gene.

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. 1 2 3 4 5 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. 1 2 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.
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