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Review
. 2017 May 25;474(12):1935-1963.
doi: 10.1042/BCJ20160822.

Amino acid homeostasis and signalling in mammalian cells and organisms

Stefan Bröer  1 , Angelika Bröer  2
Affiliations
Review

Amino acid homeostasis and signalling in mammalian cells and organisms

Stefan Bröer et al. Biochem J. .

Abstract

Cells have a constant turnover of proteins that recycle most amino acids over time. Net loss is mainly due to amino acid oxidation. Homeostasis is achieved through exchange of essential amino acids with non-essential amino acids and the transfer of amino groups from oxidised amino acids to amino acid biosynthesis. This homeostatic condition is maintained through an active mTORC1 complex. Under amino acid depletion, mTORC1 is inactivated. This increases the breakdown of cellular proteins through autophagy and reduces protein biosynthesis. The general control non-derepressable 2/ATF4 pathway may be activated in addition, resulting in transcription of genes involved in amino acid transport and biosynthesis of non-essential amino acids. Metabolism is autoregulated to minimise oxidation of amino acids. Systemic amino acid levels are also tightly regulated. Food intake briefly increases plasma amino acid levels, which stimulates insulin release and mTOR-dependent protein synthesis in muscle. Excess amino acids are oxidised, resulting in increased urea production. Short-term fasting does not result in depletion of plasma amino acids due to reduced protein synthesis and the onset of autophagy. Owing to the fact that half of all amino acids are essential, reduction in protein synthesis and amino acid oxidation are the only two measures to reduce amino acid demand. Long-term malnutrition causes depletion of plasma amino acids. The CNS appears to generate a protein-specific response upon amino acid depletion, resulting in avoidance of an inadequate diet. High protein levels, in contrast, contribute together with other nutrients to a reduction in food intake.

Keywords: amino acid metabolism; amino acid transporters; starvation signalling.

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Conflict of interest statement

The Authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. Amino acid sensing by the mTORC1 complex.
When amino acids are depleted, mTORC1 is located in the cytosol and inactive. Energy depletion can also switch off mTORC1 signalling by converting Rheb into its GDP-bound form. In the presence of growth factors, TSC2 is inactive and mTORC1 binds to GTP-bound Rheb at the surface of lysosomes. Cytosolic amino acids such as leucine and arginine can activate mTORC1 by inhibiting GATOR1. This switches the GTP/GDP-bound state of Rag proteins (green) and activates mTORC1. In the lysosome, arginine binds to transceptor SLC38A9, which activates mTORC1 through associated proteins. Some parts of the model are not universally accepted (for details see text).
Figure 2.
Figure 2.. Regulation of protein translation at the initiation stage.
To initiate translation, the capped (m7G) mRNA has to form a complex with eIF4A/G/E (termed eIF4F), which is facilitated by phosphorylation of the eIF4E-binding protein 4E-BP1 through the action of mTORC1. This complex binds to the 40S ribosomal subunit, which starts scanning the mRNA until it reaches the start cordon. At this point eIF2α·GTP·Met-tRNAiMet can bind to the start codon, resulting in formation of the full ribosome and start of translation. In this process, eIF2α·GTP is hydrolysed to eIF2α·GDP, which needs to be recharged to eIF2α·GTP through the action of eIF2B to initiate another translation event. When GCN2 is activated by uncharged tRNAs, it phosphorylates eIF2α, thereby inhibiting the exchange from GDP back to GTP.
Figure 3.
Figure 3.. The repertoire of amino acid transporters in cancer cells.
In rapidly growing cancer cells, certain amino acid transporters are prevalent. Amino acid transporter transcript levels were analysed through Oncomine in 917 cell lines of the Barretina dataset [58] and are depicted as vertical blue bars. The dataset is subdivided by vertical lines into different groups of cancers. Data are depicted as log2 expression levels relative to the median expression of all genes in the genome. The size of each panel was adjusted to fit the scale. Blue-coloured bars pointing upwards from the median indicate well-expressed genes; bars pointing downwards indicate weakly expressed genes. Only a handful of transporter genes show high expression in essentially all cell lines (upward-pointing blue bars across the complete x-axis). These transporters are likely to be essential for amino acid homeostasis, whereas other transporters occur only in selected cancer cell lines and are likely to have specialised roles.
Figure 4.
Figure 4.. A general model of amino acid accumulation in non-epithelial cells.
The model makes use of amino acid loaders, which accumulate a certain group of amino acids in the cytosol. Mostly, the Na+-electrochemical gradient is used to actively transport amino acids. A second group of transporters are the harmonisers, which exchange one amino acid for another and have overlapping substrates with amino acid loaders. The exchange mechanism ensures that depletion of a particular amino acid is avoided. Under conditions of amino acid depletion, rescue transporters are up-regulated to bring in more amino acids.
Figure 5.
Figure 5.. Autoregulation of amino acid metabolism.
In the first step of their metabolism, BCAAs are converted into the corresponding keto-acids through BCAA transaminase. The second step is the oxidative decarboxylation into coenzyme A thioesters of branched organic acids via BCAA dehydrogenase (BCKD). Alpha-ketoisocaproate is generated from leucine and is a potent activator of protein phosphatase PP2Cm and a potent inhibitor of BCKD kinase. The two actions dephosphorylate BCKD to be active. Depletion of BCAAs will result in the cessation of metabolism through the reverse events.
Figure 6.
Figure 6.. Stress-induced translation of specific mRNAs.
Stress-induced translation makes use of upstream regulatory sequences preceding the start codon. The mRNA of transcription factor ATF4, which co-ordinates transcription of a variety of genes involved in stress responses, has two uORFs, numbered 1 and 2 in the figure. Under normal conditions (A), translation starts at the short uORF1 and the ribosome disassembles at the stop codon. The 40S subunit remains on the mRNA and reinitiates at uORF2 if levels of eIF2α·GTP·Met-tRNAiMet are sufficient (ribosome green), which is incompatible with translation of ATF4. If levels of eIF2α·GTP·Met-tRNAiMet are low (B), reinitiation is delayed (ribosome red), allowing the complex to reassemble at the more distant correct start codon for ATF4 translation. An alternative mechanism makes use of uORFs to change the secondary structure of mRNA (C and D). When translation is fast (C), uORF1 is translated, while the main ORF for the cationic amino acid transporter cat-1 is rarely translated. When cap-dependent translation is rare due to low levels of eIF2α·GTP·Met-tRNAiMet, the mRNA secondary structure changes, exposing an internal ribosome entry site (IRES). This is used to translate cat-1 more frequently (D).
Figure 7.
Figure 7.. Lysosomal amino acid and peptide transport.
Lysosomes are acidified through the action of the vacuolar proton-ATPase. This proton gradient is used to extrude amino acids through proton amino acid co-transporters (PATs) or peptide/histidine proton co-transporters (PHT1/SLC15A4 and PHT2/SLC15A3). Other amino acids can transfer in both directions through exchangers. SLC38A9 is the main lysosomal arginine sensor for mTORC1. SNAT4 and SNAT7 are putative (indicated by ?) lysosomal transporters.
Figure 8.
Figure 8.. Cellular processes involved in amino acid homeostasis.
Under nutrient-sufficient conditions, cells have a constant turnover of proteins that recycles most amino acids (AA) over time. Cellular protein forms a major storage polymer of amino acids. Net loss is mainly due to amino acid oxidation in the mitochondria, which is compensated through uptake of amino acids and/or biosynthesis. Homeostasis is achieved through exchange of essential amino acids (EAAs) with non-essential amino acids (NEAAs) and the transfer of amino groups from oxidised amino acids to amino acid biosynthesis. This homeostatic condition is maintained through an active mTORC1 complex. Under conditions of amino acid depletion, mTORC1 is inactivated. This increases the breakdown of cellular proteins through autophagy and reduces protein biosynthesis. The GCN2/ATF4 pathway may be activated in addition, resulting in transcription of genes involved in amino acid transport and biosynthesis of non-essential amino acids. These are used to import essential amino acids. Metabolism is autoregulated to minimise oxidation of amino acids.
Figure 9.
Figure 9.. Epithelial amino acid transport.
The apical and basolateral membrane of epithelial cells is endowed with different sets of transporters. Apical transporters actively translocate amino acids and peptides from the lumen of the intestine or of the proximal tubulus into the cytosol. Efflux is mediated by a mixture of uniporters and antiporters. Additional transporters (not shown) mediate the uptake of amino acids from blood plasma when required.
Figure 10.
Figure 10.. Systemic amino acid homeostasis.
After food intake, gastrointestinal hormones are secreted that suppress appetite. The plasma amino acid pool increases, which contributes to insulin release from the pancreas. Insulin increases transport of amino acids into muscle and their incorporation into protein. The remaining amino acids are metabolised. Amino groups are delivered as glutamine to the liver, where they are together with ammonia used to generate urea. During fasting, amino acid oxidation is reduced. Muscle protein is degraded to replete the amino acid pool if necessary. Alanine is released from muscle to synthesise glucose. Amino acid imbalance or restriction will activate GCN2 signalling in the anterior piriform cortex (APC) to change the source of food. ARC, arcuate hypothalamic nucleus.
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