The crosstalk between metabolism and translation

Abstract

Metabolism and mRNA translation represent critical steps involved in modulating gene expression and cellular physiology. Being the most energy-consuming process in the cell, mRNA translation is strictly linked to cellular metabolism and in synchrony with it. Indeed, several mRNAs for metabolic pathways are regulated at the translational level, resulting in translation being a coordinator of metabolism. On the other hand, there is a growing appreciation for how metabolism impacts several aspects of RNA biology. For example, metabolic pathways and metabolites directly control the selectivity and efficiency of the translational machinery, as well as post-transcriptional modifications of RNA to fine-tune protein synthesis. Consistently, alterations in the intricate interplay between translational control and cellular metabolism have emerged as a critical axis underlying human diseases. A better understanding of such events will foresee innovative therapeutic strategies in human disease states.

Keywords: disease; mRNA translation; metabolism; protein synthesis; signaling.

Figure 1. An overview on metabolism and translation interconnection

(A) At the systemic level nutrients are absorbed in the gut, leading to glycemia and pancreatic insulin secretion. In the liver, glucose is absorbed and insulin stimulates protein synthesis. mRNAs encoding for lipogenic transcription factors are translated, leading to lipid synthesis and accumulation. Triglycerides can be secreted as low-density particles (LDL). Adipose tissue can absorb glucose and convert it into fat or triglycerides. Insulin-driven mRNA translation includes the synthesis of proteins involved in lipid storage. In the muscle, mTOR-mediated protein synthesis is driven by branched amino acids (also absorbed by the gut), whereas glucose drives oxidative catabolism. (B) At the cellular level, translation is regulated by extracellular cell receptor-mediated and nutrient signaling via defined pathways. TCR and insulin/growth factor signaling converges on the PI3K-mTOR and Ras/Erk cascades (other pathways can share some signalling). Aminoacids import is also essential for mTOR activation. The PI3K-mTOR and Ras/Erk cascades activate protein synthesis on polysomes which leads to increased translation of mRNA encoding lipidogenic factors in liver and fat tissue, as well of mRNAs encoding proteins necessary for cell cycle progression in the immune system. Insulin stimulates also glucose entry that is utilized in mitochondria to generate the high levels of energy necessary for translational elongation. In some cells fatty acid oxidation may be used for energy generation to sustain translation, example lymphocytes.

Figure 2. Translation control mechanisms by nutrient signaling

Diagram depicting the formation of the 43S preinitiation complex (PIC) through the binding of eIF2 complex to 40S (top left), followed by the loading of mRNA-eIF4F complex and formation of 48S. Initiations proceeds by scanning to the AUG and is followed by elongation. In the middle part of the panel, nutrient signaling to the translational machinery is outlined. On one side the Ras cascade leads to the activation of Mnk kinases that phosphorylate eIF4E. On the other side, the PI3K-mTORC1 cascade leads to the phosphorylation of the 4E-BPs proteins, relieving their inhibition of eIF4F complex formation. These two regulatory steps modulate the activity of the eIF4F complex and to the efficient translation of mRNAs with specific 5’ UTR regions. mTORC1 kinase activates also the S6K cascade and the eEF2K cascade. The first leads to the phosphorylation of rPS6, the second to relieving the inhibitory action of eEF2K on elongation. In this way, elongation increases thus accelerating the rate of protein synthesis. Phosphorylation of eIF6 regulates the availability of 60S. Activation of AMPK, downstream of reduced ATP/AMP ratio inhibits the activation of mTORC1 and provides a feedback from respiration (and hypoxia) to protein synthesis.

Figure 3. Signaling to eIF2α regulates translational adaptation under various metabolic stresses

Four different kinases converge on phosphorylation of initiation factor eIF2α. The eIF2 ternary complex is defined as GTP–bound eIF2 with the three subunits, α, β, γ plus the initiator methionyl tRNAi (tRNAiMet). Phosphorylation of eIF2α subunit reduces eIF2 activity through a mechanism that delays the kinetics of GTP recharging. The outcome of eIF2α phosphorylation is the inhibition of cap-dependent translation, thus reducing the rate of protein synthesis, coupled to the increase of translation of mRNAs containing upstream Open Reading Frames such as ATF4. ATF4 acts as a transcription factor than in the nucleus initiates a complex response that comprehends among others an increase in amino acid transport. The four kinases are activated downstream of ER stress, heme deficiency, double-stranded viral RNA and amino acid starvation.

Figure 4. Mechanisms of translational regulation of metabolism

(A) Iron metabolism regulation at the translational levels includes the synthesis of several iron-binding proteins. Schematically, 5’UTR of ferritin, as an example, contains IRE sequences that are bound by iron-free IRP1 protein that blocks scanning and translation. In the presence of iron, IRP1 does not bind IRE sequences, and ferritin mRNA can be translated. IRP1-Fe₄S₄ acts as an aconitase. (B) Polyamine metabolism is controlled by programmed frameshifting. The rate-limiting enzyme ornithine decarboxylase (ODC) produces spermidine. ODC is proteolytically inactivated upon binding to the antizyme (AZ) peptide. AZ peptide, in turn, is synthesized by translation frameshifting induced by free spermidine, completing the regulatory loop. (C) Selenoproteins synthesis occurs through the incorporation of the unusual selenocysteine amino acid that occurs by reassignment of the STOP codon UGA as Sec. Organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons embedded in a cis-acting Sec insertion sequence (SECIS) element. Selenoproteins are important in different REDOX reactions. (D) Lipid metabolism is controlled at the translational level by eIF6 and eIF4E initiation factors. eIF6 favors bypassing of inhibitory uORFS present in lipidogenic transcription factors. eIF4E, part of the eIF4F complex, unwinds structural elements present in the 5’UTRs of mRNAs that are rate-limiting for lipid synthesis or storage. (E) Short elements known as TISU are present in the 5’ untranslated regions of mRNAs encoding mitochondrial factors. These elements facilitate the translation of mitochondrial mRNAs also in conditions of stress, through the specific activity of initiation factors such as eIF4G1 and eIF1. In parallel, spermidine leads to hypusination of eIF5A. Hypusinated eIF5A increases mitochondrial activity through preferential translation of several mitochondrial-associated mRNAs

Figure 5. Translational control of metabolism in disease and in the immune system

(A) MYC regulates metabolism by different ways: indirectly, MYC promotes the transcription and upregulation of ribosomal RNA (rRNA); directly, Myc may increase the transcription of mRNAs encoding for ribosomal proteins (rPS, rpL) and translation factors. Upregulation of specific elements of the ribosomal apparatus, such as eIF4E or eIF6 leads to the efficient translation of mRNA that are involved in cell cycle progression and growth. (B) In cancer cells, hypoxic environment leads to polysomal and translation machinery remodeling in a way that preferential translation of metabolic, angiogenic and metastatic mRNAs occurs allowing tumor angiogenesis, metabolic rewiring and tumor invasion. (C) In endothelial cells, both VEGF and VEGFR2 are under translational control. VEGF mRNA translation can be regulated both in an eIF-4E/cap-dependent and hypoxic-driven IRES-dependent manner. VEGFR2 mRNA translation is controlled by mTORC1 signaling via aspartate. Such pathways are used in both developmental and pathological angiogenesis. (D) TCR stimulation in lymphocytes results in a massive translational activation through the mTOR cascade. This leads to the activation of eIF4F and eIF6 that drive the translation of the mRNA for glycolytic and lipid synthesis enzymes. eIF3 activity facilitates the translation of mRNAs encoding for TCR chains. eIF5A is responsible for the translational control of mRNAs encoding for mitochondrial-associated proteins.