tRNA wobble-uridine modifications as amino acid sensors and regulators of cellular metabolic state
Cells must appropriately sense available nutrients and accordingly regulate their metabolic outputs, to survive. This mini-review considers the idea that conserved chemical modifications of wobble (U34) position tRNA uridines enable cells to sense nutrients and regulate their metabolic state. tRNA wobble uridines are chemically modified at the 2- and 5- positions, with a thiol (s2), and (commonly) a methoxycarbonylmethyl (mcm5) modification, respectively. These modifications reflect sulfur amino acid (methionine and cysteine) availability. The loss of these modifications has minor translation defects. However, they result in striking phenotypes consistent with an altered metabolic state. Using yeast, we recently discovered that the s2 modification regulates overall carbon and nitrogen metabolism, dependent on methionine availability. The loss of this modification results in rewired carbon (glucose) metabolism. Cells have reduced carbon flux towards the pentose phosphate pathway and instead increased flux towards storage carbohydrates—primarily trehalose, along with reduced nucleotide synthesis, and perceived amino acid starvation signatures. Remarkably, this metabolic rewiring in the s2U mutants is caused by mechanisms leading to intracellular phosphate limitation. Thus this U34 tRNA modification responds to methionine availability and integratively regulates carbon and nitrogen homeostasis, wiring cells to a ‘growth’ state. We interpret the importance of U34 modifications in the context of metabolic sensing and anabolism, emphasizing their intimate coupling to methionine metabolism.
KeywordstRNA modification Methionine S-adenosyl methionine Amino acid sensing Phosphate Metabolism
The authors are grateful to the Wellcome Trust-DBT India Alliance grant IA/I/14/2/501523 (SL) and the DST-SERB National Postdoctoral Fellowship grant PDF/2016/000416 (RG) for funding and support.
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Conflict of interest
The authors declare that they have no conflict of interest.
- Cai L, Tu BP (2012) Driving the cell cycle through metabolism. Annu Rev Cell Dev Biol 28:59–87. https://doi.org/10.1146/annurev-cellbio-092910-154010 CrossRefPubMedGoogle Scholar
- Hinnebusch AG (2005) translational regulation of GCN4 and the general amino acid control of yeast*. Annu Rev Microbiol 59:407–450. https://doi.org/10.1146/annurev.micro.59.031805.133833 CrossRefPubMedGoogle Scholar
- Teng X, Hardwick JM (2019) Whi2: a new player in amino acid sensing. Curr, GenetGoogle Scholar