A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis.

Ritu Gupta,Zeenat Rashida,Adhish S Walvekar,Sunil Laxman,Shun Liang,Premal Shah

doi:10.7554/elife.44795

Abstract

Cells must appropriately sense and integrate multiple metabolic resources to commit to proliferation. Here, we report that S. cerevisiae cells regulate carbon and nitrogen metabolic homeostasis through tRNA U34-thiolation. Despite amino acid sufficiency, tRNA-thiolation deficient cells appear amino acid starved. In these cells, carbon flux towards nucleotide synthesis decreases, and trehalose synthesis increases, resulting in a starvation-like metabolic signature. Thiolation mutants have only minor translation defects. However, in these cells phosphate homeostasis genes are strongly down-regulated, resulting in an effectively phosphate-limited state. Reduced phosphate enforces a metabolic switch, where glucose-6-phosphate is routed towards storage carbohydrates. Notably, trehalose synthesis, which releases phosphate and thereby restores phosphate availability, is central to this metabolic rewiring. Thus, cells use thiolated tRNAs to perceive amino acid sufficiency, balance carbon and amino acid metabolic flux and grow optimally, by controlling phosphate availability. These results further biochemically explain how phosphate availability determines a switch to a 'starvation-state'.

Highlights

Cells utilize multiple mechanisms to sense available nutrients, and appropriately alter their internal metabolic state
Amino acid and nucleotide metabolism are decoupled in tRNA thiolation deficient cells Earlier studies had observed an increased expression of amino acid biosynthetic genes, and an activation of the amino acid starvation responsive transcription factor Gcn4, in cells lacking tRNA thiolation (Laxman et al, 2013; Zinshteyn and Gilbert, 2013; Nedialkova and Leidel, 2015)
Summarizing, these results show that tRNA thiolation-mediated regulation of metabolic homeostasis, leading towards regulated nucleotide synthesis, is required for appropriately coupling metabolic state with normal cell cycle progression

Summary

Introduction

Cells utilize multiple mechanisms to sense available nutrients, and appropriately alter their internal metabolic state Such nutrient-sensing systems assess internal resources, relay this information to interconnected biochemical networks, and control global responses that collectively reset the metabolic state of the cell, thereby determining eventual cell fate outcomes (Jeong et al, 2000; Forster et al, 2003; Zaman et al, 2008; Broach, 2012; Cai and Tu, 2012; Ljungdahl and Daignan-Fornier, 2012). Much remains unknown about how cells sense and integrate information from multiple nutrient inputs, to coordinately regulate the metabolic state of the cell and commit to different fates. In this context, the metabolic state of the cell is closely coupled with mRNA translation. Little is known about how core components of the translation machinery might directly control metabolic outputs, and couple metabolic states with physiological cellular outcomes

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