1. Biochemistry and Chemical Biology
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A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis

  1. Ritu Gupta
  2. Adhish Walvekar
  3. Shun Liang
  4. Zeenat Rashida
  5. Premal Shah  Is a corresponding author
  6. Sunil Laxman  Is a corresponding author
  1. Institute for Stem Cell Biology and Regenerative Medicine (inStem), India
  2. Rutgers University, United States
Research Article
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Cite this article as: eLife 2019;8:e44795 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'.

Data availability

Sequencing (transcript and ribosome footprint) data have been deposited in GEO under accession codes GSE124428, and are fully open.

The following data sets were generated

Article and author information

Author details

  1. Ritu Gupta

    Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Adhish Walvekar

    Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7344-7653
  3. Shun Liang

    Department of Genetics, Rutgers University, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zeenat Rashida

    Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Premal Shah

    Department of Genetics, Rutgers University, Piscataway, United States
    For correspondence
    premal.shah@rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
  6. Sunil Laxman

    Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, India
    For correspondence
    sunil.laxman@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0861-5080

Funding

Wellcome Trust - DBT India Alliance (IA/I/14/2/501523)

  • Sunil Laxman

National Institutes of Health (GM124976)

  • Premal Shah

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Alan G Hinnebusch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States

Publication history

  1. Received: December 29, 2018
  2. Accepted: June 30, 2019
  3. Accepted Manuscript published: July 1, 2019 (version 1)
  4. Version of Record published: August 9, 2019 (version 2)

Copyright

© 2019, Gupta et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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