The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan

Nitish Mittal (), Joao C. Guimaraes, Thomas Gross, Alexander Schmidt, Arnau Vina-Vilaseca, Danny D. Nedialkova, Florian Aeschimann, Sebastian A. Leidel, Anne Spang and Mihaela Zavolan ()
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Nitish Mittal: University of Basel
Joao C. Guimaraes: University of Basel
Thomas Gross: University of Basel
Alexander Schmidt: University of Basel
Arnau Vina-Vilaseca: University of Basel
Danny D. Nedialkova: Max Planck Institute for Molecular Biomedicine
Florian Aeschimann: Friedrich Miescher Institute for Biomedical Research
Sebastian A. Leidel: Max Planck Institute for Molecular Biomedicine
Anne Spang: University of Basel
Mihaela Zavolan: University of Basel

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract In Saccharomyces cerevisiae, deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response.

Date: 2017
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DOI: 10.1038/s41467-017-00539-y

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