title: Galactose metabolic genes in yeast respond to a ratio of galactose and glucose.
abstract: Natural environments are filled with multiple, often competing, signals. In contrast, biological systems are often studied in "well-controlled" environments where only a single input is varied, potentially missing important interactions between signals. Catabolite repression of galactose by glucose is one of the best-studied eukaryotic signal integration systems. In this system, it is believed that galactose metabolic (GAL) genes are induced only when glucose levels drop below a threshold. In contrast, we show that GAL gene induction occurs at a constant external galactose:glucose ratio across a wide range of sugar concentrations. We systematically perturbed the components of the canonical galactose/glucose signaling pathways and found that these components do not account for ratio sensing. Instead we provide evidence that ratio sensing occurs upstream of the canonical signaling pathway and results from the competitive binding of the two sugars to hexose transporters. We show that a mutant that behaves as the classical model expects (i.e., cannot use galactose above a glucose threshold) has a fitness disadvantage compared with wild type. A number of common biological signaling motifs can give rise to ratio sensing, typically through negative interactions between opposing signaling molecules. We therefore suspect that this previously unidentified nutrient sensing paradigm may be common and overlooked in biology.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Renan
authors.initials: R
authors.lastname: Escalante-Chong
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Savir
authors.affiliation: Department of Organismic and Evolutionary Biology, Harvard University, MA 02138;
authors.forename: Sean M
authors.initials: SM
authors.lastname: Carroll
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: John B
authors.initials: JB
authors.lastname: Ingraham
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Organismic and Evolutionary Biology, Harvard University, MA 02138; Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, MA 02138; Department of Biological Sciences, University of Idaho, Moscow, ID 83844; and Institute for Bioinformatics and Evolutionary Studies, University of Idaho, Moscow, ID 83844.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Marx
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; michael_springer@hms.harvard.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Springer
mesh_terms: D003470:Culture Media; D005690:Galactose / Q000378:metabolism*; D005800:Genes, Fungal; D005947:Glucose / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D003470:Culture Media; D005947:Glucose; D005690:Galactose
keywords: gene regulation; nutrient signaling; ratio sensing; signal integration; yeast