title: Salt-Inducible Kinase 3 Provides Sugar Tolerance by Regulating NADPH/NADP+Redox Balance.
abstract: Nutrient-sensing pathways respond to changes in the levels of macronutrients, such as sugars, lipids, or amino acids, and regulate metabolic pathways to maintain organismal homeostasis [1, 2]. Consequently, nutrient sensing provides animals with the metabolic flexibility necessary for enduring temporal fluctuations in nutrient intake. Recent studies have shown that an animal's ability to survive on a high-sugar diet is determined by sugar-responsive gene regulation [3-8]. It remains to be elucidated whether other levels of metabolic control, such as post-translational regulation of metabolic enzymes, also contribute to organismal sugar tolerance. Furthermore, the sugar-regulated metabolic pathways contributing to sugar tolerance remain insufficiently characterized. Here, we identify Salt-inducible kinase 3 (SIK3), a member of the AMP-activated protein kinase (AMPK)-related kinase family, as a key determinant of Drosophila sugar tolerance. SIK3 allows sugar-feeding animals to increase the reductive capacity of nicotinamide adenine dinucleotide phosphate (NADPH/NADP+). NADPH mediates the reduction of the intracellular antioxidant glutathione, which is essential for survival on a high-sugar diet. SIK3 controls NADP+reduction by phosphorylating and activating Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. SIK3 gene expression is regulated by the sugar-regulated transcription factor complex Mondo-Mlx, which was previously identified as a key determinant of sugar tolerance. SIK3 converges with Mondo-Mlx in sugar-induced activation of G6PD, and simultaneous inhibition of SIK3 and Mondo-Mlx leads to strong synergistic lethality on a sugar-containing diet. In conclusion, SIK3 cooperates with Mondo-Mlx to maintain organismal sugar tolerance through the regulation of NADPH/NADP+redox balance.
authors.affiliation: Department of Biosciences, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland; Institute of Biotechnology, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Teesalu
authors.affiliation: Department of Biosciences, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland; Institute of Biotechnology, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland.
authors.forename: Bohdana M
authors.initials: BM
authors.lastname: Rovenko
authors.affiliation: Department of Biosciences, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland; Institute of Biotechnology, University of Helsinki, Viikinkaari 9, Helsinki 00014, Finland. Electronic address: ville.hietakangas@helsinki.fi.
authors.forename: Ville
authors.initials: V
authors.lastname: Hietakangas
mesh_terms: D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006706:Homeostasis; D009249:NADP / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017385:Sequence Homology; D015398:Signal Transduction
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; C581832:bigmax protein, Drosophila; C484002:mio protein, Drosophila; D009249:NADP; D005954:Glucosephosphate Dehydrogenase; C559671:salt-inducible kinase 3, Drosophila; D017346:Protein Serine-Threonine Kinases; D005978:Glutathione; D005947:Glucose
keywords: Drosophila; NADPH; SIK3; metabolism; pentose phosphate pathway; redox balance; sugar