FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores
| Autor: | Barry J. Coull, Tarika Vijayaraghavan, Maurice A.M. van Steensel, Marie-Claude Gingras, Sanaz Manteghi, Elite Possik, Thomas F. Duchaine, Arnim Pause, David H. Hall, Kathrin Schmeisser, Andrew Ajisebutu, Mathieu N. Flamand |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
lcsh:QH426-470 AMP-Activated Protein Kinases Biology Gene mutation Mice chemistry.chemical_compound Glycogen phosphorylase Osmoregulation AMP-activated protein kinase Proto-Oncogene Proteins Genetics Animals Humans Folliculin Caenorhabditis elegans Protein kinase A Glycogen synthase Molecular Biology Genetics (clinical) Ecology Evolution Behavior and Systematics Glycogen Tumor Suppressor Proteins Glycogen Phosphorylase Osmolar Concentration AMPK lcsh:Genetics Glycogen Synthase chemistry Biochemistry Mutation Commentary biology.protein Research Article |
| Zdroj: | PLoS Genetics, Vol 11, Iss 10, p e1005520 (2015) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5’-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN). FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dubé (BHD) tumor syndrome. We show that flcn-1 mutants exhibit increased resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen reserves. Upon hyperosmotic stress exposure, glycogen stores are rapidly degraded, leading to a significant accumulation of the organic osmolyte glycerol through transcriptional upregulation of glycerol-3-phosphate dehydrogenase enzymes (gpdh-1 and gpdh-2). Importantly, the hyperosmotic stress resistance in flcn-1 mutant and wild-type animals is strongly suppressed by loss of AMPK, glycogen synthase, glycogen phosphorylase, or simultaneous loss of gpdh-1 and gpdh-2 enzymes. Our studies show for the first time that animals normally exhibit AMPK-dependent glycogen stores, which can be utilized for rapid adaptation to either energy stress or hyperosmotic stress. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in renal tumors from a BHD patient. Our findings suggest a dual role for glycogen, acting as a reservoir for energy supply and osmolyte production, and both processes might be supporting tumorigenesis. Author Summary The ability of an organism to adapt to sudden changes in environmental osmolarity is critical to ensure growth, propagation, and survival. The synthesis of organic osmolytes is a common adaptive strategy to survive hyperosmotic stress. However, it was not well understood, which biosynthetic pathways and storage strategies were used by organisms to rapidly generate osmolytes upon acute hyperosmotic stress. Here, we demonstrate that glycogen is an essential reservoir that is used upon acute hyperosmotic stress to generate the organic osmolyte glycerol promoting fast and efficient protection. Importantly, we show that this pathway is regulated by FLCN-1, an ortholog of the human tumor suppressor Folliculin responsible for the Birt-Hogg-Dubé cancer syndrome, and by AMPK, the master regulator of energy homeostasis. |
| Databáze: | OpenAIRE |
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