論文 - 詳細
| RRC ID | 45627 |
|---|---|
| 著者 | Possik E, Ajisebutu A, Manteghi S, Gingras MC, Vijayaraghavan T, Flamand M, Coull B, Schmeisser K, Duchaine T, van Steensel M, Hall DH, Pause A. |
| タイトル | FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. |
| ジャーナル | PLoS Genet |
| Abstract |
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. |
| 巻・号 | 11(10) |
| ページ | e1005520 |
| 公開日 | 2015-10-1 |
| DOI | 10.1371/journal.pgen.1005520 |
| PII | PGENETICS-D-15-01326 |
| PMID | 26439621 |
| PMC | PMC4595296 |
| MeSH | AMP-Activated Protein Kinases / genetics* Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / physiology Glycogen / genetics Glycogen / metabolism* Glycogen Phosphorylase / genetics Glycogen Synthase / genetics Humans Mice Mutation Osmolar Concentration Osmoregulation / genetics* Proto-Oncogene Proteins / genetics* Tumor Suppressor Proteins / genetics* |
| IF | 5.175 |
| 引用数 | 23 |
| WOS 分野 | GENETICS & HEREDITY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 14 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm1944 tm1044 |