FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores

Elite Possik, Andrew Ajisebutu, Sanaz Manteghi, Marie Claude Gingras, Tarika Vijayaraghavan, Mathieu Flamand, Barry Coull, Kathrin Schmeisser, Thomas Duchaine, Maurice van Steensel, David H. Hall, Arnim Pause

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005520
JournalPLoS Genetics
Volume11
Issue number10
DOIs
StatePublished - 2015

Fingerprint

AMP-activated protein kinase
AMP-Activated Protein Kinases
estrone
Estrone
Glycogen
glycogen
tumor
stress resistance
protein
enzyme
stress tolerance
neoplasms
glycogen (starch) synthase
animal
Glycerolphosphate Dehydrogenase
Kidney
Glycogen Phosphorylase
Glycogen Synthase
Neoplasms
kidneys

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Possik, E., Ajisebutu, A., Manteghi, S., Gingras, M. C., Vijayaraghavan, T., Flamand, M., ... Pause, A. (2015). FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. PLoS Genetics, 11(10), [e1005520]. https://doi.org/10.1371/journal.pgen.1005520

FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. / Possik, Elite; Ajisebutu, Andrew; Manteghi, Sanaz; Gingras, Marie Claude; Vijayaraghavan, Tarika; Flamand, Mathieu; Coull, Barry; Schmeisser, Kathrin; Duchaine, Thomas; van Steensel, Maurice; Hall, David H.; Pause, Arnim.

In: PLoS Genetics, Vol. 11, No. 10, e1005520, 2015.

Research output: Contribution to journalArticle

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 2015, 'FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores', PLoS Genetics, vol. 11, no. 10, e1005520. https://doi.org/10.1371/journal.pgen.1005520
Possik E, Ajisebutu A, Manteghi S, Gingras MC, Vijayaraghavan T, Flamand M et al. FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. PLoS Genetics. 2015;11(10). e1005520. https://doi.org/10.1371/journal.pgen.1005520
Possik, Elite ; Ajisebutu, Andrew ; Manteghi, Sanaz ; Gingras, Marie Claude ; Vijayaraghavan, Tarika ; Flamand, Mathieu ; Coull, Barry ; Schmeisser, Kathrin ; Duchaine, Thomas ; van Steensel, Maurice ; Hall, David H. ; Pause, Arnim. / FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. In: PLoS Genetics. 2015 ; Vol. 11, No. 10.
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