Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival

Elite Possik, Zahra Jalali, Yann Nouët, Ming Yan, Marie Claude Gingras, Kathrin Schmeisser, Lorena Panaite, Fanny Dupuy, Dmitri Kharitidi, Laëtitia Chotard, Russell G. Jones, David H. Hall, Arnim Pause

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57 Scopus citations

Abstract

Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function.

Original languageEnglish (US)
Article numbere1004273
JournalPLoS genetics
Volume10
Issue number4
DOIs
StatePublished - Apr 2014

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ASJC Scopus subject areas

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

Cite this

Possik, E., Jalali, Z., Nouët, Y., Yan, M., Gingras, M. C., Schmeisser, K., Panaite, L., Dupuy, F., Kharitidi, D., Chotard, L., Jones, R. G., Hall, D. H., & Pause, A. (2014). Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival. PLoS genetics, 10(4), [e1004273]. https://doi.org/10.1371/journal.pgen.1004273