Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival

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.

Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα

“…These results prompted us to investigate the molecular signature of FLCN-null adipocytes responsible for the altered metabolic and lipid storage phenotype. FLCN interacts with AMPK and has been described as a negative regulator of AMPK signaling (Baba et al 2006;Possik et al 2014Possik et al , 2015Yan et al 2014). Indeed, we recently demonstrated that loss of FLCN constitutively activates AMPKα, which in turn leads to an elevation in PGC-1α levels and consequently induces mitochondrial biogenesis .…”

“…FLCN has no significant sequence homology with any known protein and is highly conserved across species, suggesting an important biological role, as illustrated by the embryonic lethality of Flcn homozygous disruption in mice (Baba et al 2008;Chen et al 2008;Hudon et al 2010). FLCN functions as a repressor of the master energy sensor AMP-activated protein kinase (AMPK) via FLCN-interacting protein (FNIP) (Baba et al 2006(Baba et al , 2008Behrends et al 2010;Preston et al 2011;Possik et al 2014;Yan et al 2014).…”

“…We reported previously that ablation of FLCN expression or loss of FLCN binding to AMPK induces chronic AMPK pathway hyperactivation in nematodes and various cellular contexts, leading to increased energy reserves, enhanced metabolic and osmotic stress resistance, and metabolic transformation (Preston et al 2011;Possik et al 2014;Yan et al 2014). This hyperactivation of AMPK induces the expression of PGC-1α in muscle cells, mouse embryonic fibroblasts (MEFs), and cancer cells, which triggers mitochondrial biogenesis and promotes transcriptional regulation of nuclear-encoded mitochondrial genes (Jäger et al 2007;Yan et al 2014).…”

Glycogen: A must have storage to survive stressful emergencies

“…14 Since the chronic AMPK activation has been shown to lead to glycogen accumulation in multiple model systems, and because we have previously demonstrated that loss of flcn-1 chronically activates AMPK in C. elegans and in mammalian cells, 15 we hypothesized that the increased accumulation of glycogen in flcn-1 animals depends on AMPK. Indeed, we demonstrated using iodine staining, that AMPK is required for glycogen accumulation in both wild-type and flcn-1 animals.…”

“…[15][16][17] We also showed that the increased resistance to energy stresses is evolutionarily conserved and requires the 5'AMP-activated protein kinase (AMPK), a major regulator of cellular energy homeostasis and stress response. 15,17 In our recent work, we demonstrate an important role for FLCN-1/ AMPK in the regulation of resistance to hyperosmotic stress in C. elegans.…”