Ramirez-Reyes, J. M. J. | Search bioRxiv

bioRxiv2026

AMPK-dependent FLCN phosphorylation activates a survival response to hypoxia

Adaptation to low oxygen tensions is required to survive physiological and pathological stress conditions. We discovered an adenosine monophosphate-activated protein kinase (AMPK)-dependent, hypoxia-specific survival pathway through transcription factors (TFEB, TFE3). This pathway is distinct from nutrient sensing and independent of GAP Activity Towards Rags 1 (GATOR1). Mechanistically, AMPK phosphorylates the tumor suppressor folliculin (FLCN) at a highly conserved serine, inhibiting its GAP activity towards the Rag-GTPases, resulting in mechanistic target of rapamycin complex 1 (mTORC1) inhibition, TFE3 activation, resulting in lysosomal and mitochondrial biogenesis essential for hypoxia adaptation. TFEB/3 activity correlates with the hypoxia signature in hypoxic tumor areas. Cancer patients with elevated TFEB/3 activity show poor survival, specifically in hypoxia. These findings identify the AMPK-FLCN-TFE3 axis as a therapeutic target in tumors.

biochemistry↗

bioRxiv2020

FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model

Non-alcoholic steatohepatitis (NASH) represents a major economic burden and is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat this condition. Emerging data suggests an important role of autophagy in this condition, which serves to degrade intracellular lipid stores, reduce hepatocellular damage, and dampen inflammation. Autophagy is primarily regulated by the transcription factors TFEB and TFE3, which are negatively regulated by mTORC1. Given that FLCN is an mTORC1 activator via its GAP activity towards RagC/D, we generated a liver specific Flcn knockout mouse model to study its role in NASH progression. We demonstrate that loss of FLCN results in reduced triglyceride accumulation, fibrosis, and inflammation in mice exposed to a NASH-inducing diet. Hence, the GAP activity of FLCN could a promising target for small molecule drugs to treat NASH progression by specifically activating autophagy and lysosomal biogenesis while leaving mRNA translation machinery unperturbed. Collectively, these results show an unexpected role for FLCN in NASH progression and highlight new possibilities for treatment strategies through its role in hepatocyte homeostasis.

pathology↗