AMPK-dependent FLCN phosphorylation activates a survival response to hypoxia

Ramirez-Reyes, J. M. J.; Pollato-Blanco, A.; Duhamel, S.; Hebert, S.; Kleinman, C. L.; Nagar, B.; Park, M. M.; Ursini-Siegel, J.; Pause, A.

doi:10.64898/2026.05.20.726614

bioRxiv · 10.64898/2026.05.20.726614

AMPK-dependent FLCN phosphorylation activates a survival response to hypoxia

Ramirez-Reyes, J. M. J.·Pollato-Blanco, A.·Duhamel, S.·Hebert, S.·Kleinman, C. L.·Nagar, B.·Park, M. M.·Ursini-Siegel, J.·Pause, A.

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Abstract

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.

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Ramirez-Reyes, J. M. J., Pollato-Blanco, A., Duhamel, S., Hebert, S., Kleinman, C. L., Nagar, B., Park, M. M., Ursini-Siegel, J., Pause, A.. 2026-05-22. AMPK-dependent FLCN phosphorylation activates a survival response to hypoxia. https://doi.org/10.64898/2026.05.20.726614

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