Folliculin regulates ampk-dependent autophagy and metabolic stress survival.
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.
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Elite
E
Possik
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Zahra
Z
Jalali
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Yann
Y
Nouët
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Ming
M
Yan
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Marie-Claude
MC
Gingras
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Kathrin
K
Schmeisser
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Lorena
L
Panaite
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Physiology, McGill University, Montréal, Québec, Canada.
Fanny
F
Dupuy
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Dmitri
D
Kharitidi
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Laëtitia
L
Chotard
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Physiology, McGill University, Montréal, Québec, Canada.
Russell G
RG
Jones
Department of Neuroscience, Albert Einstein College of Medicine, New York, New York, United States of America.
David H
DH
Hall
Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Arnim
A
Pause
D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics*; D002460:Cell Line; D004970:Estrone / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D025521:Tumor Suppressor Proteins; D004970:Estrone; D055372:AMP-Activated Protein Kinases