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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-04-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3998892?pdf=render |
| _version_ | 1818303087387869184 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Elite Possik |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T05:49:13Z |
| format | Article |
| id | doaj.art-ef48d48370b1463d827a541d13d5f7ae |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T05:49:13Z |
| publishDate | 2014-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-ef48d48370b1463d827a541d13d5f7ae2022-12-21T23:57:36ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-04-01104e100427310.1371/journal.pgen.1004273Folliculin regulates ampk-dependent autophagy and metabolic stress survival.Elite PossikZahra JalaliYann NouëtMing YanMarie-Claude GingrasKathrin SchmeisserLorena PanaiteFanny DupuyDmitri KharitidiLaëtitia ChotardRussell G JonesDavid H HallArnim PauseDysregulation 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.http://europepmc.org/articles/PMC3998892?pdf=render |
| spellingShingle | 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 Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS Genetics |
| title | Folliculin regulates ampk-dependent autophagy and metabolic stress survival. |
| title_full | Folliculin regulates ampk-dependent autophagy and metabolic stress survival. |
| title_fullStr | Folliculin regulates ampk-dependent autophagy and metabolic stress survival. |
| title_full_unstemmed | Folliculin regulates ampk-dependent autophagy and metabolic stress survival. |
| title_short | Folliculin regulates ampk-dependent autophagy and metabolic stress survival. |
| title_sort | folliculin regulates ampk dependent autophagy and metabolic stress survival |
| url | http://europepmc.org/articles/PMC3998892?pdf=render |
| work_keys_str_mv | AT elitepossik folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT zahrajalali folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT yannnouet folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT mingyan folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT marieclaudegingras folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT kathrinschmeisser folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT lorenapanaite folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT fannydupuy folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT dmitrikharitidi folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT laetitiachotard folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT russellgjones folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT davidhhall folliculinregulatesampkdependentautophagyandmetabolicstresssurvival AT arnimpause folliculinregulatesampkdependentautophagyandmetabolicstresssurvival |