Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia*

Folliculin (FLCN) is the tumor suppressor associated with Birt-Hogg-Dubé (BHD) syndrome that predisposes patients to incident of hamartomas and cysts in multiple organs. Its inactivation causes deregulation in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the underlying mechanism is poorly defined. In this study, we show that FLCN is a ciliary protein that functions through primary cilia to regulate mTORC1. In response to flow stress, FLCN associates with LKB1 and recruits the kinase to primary cilia for activation of AMPK resided at basal bodies, which causes mTORC1 down-regulation. In cells depleted of FLCN, LKB1 fails to accumulate in primary cilia and AMPK at the basal bodies remains inactive, thus nullifying the inhibitory effect of flow stress on mTORC1 activity. Our results demonstrate that FLCN is part of a flow sensory mechanism that regulates mTORC1 through primary cilia.

[1]  K. Nagashima,et al.  Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn , 2015, Proceedings of the National Academy of Sciences.

[2]  Ming Yan,et al.  The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. , 2014, The Journal of clinical investigation.

[3]  A. Tee,et al.  Birt-Hogg-Dube syndrome is a novel ciliopathy. , 2013, Human molecular genetics.

[4]  J. Scholey.  Kinesin-2: a family of heterotrimeric and homodimeric motors with diverse intracellular transport functions. , 2013, Annual review of cell and developmental biology.

[5]  L. Schmidt.  Birt–Hogg–Dubé syndrome: from gene discovery to molecularly targeted therapies , 2013, Familial Cancer.

[6]  B. Dynlacht,et al.  Assembling a primary cilium. , 2013, Current opinion in cell biology.

[7]  W. Linehan,et al.  The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development. , 2012, Blood.

[8]  E. Golemis,et al.  The role of the cilium in normal and abnormal cell cycles: emphasis on renal cystic pathologies , 2012, Cellular and Molecular Life Sciences.

[9]  John F. Dishinger,et al.  Kinesin motors and primary cilia. , 2011, Biochemical Society transactions.

[10]  G. Walz,et al.  mTOR and rapamycin in the kidney: signaling and therapeutic implications beyond immunosuppression. , 2011, Kidney international.

[11]  Gerd Walz,et al.  Primary cilia regulate mTORC1 activity and cell size through Lkb1 , 2010, Nature Cell Biology.

[12]  K. Anderson,et al.  The primary cilium: a signalling centre during vertebrate development , 2010, Nature Reviews Genetics.

[13]  P. Wilson,et al.  Carboxy Terminal Tail of Polycystin-1 Regulates Localization of TSC2 to Repress mTOR , 2010, PloS one.

[14]  Peter Satir,et al.  The primary cilium at a glance , 2010, Journal of Cell Science.

[15]  W. Linehan,et al.  Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2 , 2009, Proceedings of the National Academy of Sciences.

[16]  A. Pause,et al.  Renal tumour suppressor function of the Birt–Hogg–Dubé syndrome gene product folliculin , 2009, Journal of Medical Genetics.

[17]  B. Yoder,et al.  The Primary Cilium as a Complex Signaling Center , 2009, Current Biology.

[18]  Madeline A Lancaster,et al.  The primary cilium as a cellular signaling center: lessons from disease. , 2009, Current opinion in genetics & development.

[19]  E. Henske,et al.  The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis , 2009, Oncogene.

[20]  Ximing J. Yang,et al.  Deficiency of FLCN in Mouse Kidney Led to Development of Polycystic Kidneys and Renal Neoplasia , 2008, PloS one.

[21]  E. Henske,et al.  The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway , 2008, Human molecular genetics.

[22]  T. Kobayashi,et al.  Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein , 2008, Oncogene.

[23]  B. Turk,et al.  AMPK phosphorylation of raptor mediates a metabolic checkpoint. , 2008, Molecular cell.

[24]  P. Choyke,et al.  Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. , 2008, Journal of the National Cancer Institute.

[25]  W. Linehan,et al.  The UOK 257 cell line: a novel model for studies of the human Birt-Hogg-Dubé gene pathway. , 2008, Cancer genetics and cytogenetics.

[26]  J. Scholey.  Intraflagellar transport motors in cilia: moving along the cell's antenna , 2008, The Journal of cell biology.

[27]  J. Hartley,et al.  Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling , 2006, Proceedings of the National Academy of Sciences.

[28]  J. Reiter,et al.  The Primary Cilium as the Cell's Antenna: Signaling at a Sensory Organelle , 2006, Science.

[29]  K. Inoki,et al.  TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival , 2003, Cell.

[30]  G. Pazour,et al.  The vertebrate primary cilium is a sensory organelle. , 2003, Current opinion in cell biology.

[31]  Maria Merino,et al.  Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. , 2002, Cancer cell.

[32]  G. Pazour,et al.  Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella , 2000, The Journal of cell biology.

[33]  W. J. Dubé,et al.  Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. , 1977, Archives of dermatology.

[34]  P. Beales,et al.  Modeling ciliopathies: Primary cilia in development and disease. , 2008, Current topics in developmental biology.

[35]  P. Beales,et al.  Chapter 5 Modeling Ciliopathies , 2008 .