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Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia
Mingming Zhong1, Xuwen Zhao1, Jinmei Li1
1From the Guangdong Provincial Key Laboratory of Proteomics; Key laboratory of Transcriptomics and Proteomics of Ministry of Education of China, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
Abstract:
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.
Insights
Folliculin (FLCN) protein regulates cell growth via primary cilia. FLCN inactivation disrupts flow sensing, leading to abnormal mTORC1 signaling in Birt-Hogg-Dubé syndrome.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Folliculin (FLCN) is a tumor suppressor linked to Birt-Hogg-Dubé (BHD) syndrome.
- FLCN inactivation disrupts mammalian target of rapamycin complex 1 (mTORC1) signaling, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism by which FLCN regulates mTORC1 signaling.
- To investigate the role of primary cilia in FLCN's tumor suppressor function.
Main Methods:
- Utilized cell-based assays to examine FLCN localization and function.
- Investigated the interaction between FLCN, LKB1, and AMPK in primary cilia.
- Analyzed mTORC1 activity under conditions of flow stress in FLCN-depleted cells.
Main Results:
- Folliculin (FLCN) is localized to primary cilia and regulates mTORC1 signaling through this organelle.
- FLCN facilitates the recruitment and activation of LKB1 and AMPK in primary cilia in response to flow stress.
- FLCN depletion prevents flow stress-induced mTORC1 inhibition due to impaired LKB1-AMPK activation.
Conclusions:
- FLCN functions as a critical component of a primary cilia-based flow sensory mechanism.
- This mechanism links mechanical stimuli to mTORC1 pathway regulation, impacting cell growth and tumor suppression.
- Understanding this pathway offers insights into Birt-Hogg-Dubé syndrome pathogenesis.
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