Abstract
Folliculin (FLCN) is a tumor suppressor gene responsible for the inherited Birt-Hogg-Dubé (BHD) syndrome, which affects kidneys, skin and lungs. FLCN is a highly conserved protein that forms a complex with folliculin interacting proteins 1 and 2 (FNIP1/2). Although its sequence does not show homology to known functional domains, structural studies have determined a role of FLCN as a GTPase activating protein (GAP) for small GTPases such as Rag GTPases. FLCN GAP activity on the Rags is required for the recruitment of mTORC1 and the transcriptional factors TFEB and TFE3 on the lysosome, where mTORC1 phosphorylates and inactivates these factors. TFEB/TFE3 are master regulators of lysosomal biogenesis and function, and autophagy. By this mechanism, FLCN/FNIP complex participates in the control of metabolic processes. AMPK, a key regulator of catabolism, interacts with FLCN/FNIP complex. FLCN loss results in constitutive activation of AMPK, which suggests an additional mechanism by which FLCN/FNIP may control metabolism. AMPK regulates the expression and activity of the transcriptional cofactors PGC1α/β, implicated in the control of mitochondrial biogenesis and oxidative metabolism. In this review, we summarize our current knowledge of the interplay between mTORC1, FLCN/FNIP, and AMPK and their implications in the control of cellular homeostasis through the transcriptional activity of TFEB/TFE3 and PGC1α/β. Other pathways and cellular processes regulated by FLCN will be briefly discussed.
Highlights
Folliculin (FLCN) gene was first identified in 2002 as the gene responsible for the Birt-Hogg-Dubé (BHD) syndrome (Birt et al, 1977; Nickerson et al, 2002)
FLCN/FNIP complex has emerged as an essential modulator of metabolic processes, and its dysregulation has been associated with metabolic diseases and cancer
FLCN/FNIP complex shows GTPase activating protein (GAP) activity for related GTP-binding protein (Rag) C/D, which was initially proposed to be essential for mechanistic target of rapamycin complex 1 (mTORC1) recruitment to lysosome and activation
Summary
Folliculin (FLCN) gene was first identified in 2002 as the gene responsible for the Birt-Hogg-Dubé (BHD) syndrome (Birt et al, 1977; Nickerson et al, 2002). We discuss the role of FLCN/FNIP complex as a modulator of mTORC1 and AMPK pathways, emphasizing its effect on the function of downstream transcription factor binding to IGHM enhancer B (TFEB) and TFE3, and transcriptional coactivator peroxisome proliferatoractivated receptor-γ coactivator 1α (PGC1α). MTORC1 substrates without a TOS motif such as the transcription factors TFE3 and TFEB need FLCN GAP activity to interact with the Rags to be phosphorylated (Napolitano et al, 2020).
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