Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin

Abstract

FLCN was identified as the gene responsible for Birt-Hogg-Dubé (BHD) syndrome, a hereditary syndrome associated with the appearance of familiar renal oncocytomas. Most mutations affecting FLCN result in the truncation of the protein, and therefore loss of its associated functions, as typical for a tumor suppressor. FLCN encodes the protein folliculin (FLCN), which is involved in numerous biological processes; mutations affecting this protein thus lead to different phenotypes depending on the cellular context. FLCN forms complexes with two large interacting proteins, FNIP1 and FNIP2. Structural studies have shown that both FLCN and FNIPs contain longin and differentially expressed in normal versus neoplastic cells (DENN) domains, typically involved in the regulation of small GTPases. Accordingly, functional studies show that FLCN regulates both the Rag and the Rab GTPases depending on nutrient availability, which are respectively involved in the mTORC1 pathway and lysosomal positioning. Although recent structural studies shed light on the precise mechanism by which FLCN regulates the Rag GTPases, which in turn regulate mTORC1, how FLCN regulates membrane trafficking through the Rab GTPases or the significance of the intriguing FLCN-FNIP-AMPK complex formation are questions that still remain unanswered. We discuss the recent progress in our understanding of FLCN regulation of both growth signaling and lysosomal positioning, as well as future approaches to establish detailed mechanisms to explain the disparate phenotypes caused by the loss of FLCN function and the development of BHD-associated and other tumors.

Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

“…This implies that the concurrence in each patient of variants in two or more genes acting in various steps of the autophagy–lysosomal pathway might explain differences in the clinical expressivity of the GAA mutations. Remarkably, in this study, we identified five LOPD patients (F1-II4, F1-II5, F1-II9, F2-II4 and F2-II5) showing the highest severity index score, deleterious variants affecting important domains of RILP and FNIP2 proteins involved in lysosome cellular positioning and autophagy [ 36 ].…”

“…Moreover, during nutrient insufficiency, the FLCN–FNIP complex modulates the formation of a FLCN–RILP–Rab complex for promoting the clustering of lysosomes around the nucleus [ 36 ].…”

“…Moreover, FLCN and FNIP proteins each contain both a longin and a differentially expressed in normal versus neoplastic cells (DENN) domain [ 40 ], which are implicated in the regulation of small GTPases and membrane trafficking. In fact, the FLCN–FNIP complex regulates both the Rag and Rab GTPase families [ 41 , 42 ], which in turn modulate the key mTORC1 signalling pathway and lysosomal distribution, respectively, in a manner dependent on amino acid availability [ 36 ]. Noteworthy, the two rare and deleterious variants identified in the two LOPD families alter the longin and DENN domains of the protein, suggesting that they might disturb the formation of this complex.…”

Folliculin Haploinsufficiency Causes Cellular Dysfunction of Pleural Mesothelial Cells

“…We speculate that this is partially because folliculin has so many binding partners, and may select one or more unique partner(s) depending on the differentiation stage and nutrient signaling 46,47 . Furthermore, a long-lasting state of FLCN haploinsu ciency, rather than abrupt null FLCN expression by deletion, may cause different intracellular signaling pathways to keep cellular homeostasis.…”

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets

“…Recent studies support a functional role for the FLCN-FNIP complex as a GTPase activating protein involved in the fine modulation of Rag GTPase are nucleotide binding and transmission of the nutrient status to mTORC1 [ 116 ]. It was proposed that the GTPase activating properties of the FLCN-FNIP complex occurs downstream of GATAR1 protein complex and together orchestrate a unique molecular regulation: when amino acid levels are low, the GTPase activating protein activity of GATOR1 promotes the GDP-Rag A7B condition and the FLCN-FNIP complex is recruited at the level of lysosomes to drive the GTPase activating properties toward Rag C/D [ 117 , 118 ].…”