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

Natàlia De Martín Garrido,Christopher H S Aylett

doi:10.3389/fcell.2020.00108

Natàlia De Martín Garrido, Christopher H S Aylett

Open Access

https://doi.org/10.3389/fcell.2020.00108

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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.

Highlights

In 2018, over 400,000 new cases of kidney cancer were diagnosed worldwide according the Global Cancer Observatory, being the fourteenth most commonly occurring cancer and resulting in more than 175,000 deaths due to a paucity of effective treatments
Amino acid availability promotes the active Rag GTPase nucleotide configuration, RagA/B-GTP and RagC/D-GDP, which is capable of recruiting mTORC1 through a direct interaction with Raptor (Sancak et al, 2008)
We have covered the means by which the FLCN-Folliculin interacting proteins (FNIPs) complex is recruited to the lysosome upon starvation, where it interacts with the Rag GTPases and has GTPase activating protein (GAP) activity toward RagC (Petit et al, 2013; Tsun et al, 2013), playing a crucial role in the proper recruitment of mTORC1 to the lysosome

Summary

Introduction

In 2018, over 400,000 new cases of kidney cancer were diagnosed worldwide according the Global Cancer Observatory, being the fourteenth most commonly occurring cancer and resulting in more than 175,000 deaths due to a paucity of effective treatments. Functional studies support the notion that FLCN-FNIP complex regulates both the Rag and Rab GTPase families (Dodding, 2017; Schmidt and Linehan, 2018), which in turn modulate the key mTORC1 signaling pathway and lysosomal distribution respectively, in a manner dependent on amino acid availability.

Results

Conclusion