Folliculin – A tumor suppressor at the intersection of metabolic signaling and membrane traffic

Dodding, Mark P.

doi:10.1080/21541248.2016.1204808

Cited by 8 publications

(8 citation statements)

References 50 publications

(12 reference statements)

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“…Recent structural studies have shown that the FLCN and FNIP proteins each contain both a longin and a differentially expressed in normal versus neoplastic cells (DENN) domain (Nookala et al, 2012;Zhang et al, 2012;Lawrence et al, 2019;Shen et al, 2019), which are protein folds that have been variously implicated in the regulation of small GTPases and membrane trafficking. Accordingly, 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. Here we attempt to summarize our current knowledge of FLCN both in nutrient signaling and in lysosomal positioning.…”

Section: Introductionmentioning

confidence: 55%

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

Garrido

Chs

2020

Front. Cell Dev. Biol.

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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.

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Section: Introductionmentioning

confidence: 55%

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

Garrido

Chs

2020

Front. Cell Dev. Biol.

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“…The mechanism of how FLCN might negatively regulate the miRNAs is still not known. However, a recent study shows that FLCN knockdown inhibits the motility and perinuclear clustering of lysosome,37 which alters the cellular function of lysosome by increasing its PH 38. Interestingly, a similar change in lysosome has been linked to the increase of exosomal secretion in cells,39 indicating that FLCN deficiency may involve in hypersecretion of miRNAs, presumably in lung epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome

Min

Mao

Zou

et al. 2020

Thorax

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BackgroundBirt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma.MethodsThe expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts.ResultsCystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424–5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424–5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency.ConclusionThe upregulation of miR-424–5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients.

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“…Similar to previous reports 6,9,10 , the MAGs were found to be highly enriched with ESP ( Figure 1c ), which further reinforced their ancestral linkage to eukaryotes. In addition to the reported ESP 6 , we identified a potential subunit of the COPII vesicle coat complex (associated with intracellular vesicle traffic and secretion) in Thorarchaeia and proteins that harbor the N-terminal domain of folliculin - a eukaryote-specific protein which is known to be involved in membrane trafficking in humans 11 ( Figure 1c) in Lokiarchaea. Furthermore, we retrieved conclusive hits for the ESP-related domains Ezrin/radixin/moesin C-terminal domain and active zone protein ELKS in Lokiarchaeia.…”

Section: Mainmentioning

confidence: 96%

The sunlit microoxic niche of the archaeal eukaryotic ancestor comes to light

Bulzu

Andrei

Salcher

et al. 2018

Preprint

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SummaryRecent advances in phylogenomic analyses and increased genomic sampling of uncultured prokaryotic lineages brought compelling evidence in support of the emergence of eukaryotes from within the Archaea domain of life. The discovery of Asgardaeota archaea and their recognition as the closest extant relative of eukaryotes fuelled the revival of a decades-old debate regarding the topology of the tree of life. While it is apparent that Asgardaeota encode a plethora of eukaryotic-specific proteins (the highest number identified to date in prokaryotes), the lack of genomic information and metabolic characterization has precluded inferences about their lifestyles and the metabolic landscape that may have favoured the emergence of the hallmark eukaryotic subcellular architecture. Here, we use advanced phylogenetic analyses to infer the deep ancestry of eukaryotes and genome-scale metabolic reconstructions to shed light on the metabolic milieu of the closest archaeal eukaryotic ancestors discovered till date. In doing so, we: i) generate the largest Asgardaeota genomic dataset available so far, ii) describe a new clade of rhodopsins encoded within the recovered genomes, iii) provide unprecedented evidence for mixotrophy within Asgardaeota, iv) present first-ever proofs that the closest extant archaeal relatives to all eukaryotes (Heimdallarchaeia) have microoxic lifestyles with aerobic metabolic pathways unique among Archaea (i.e. kynurenine pathway) and v) generate the first images of Asgardaeota.

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Folliculin – A tumor suppressor at the intersection of metabolic signaling and membrane traffic

Cited by 8 publications

References 50 publications

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

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

FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome

The sunlit microoxic niche of the archaeal eukaryotic ancestor comes to light

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