Ciliary localization of folliculin mediated via a kinesin‐2‐binding motif is required for its functions in mTOR regulation and tumor suppression

Zhang, Yunlong; Liu, Ying; Dai, Yu; Ren, Yazhe; Bao, Guangsen; Ai, Bo; Jiang, Yu

doi:10.1002/1873-3468.13959

Cited by 5 publications

(4 citation statements)

References 31 publications

(56 reference statements)

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“…A potential explanation linking aerobic glycolysis to TFEB activation is the recent observation that folliculin inhibits lactate dehydrogenase A. Predictably, loss of folliculin activity would promote a Warburg-type phenotype and result in inhibition of nuclear TFEB egress ( 35 ). Folliculin has also been localized to the cilia, where it controls mTORC1 signaling in response to flow stress ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1

Shillingford

Shayman

2023

American Journal of Physiology-Renal Physiology

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Polycystic kidney disease is a disorder of renal epithelial growth and differentiation. Transcription factor EB (TFEB), a master regulator of lysosome biogenesis and function, was studied for a potential role in this disorder. The nuclear translocation and functional responses to TFEB activation were studied in three murine models of renal cystic disease, including knockouts of folliculin, folliculin interacting proteins 1 and 2, and Pkd1 as well as in mouse embryonic fibroblasts lacking Pkd1 and 3-dimensional cultures of MDCK cells. Nuclear translocation of Tfeb characterized cystic but not non-cystic renal tubular epithelia in all three murine models as both an early and sustained response to cyst formation. The epithelia expressed elevated levels of Tfeb-dependent gene products, including cathepsin B and Gpnmb. Nuclear Tfeb translocation was observed in mouse embryonic fibroblasts lacking Pkd1, but not wild type fibroblasts. Pkd1 knockout fibroblasts were characterized by increased Tfeb dependent transcripts, lysosomal biogenesis and repositioning, and increased autophagy. The growth of MDCK cell cysts was markedly increased following exposure to the TFEB agonist, compound C1, and nuclear Tfeb translocation was observed in response to both forskolin and compound C1 treatment. Nuclear TFEB also characterized the cystic epithelia but not non-cystic tubular epithelia in human ADPKD patients. The non-canonical activation of TFEB is characteristic of cystic epithelia in multiple models of renal cystic disease including those associated with the loss of Pkd1. Nuclear TFEB translocation is functionally active in these models and may be a component of a general pathway contributing to cystogenesis and growth.

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Section: Discussionmentioning

confidence: 99%

Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1

Shillingford

Shayman

2023

American Journal of Physiology-Renal Physiology

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“…Several studies have proposed that BHD is a novel ciliopathy ( 13 , 14 , 20 ). Single point mutations within FLCN can disrupt its ciliary location and cause cilia-related diseases ( 14 ). Basten et al.…”

Section: Discussionmentioning

confidence: 99%

“…FLCN is essential for ciliary localization and regulates mTOR signaling through primary cilia ( 13 ). Single point mutations within FLCN may disrupt these functions and cause cilia-related diseases ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Concurrent Germline and Somatic Mutations in FLCN and Preliminary Exploration of Its Function: A Case Report

et al. 2022

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Birt–Hogg–Dube syndrome is an autosomal dominant condition that arises from germline folliculin (FLCN) mutations. It is characterized by skin fibrofolliculomas, lung cysts, pneumothorax, and renal cancer. Here, we present the case of a 36-year-old woman with asymptomatic, multiple renal tumors and a history of spontaneous pneumothorax. Genetic analysis revealed a hotspot FLCN germline mutation, c.1285dupC (p.H429fs), and a novel somatic mutation, c.470delT (p.F157fs). This information and the results of immunohistochemical analysis of the renal tumors indicated features compatible with a tumor suppressor role of FLCN. Two transcription factors, oncogenic TFEB and TFE3, were shown to be regulated by FLCN inactivation, which results in their nuclear localization. We showed that a deficiency in the tumor suppressor FLCN leads to deregulation of the mammalian target of rapamycin signaling (mTOR) pathway. A potential link between FLCN mutation and ciliary length was also examined. Thus, the mutation identified in our patient provides novel insights into the relationship among FLCN mutations, TFEB/TFE3, mTOR, and cilia. However, an in-depth understanding of the role of folliculin in the molecular pathogenesis of renal cancer requires further study.

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“…Intraflagellar transport (IFT) is a two-way cargo transport system, and all signaling within the primary cilia must be IFT-dependent to complete. Generally, it is divided into anterograde IFT (moves from the base of a cilium to the tip) and retrograde IFT (moves from the tip back to the base), which are mediated by heterotrimeric kinesin-2 and cytoplasmic dynein 2 motor (some call cytoplasmic dynein 1b motor), respectively [ 36 , 37 ]. In this IFT train, when the cargo needs to be transported in the basal body, the IFT-B complex aggregates and activates kinesin-2 and moves the cargo to the tip of axoneme and they dissociate, releasing the substance; then, the new cargo comes in and kinesin-2 deactivates whereas dynein 2 activates in bonding with the IFT-A complex and transports the new cargo to the basal body [ 38 ].…”

Section: The Materials Transport Of Primary Ciliamentioning

confidence: 99%

Primary Cilia: A Cellular Regulator of Articular Cartilage Degeneration

Zhou

Ling

et al. 2022

Stem Cells International

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Osteoarthritis (OA) is the most common joint disease that can cause pain and disability in adults. The main pathological characteristic of OA is cartilage degeneration, which is caused by chondrocyte apoptosis, cartilage matrix degradation, and inflammatory factor destruction. The current treatment for patients with OA focuses on delaying its progression, such as oral anti-inflammatory analgesics or injection of sodium gluconate into the joint cavity. Primary cilia are an important structure involved in cellular signal transduction. Thus, they are very sensitive to mechanical and physicochemical stimuli. It is reported that the primary cilia may play an important role in the development of OA. Here, we review the correlation between the morphology (location, length, incidence, and orientation) of chondrocyte primary cilia and OA and summarize the relevant signaling pathways in chondrocytes that could regulate the OA process through primary cilia, including Hedgehog, Wnt, and inflammation-related signaling pathways. These data provide new ideas for OA treatment.

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Ciliary localization of folliculin mediated via a kinesin‐2‐binding motif is required for its functions in mTOR regulation and tumor suppression

Cited by 5 publications

References 31 publications

Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1

Functional TFEB activation characterizes multiple models of renal cystic disease and loss of polycystin-1

Concurrent Germline and Somatic Mutations in FLCN and Preliminary Exploration of Its Function: A Case Report

Primary Cilia: A Cellular Regulator of Articular Cartilage Degeneration

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