DOCSLIB.ORG

Novel Folliculin Gene Mutations in Polish Patients with Birt–Hogg–Dubé Syndrome Elżbieta Radzikowska1*, Urszula Lechowicz2, Jolanta Winek3 and Lucyna Opoka4

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Novel Folliculin Gene Mutations in Polish Patients with Birt–Hogg–Dubé Syndrome Elżbieta Radzikowska1*, Urszula Lechowicz2, Jolanta Winek3 and Lucyna Opoka4 Radzikowska et al. Orphanet J Rare Dis (2021) 16:302 https://doi.org/10.1186/s13023-021-01931-0 RESEARCH Open Access Novel folliculin gene mutations in Polish patients with Birt–Hogg–Dubé syndrome Elżbieta Radzikowska1*, Urszula Lechowicz2, Jolanta Winek3 and Lucyna Opoka4 Abstract Background: Birt–Hogg–Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by muta- tions in the folliculin gene (FLCN). The disease is characterised by skin lesions (fbrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts with pneumothoraces and renal tumours. We present the features of Polish patients with BHDS. Materials and methods: The frst case of BHDS in Poland was diagnosed in 2016. Since then, 15 cases from 10 fami- lies have been identifed. Thirteen patients were confrmed via direct FLCN sequencing, and two according to their characteristic clinical and radiological presentations. Results: BHDS was diagnosed in 15 cases (13 women and 2 men) from 10 families. The mean ages at the time of frst pneumothorax and diagnosis were 38.4 13.9 and 47.7 13 years, respectively. Five patients (33%) were ex- smokers (2.1 1.37 packyears), and 10 (67%)± had never smoked± cigarettes. Twelve patients (83%) had a history of recurrent symptomatic± pneumothorax. Three patients had small, asymptomatic pneumothoraces, which were only detected upon computed tomography examination. All patients had multiple bilateral pulmonary cysts, distributed predominantly in the lower and middle, peripheral, and subpleural regions of the lungs. Generally, patients exhibited preserved lung function. Skin lesions were seen in four patients (27%), one patient had renal angiomyolipoma, and one had bilateral renal cancer. Diferent mutations of the FLCN gene were identifed (mainly in exon 6), with two novel heterozygous variants: c.490delA p.(Arg164GlyTer13) and c.40delC p.(His14ThrsfTer41). Conclusions: All analysed patients with BHDS presented with lung lesions and with less frequent skin and renal lesions than previously reported in other populations. In addition, more frequent mutations located in exon 6 were detected, and two novel FLCN gene mutations were identifed. Introduction proliferation. Expression of FLNC is observed in the lung, Birt–Hogg–Dubé syndrome (BHDS) is a rare, autoso- skin, distal nephrons, brain, heart, placenta, and testis mal dominant, inherited disease caused by mutations [1–3]. Terefore, afected patients present with lesions in in the folliculin gene (FLCN) located on the short arm these organs [1, 4–6]. of chromosome 17p11.2. FLCN functions as a tumour Te disease is characterised by skin lesions (fbrofol- suppressor gene. Te protein product of this gene, fol- liculomas, trichodiscomas, acrochordons) that usually liculin, participates in the proper functioning of the cel- occur on the face, neck and upper torso, pulmonary cysts lular cytoskeleton and extracellular matrix as well as with pneumothoraces, and renal tumours. BHDS was frst described more than 50 years ago, and since then, approximately 600 families with the syndrome have been *Correspondence: [email protected] identifed worldwide [4, 5, 7–9]. 1 3rd Department of Lung Diseases and Oncology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland A wide spectrum of BHDS symptoms has been found Full list of author information is available at the end of the article in diferent populations, and phenotypic variability is © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Radzikowska et al. Orphanet J Rare Dis (2021) 16:302 Page 2 of 10 seen, even within the same family. Usually, the frst mani- cyst size (maximum diameter: < 6 mm, > 15 mm), cyst festation of the syndrome is skin lesions, which develop shape (round, oval) and lung involvement (25%, 50% and at the age of 20–30 years in > 80–90% of patients [2, 75% of lung felds). 9–12]. Subsequently, pneumothorax, as a typical feature Pulmonary function tests (PFTs) were performed of lung involvement, presents at the age of 30–40 years; according to the joint guidelines of the American To- 50–60% of patients experience pneumothorax, which is racic Society and European Respiratory Society, at usually recurrent. Various sizes, shapes and numbers of 3–6 months after an episode of pneumothorax. Lung thin-walled cysts, located in the middle and lower parts volumes were measured using body plethysmography of the lungs and in the subpleural regions, are frequently (Jaeger MasterScreen software ver. 4.65; Würzburg, observed in approximately 90% of BHDS patients [8, 9, Germany), and the difusion capacity of the lungs for 13–15]. Generally, lung function is preserved, and even carbon monoxide (T L,CO) was determined using the sin- in patients with multiple cysts, there is no respiratory gle-breath technique. Te predicted values were analysed. insufciency[14]. CT or magnetic resonance imaging of the abdomen Renal tumours occur, usually in the ffth decade of life was used for abdominal assessment. in < 30% of patients, and sometimes this is an isolated FLCN gene detection was performed based on methods presentation of the disease [16–18]. Patients with BHDS described in the literature. Genomic DNA was extracted develop various kinds of renal tumours, often diferenti- from peripheral blood leukocytes and subjected to pol- ated within the same organ. Te most frequently identi- ymerase chain reaction and Sanger sequencing. Te fed tumours are hybrid oncocytic tumours with features sequencing reactions were conducted on an ABI 3730 of both chromophobe renal cell carcinoma (RCC) and DNA Analyzer (Termo Fisher Scientifc, Waltham, MA, oncocytoma, chromophobe RCC, and clear cell RCC [6, USA), and the resulting chromatograms were analysed 8–11]. using Variant Reporter 1.1 software (Applied Biosystems, To date, more than 200 mutations in the FLCN gene Termo Fisher Scientifc) [11]. have been identifed and documented in the FLCN Lei- In addition, for two patients, next-generation sequenc- den Open Variation Database. Te most frequently ing reactions were performed on a HiSeq 4000 Sequencer detected mutations are protein truncations, including (Illumina Inc., San Diego, CA, USA) with a reading frameshift (small deletions or insertions), nonsense or length of 2 × 151 nucleotides and an average cover- splice variants. Te detection rate of FLCN mutations in age of 230 × with a quality threshold of 100%. Libraries patients with BHDS features is approximately 90% [7, 14, were prepared using the enrichment method. Genetic 19–28]. variants were identifed using Burrows-Wheeler Aligner. We present the clinical, radiological and genetic fea- Te method allows detection of 100% of substitutions tures of Polish patients with BHDS. and 95% of small deletions and insertions. Te cod- ing sequence of the FLCN gene was analysed along with Materials 10–20-nucleotide intron fanks. From 2016 to 2020, 15 patients with BHDS have been Te pathogenic variant nomenclature presented follows diagnosed in our department. Te diagnosis, based on the Human Genome Variation Society recommendations criteria proposed by the European BHD Consortium, (https:// varno men. hgvs. org/; version 20.05). DNA muta- was established when patients fulflled at least one major tion numbering is based on the FLCN cDNA sequence or two minor criteria. Te major criteria were at least (GenBank accession numbers NM_144997.7) with the A fve fbrofolliculomas or trichodiscomas (at least one of the ATG translation‐initiation codon numbered as + 1. histologically confrmed, of adult onset) and a patho- Similarly, amino-acid numbering starts with the transla- genic FLCN germline mutation. Te minor criteria were tion initiator methionine as + 1 (NP_659434.2). multiple lung cysts (bilateral basally located lung cysts Te study was approved by the Ethics Committee of with no other apparent cause, with or without a sponta- the National Tuberculosis and Lung Diseases Research neous primary pneumothorax), renal cancer (early onset Institute (Number 36/2020) and performed according to before age 50 y, multifocal or bilateral, mixed chromo- the tenets of the Declaration of Helsinki. phobe, and oncocytic histology) and a frst-degree rela- tive with BHDS [27]. Results Fibrofolliculomas and trichodiscomas were diagnosed by dermatological evaluation. BHDS was diagnosed in 15 patients from 10 families. Chest computed tomography (CT) scans were evalu- Tirteen patients were confrmed by direct sequencing ated in all patients for the presence of pneumothorax, of the FLCN gene and two by clinical diagnosis. Tree cysts and cyst localisation (central part of both lungs), patients have been reported previously [29, 30]. Radzikowska et al. Orphanet J Rare Dis (2021) 16:302 Page 3 of 10 Te mean ages at the time of frst pneumothorax and families in exon 6. Tis deletion cause frameshift and diagnosis were 38.4 ± 13.9 and 47.7 ± 13 years, respec- premature STOP codon. In addition, deletion c.40delC tively. Five patients (33%) were ex-smokers (2.1 ± 1.37 p.(His14TrsfTer41) was identifed in exon 4. Tese packyears), and 10 (67%) had never smoked cigarettes.
Load more

Recommended publications
  • Clinical and Genetic Characteristics of Chinese Patients with Birt-Hogg
    Liu et al. Orphanet Journal of Rare Diseases (2017) 12:104 DOI 10.1186/s13023-017-0656-7 RESEARCH Open Access Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome Yaping Liu1†, Zhiyan Xu2†, Ruie Feng3, Yongzhong Zhan4,5, Jun Wang4, Guozhen Li4, Xue Li4, Weihong Zhang6, Xiaowen Hu7, Xinlun Tian4*†, Kai-Feng Xu4† and Xue Zhang1† Abstract Background: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax. The known causative gene for BHD syndrome is the folliculin (FLCN) gene on chromosome 17p11.2. Studies of the FLCN mutation for BHD syndrome are less prevalent in Chinese populations than in Caucasian populations. Our study aims to investigate the genotype spectrum in a group of Chinese patients with BHD. Methods: We enrolled 51 patients with symptoms highly suggestive of BHD from January 2014 to February 2017. The FLCN gene was examined using PCR and Sanger sequencing in every patient, for those whose Sanger sequencing showed negative mutation results, multiplex ligation-dependent probe amplification (MLPA) testing was conducted to detect any losses of large segments. Main results: Among the 51 patients, 27 had FLCN germline mutations. In total, 20 mutations were identified: 14 were novel mutations, including 3 splice acceptor site mutations, 2 different deletions, 6 nonsense mutations, 1 missense mutation, 1 small insertion, and 1 deletion of the whole exon 8. Conclusions: We found a similar genotype spectrum but different mutant loci in Chinese patients with BHD compared with European and American patients, thus providing stronger evidence for the clinical molecular diagnosis of BHD in China.
    [Show full text]
  • Association Between Birt Hogg Dubé Syndrome and Cancer Predisposition
    ANTICANCER RESEARCH 30: 751-758 (2010) Review Association Between Birt Hogg Dubé Syndrome and Cancer Predisposition RAFFAELE PALMIROTTA1, ANNALISA SAVONAROLA1, GIORGIA LUDOVICI1, PIETRO DONATI2, FRANCESCO CAVALIERE3, MARIA LAURA DE MARCHIS1, PATRIZIA FERRONI1 and FIORELLA GUADAGNI1 1Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, 00165 Rome, Italy; 2Unit of Skin Histopathology, IRCCS San Gallicano Dermatologic Institute, 00144 Rome, Italy; 3Breast Unit, San Giovanni Hospital, 00184 Rome, Italy Abstract. The Birt Hogg Dubé syndrome (BHD) is a rare Clinically, the BHD syndrome exhibits numerous autosomal dominant genodermatosis predisposing patients to asymptomatic, skin colored, dome-shaped papules over the developing fibrofolliculoma, trichodiscoma and acrochordon. face, neck, and upper trunk. These lesions represent benign The syndrome is caused by germline mutations in the folliculin proliferations of the ectodermal and mesodermal components (FLCN) gene, encoding the folliculin tumor-suppressor of the pilar apparatus (2). Fibrofolliculomas are benign protein. Numerous mutations have been described in the tumors of the perifollicular connective tissue, occurring as FLCN gene, the most frequent occurring within a C8 tract of one or more yellowish dome-shaped papules, usually on the exon 11. This hypermutability is probably due to a slippage in face. Trichodiscomas are parafollicular mesenchymal DNA polymerase during replication, resulting in gains/losses hamartomas of the mesodermal portion of the hair disk, of repeat units, causing cancer predisposition. The main usually occurring as multiple small papules. Acrochordons phenotypic manifestations related to this disease are lung are small outgrowths of epidermal and dermal tissue, which cysts, leading to pneumothorax, and a 7-fold increased risk may be pedunculated, smooth or irregular, flesh-colored and for renal neoplasia, although other neoplastic manifestations benign; they usually appear as pedunculated skin tags, have been described in BHD-affected individuals.
    [Show full text]
  • Folliculin Encoded by the BHD Gene Interacts with a Binding Protein, FNIP1, and AMPK, and Is Involved in AMPK and Mtor Signaling
    Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling Masaya Baba*†, Seung-Beom Hong*†, Nirmala Sharma*, Michelle B. Warren*†, Michael L. Nickerson*‡, Akihiro Iwamatsu§, Dominic Esposito¶, William K. Gillette¶, Ralph F. Hopkins III¶, James L. Hartley¶, Mutsuo Furihataʈ, Shinya Oishi**, Wei Zhen*, Terrence R. Burke, Jr.**, W. Marston Linehan†, Laura S. Schmidt*†,††‡‡, and Berton Zbar* Laboratories of *Immunobiology and **Medicinal Chemistry, Center for Cancer Research, National Cancer Institute–Frederick, Frederick, MD 21702; ¶Protein Expression Laboratory, Research Technology Program and ††Basic Research Program, SAIC–Frederick, Inc., National Cancer Institute–Frederick, Frederick, MD 21702; ʈDepartment of Pathology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan; §Protein Research Network, Yokohama 236-0004, Japan; and †Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894 Edited by Bert Vogelstein, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, and approved August 23, 2006 (received for review May 8, 2006) Birt–Hogg–Dube´ syndrome, a hamartoma disorder characterized BHD syndrome, also a hamartoma disorder, displays phenotypic by benign tumors of the hair follicle, lung cysts, and renal neopla- similarities to TSC that have led to speculation that BHD may sia, is caused by germ-line mutations in the BHD(FLCN) gene, which function in the pathway(s) signaling through mTOR (12, 23). To encodes a tumor-suppressor protein, folliculin (FLCN), with un- ascertain FLCN function, we searched for interacting proteins by known function. The tumor-suppressor proteins encoded by genes coimmunoprecipitation. We identified a 130-kDa FLCN- responsible for several other hamartoma syndromes, LKB1, interacting protein, FNIP1, and demonstrated its interaction with TSC1͞2, and PTEN, have been shown to be involved in the mam- AMPK, a protein important in nutrient͞energy sensing (24, 25).
    [Show full text]
  • Novel Mutations in the Folliculin Gene Associated with Spontaneous Pneumothorax
    ’ Eur Respir J 2008; 32: 1316–1320 DOI: 10.1183/09031936.00132707 CopyrightßERS Journals Ltd 2008 Novel mutations in the folliculin gene associated with spontaneous pneumothorax B.A. Fro¨hlich*, C. Zeitz#,",G.Ma´tya´s#, H. Alkadhi+, C. Tuor*, W. Berger# and E.W. Russi* ABSTRACT: Spontaneous pneumothorax is mostly sporadic but may also occur in families with AFFILIATIONS genetic disorders, such as Birt–Hogg–Dube´ syndrome, which is caused by mutations in the *Pulmonary Division, +Institute of Diagnostic Radiology, folliculin (FLCN) gene. University Hospital of Zurich, The aim of the present study was to investigate the presence and type of mutation in a Swiss #Division of Medical Molecular pedigree and in a sporadic case. Clinical examination, lung function tests and high-resolution Genetics and Gene Diagnostics, computed tomography were performed. All coding exons and flanking intronic regions of FLCN Institute of Medical Genetics, University of Zurich, Zurich, were amplified by PCR and directly sequenced. The amount of FLCN transcripts was determined Switzerland, and by quantitative real-time RT-PCR. "Institut de la Vision, INSERM U592, Two novel mutations in FLCN were identified. Three investigated family members with a history Universite´ Pierre et Marie Curie6, of at least one spontaneous pneumothorax were heterozygous for a single nucleotide substitution Paris, France. (c.779G A) that leads to a premature stop codon (p.W260X). Quantitative real-time RT-PCR CORRESPONDENCE revealed a reduction of FLCN transcripts from the patient compared with an unaffected family E.W. Russi member. DNA from the sporadic case carried a heterozygous missense mutation (c.394G.A).
    [Show full text]
  • Clinical Utility of Next-Generation Sequencing-Based Panel Testing Under the Universal Health Care System in Japan: a Retrospect
    Supplementary Materials Clinical utility of Next‐Generation Sequencing‐Based Panel Testing under the Universal Health Care System in Japan: A Retrospective Analysis at a Single University Hospital Chiaki Inagaki, Daichi Maeda, Kazue Hatake, Yuki Sato, Kae Hashimoto, Daisuke Sakai, Shinichi Yachida, Iwao Nonomura and Taroh Satoh Figure S1. CONSORT diagram of patients enrolled in the study. MTB; molecular tumor board. Cancers 2021, 13, 1121. https://doi.org/10.3390/cancers13051121 www.mdpi.com/journal/cancers Cancers 2021, 13, 1121 2 of 5 Figure S2. Top 20 frequent genomic alterations with the treatment recommendation. Figure S3. The operation workflow for evaluating and nominating presumed germline findings from tumor‐only sequencing panel The workflow is adapted from the proposal of the Japan Agency for Medical Research and Development (AMED) study group concerning the information transmission process in genomic medicine). APC; adenomatous polyposis coli, BRCA1; breast cancer susceptibility gene 1, BRCA2; breast cancer susceptibility gene 2, RB1; retinoblastoma 1, TP53; tumor protein P53 Cancers 2021, 13, 1121 3 of 5 Table S1. Actionable alterations according to cancer type. No. of pa‐ Level of Evidence, n (%) No. of action‐ tients with ac‐ Cancer Type Patient, n able muta‐ tionable mu‐ 1 2 3A 3B 4 Other tion, n tation, n (%) Total 168 70 (64.8) 107 9 (8.4) 6 (5.6) 6 (5.6) 44 (41.1) 17 (15.9) 25 (23.4) Colorectal 45 19 (42.4) 26 1 (3.8) 3 (11.5) 0 (0) 8 (30.8) 3 (11.5) 11 (42.3) Sarcoma 22 8 (36.4) 16 1 (6.3) 1 (6.3) 1 (6.3) 11 (68.8)
    [Show full text]
  • “Sugar” Tumor of the Lung in a Patient with Birt-Hogg-Dubé Syndrome
    Gunji-Niitsu et al. BMC Medical Genetics (2016) 17:85 DOI 10.1186/s12881-016-0350-y CASEREPORT Open Access Benign clear cell “sugar” tumor of the lung in a patient with Birt-Hogg-Dubé syndrome: a case report Yoko Gunji-Niitsu1,8, Toshio Kumasaka2,8, Shigehiro Kitamura3, Yoshito Hoshika1,8, Takuo Hayashi4,8, Hitoshi Tokuda5, Riichiro Morita6, Etsuko Kobayashi1,8, Keiko Mitani4,8, Mika Kikkawa7, Kazuhisa Takahashi1 and Kuniaki Seyama1,8* Abstract Background: Birt-Hogg-Dubé (BHD) syndrome is a rare inherited autosomal genodermatosis and caused by germline mutation of the folliculin (FLCN) gene, a tumor suppressor gene of which protein product is involved in mechanistic target of rapamycin (mTOR) signaling pathway regulating cell growth and metabolism. Clinical manifestations in BHD syndrome is characterized by fibrofolliculomas of the skin, pulmonary cysts with or without spontaneous pneumothorax, and renal neoplasms. There has been no pulmonary neoplasm reported in BHD syndrome, although the condition is due to deleterious sequence variants in a tumor suppressor gene. Here we report, for the first time to our knowledge, a patient with BHD syndrome who was complicated with a clear cell “sugar” tumor (CCST) of the lung, a benign tumor belonging to perivascular epithelioid cell tumors (PEComas) with frequent causative relation to tuberous sclerosis complex 1 (TSC1)or2 (TSC2) gene. Case presentation: In a 38-year-old Asian woman, two well-circumscribed nodules in the left lung and multiple thin-walled, irregularly shaped cysts on the basal and medial area of the lungs were disclosed by chest roentgenogram and computer-assisted tomography (CT) during a preoperative survey for a bilateral faucial tonsillectomy.
    [Show full text]
  • Investigation of the Folliculin (Flcn) Tumor Suppressor Gene in Energy Metabolism Ming Yan Department of Biochemistry Mcgill
    Investigation of the Folliculin (Flcn) tumor suppressor gene in energy metabolism Ming Yan Department of Biochemistry McGill University Montréal, Canada Dec., 2015 A thesis submitted to McGill University in partial fulfillment of the requirements for the degree of Doctor of Philosophy. © Ming Yan, 2015 ABSTRACT Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant hereditary disorder characterized by skin fibrofolliculomas, lung cyst, spontaneous pneumothorax and renal cell carcinoma (RCC). This condition is caused by germline mutations of folliculin (Flcn) gene, which encodes a 64-kDa protein named folliculin (FLCN). The AMP-actived protein kinase (AMPK) is a master regulator of cellular energy homeostasis. FLCN interacts with AMPK through FLCN-interacting proteins (FNIP1/2). Molecular function of FLCN and how FLCN interacts with AMPK in energy metabolism are largely unknown. We used mouse embryonic fibroblasts (MEFs) and adipose specific Flcn knockout mouse model to investigate the role of Flcn and its function associated with AMPK in energy metabolism. We found that loss of FLCN constitutively activates AMPK, which in turn leads to elevation in peroxisome proliferator-activated receptor gama coactivator 1 α (PGC-1α), which mediates mitochondrial biogenesis and increase reactive oxygen species (ROS) production. Elevated ROS induces hypoxia-inducible factor (HIF) transcriptional activity and drives Warburg metabolic reprogramming. These findings indicate that Flcn exert tumor suppressor activity by acting as a negative regulator of AMPK-dependent HIF activation and Warburg effect. To investigate the potential role of FLCN/AMPK/ PGC-1α in fat metabolism, we generated an adipose-specific Flcn knockout mouse model. Flcn KO mice exhibit elevated energy expenditure associated with increased O2 consumption, and are protected from diet-induced obesity.
    [Show full text]
  • Myeloid Folliculin Balances Mtor Activation to Maintain Innate Immunity Homeostasis
    Myeloid folliculin balances mTOR activation to maintain innate immunity homeostasis Jia Li, … , Edward M. Behrens, Zoltan Arany JCI Insight. 2019;4(6):e126939. https://doi.org/10.1172/jci.insight.126939. Research Article Cell biology Immunology The mTOR pathway is central to most cells. How mTOR is activated in macrophages and how it modulates macrophage physiology remain poorly understood. The tumor suppressor folliculin (FLCN) is a GAP for RagC/D, a regulator of mTOR. We show here that LPS potently suppresses FLCN in macrophages, allowing nuclear translocation of the transcription factor TFE3, leading to lysosome biogenesis, cytokine production, and hypersensitivity to inflammatory signals. Nuclear TFE3 additionally activates a transcriptional RagD-positive feedback loop that stimulates FLCN-independent canonical mTOR signaling to S6K and increases cellular proliferation. LPS thus simultaneously suppresses the TFE3 arm and activates the S6K arm of mTOR. In vivo, mice lacking myeloid FLCN reveal chronic macrophage activation, leading to profound histiocytic infiltration and tissue disruption, with hallmarks of human histiocytic syndromes, such as Erdheim- Chester disease. Our data thus identify a critical FLCN-mTOR-TFE3 axis in myeloid cells, modulated by LPS, that balances mTOR activation and curbs innate immune responses. Find the latest version: https://jci.me/126939/pdf RESEARCH ARTICLE Myeloid folliculin balances mTOR activation to maintain innate immunity homeostasis Jia Li,1,2 Shogo Wada,1 Lehn K. Weaver,3 Chhanda Biswas,3 Edward M. Behrens,3 and Zoltan Arany1 1Department of Medicine, Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2Department of Aerospace Medicine, Fourth Military Medical University, Xi’an, China.
    [Show full text]
  • C9orf72 Binds SMCR8, Localizes to Lysosomes and Regulates Mtorc1 Signaling
    C9orf72 binds SMCR8, localizes to lysosomes and regulates mTORC1 signaling Joseph Amick1,2, Agnes Roczniak-Ferguson1,2 and Shawn M. Ferguson1,2* Department of Cell Biology1, Program in Cellular Neuroscience, Neurodegeneration and Repair2, Yale University School of Medicine, New Haven, CT, 06510 *To whom correspondence should be addressed e-mail: [email protected] phone: 203-737-5505 fax: 203-737-2065 Running Title: Lysosomal functions for C9orf72 Supplemental Material can be found at: 1 http://www.molbiolcell.org/content/suppl/2016/08/22/mbc.E16-01-0003v1.DC1.html Abstract Hexanucleotide expansion in an intron of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, beyond bioinformatics predictions that have suggested structural similarity to folliculin (FLCN), the Birt-Hogg-Dubé syndrome tumor suppressor, little is known about the normal functions of the C9orf72 protein. To address this problem, we used genome editing strategies to investigate C9orf72 interactions, subcellular localization and knockout (KO) phenotypes. We found that C9orf72 robustly interacts with SMCR8 (a protein of previously unknown function). We furthermore observed that C9orf72 localizes to lysosomes and that such localization is negatively regulated by amino acid availability. Analysis of C9orf72 KO, SMCR8 KO and double KO cell lines revealed phenotypes that are consistent with a function for C9orf72 at lysosomes. These include abnormally swollen lysosomes in the absence of C9orf72 as well as impaired responses of mTORC1 signaling to changes in amino acid availability (a lysosome-dependent process) following depletion of either C9orf72 or SMCR8. Collectively, these results identify strong physical and functional interactions between C9orf72 and SMCR8 and furthermore support a lysosomal site-of-action for this protein complex.
    [Show full text]
  • Mit Family Transcriptional Factors in Immune Cell Functions Seongryong Kim Et Al
    Molecules and Cells Minireview MiT Family Transcriptional Factors in Immune Cell Functions Seongryong Kim1,3, Hyun-Sup Song1,3, Jihyun Yu1, and You-Me Kim1,2,* 1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea, 2The Center for Epidemic Preparedness, KAIST, Daejeon 34141, Korea, 3These authors contributed equally to this work. *Correspondence: [email protected] https://doi.org/10.14348/molcells.2021.0067 www.molcells.org The microphthalmia-associated transcription factor family transcription factor E3 (TFE3), transcription factor EB (TFEB), (MiT family) proteins are evolutionarily conserved transcription transcription factor EC (TFEC) factors that perform many essential biological functions. In mammals, the MiT family consists of MITF (microphthalmia- INTRODUCTION associated transcription factor or melanocyte-inducing transcription factor), TFEB (transcription factor EB), TFE3 The microphthalmia-associated transcription factor fami- (transcription factor E3), and TFEC (transcription factor EC). ly (MiT family) consists of four transcription factors: MITF These transcriptional factors belong to the basic helix-loop- (microphthalmia-associated transcription factor or melano- helix-leucine zipper (bHLH-LZ) transcription factor family and cyte-inducing transcription factor), TFEB (transcription factor bind the E-box DNA motifs in the promoter regions of target EB), TFE3 (transcription factor E3), and TFEC (transcription genes to enhance transcription. The best studied functions factor EC) (Goding and Arnheiter, 2019; Napolitano and of MiT proteins include lysosome biogenesis and autophagy Ballabio, 2016; Oppezzo and Rosselli, 2021). The Mitf gene induction. In addition, they modulate cellular metabolism, encoding the first member of the MiT family, MITF, was dis- mitochondria dynamics, and various stress responses.
    [Show full text]
  • Folliculin Regulates Mtorc1/2 and WNT Pathways in Early Human Pluripotency
    ARTICLE https://doi.org/10.1038/s41467-018-08020-0 OPEN Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency J. Mathieu1,2,3, D. Detraux1,2,8, D. Kuppers4, Y. Wang2,5, C. Cavanaugh2,3, S. Sidhu1,2,S.Levy1,2, A.M. Robitaille2,6, A. Ferreccio1,2, T. Bottorff1,2, A. McAlister1,2, L. Somasundaram1,2, F. Artoni1,2, S. Battle2,7, R.D. Hawkins2,7, R.T. Moon2,6, C.B. Ware2,3, P.J. Paddison2,4 & H. Ruohola-Baker 1,2 To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting 1234567890():,; the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency. 1 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. 2 Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
    [Show full text]
  • Folliculin Variants Linked to Birt-Hogg-Dubé Syndrome Are Targeted for Proteasomal Degradation
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.30.015248; this version posted March 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Folliculin variants linked to Birt-Hogg-Dubé syndrome are targeted for proteasomal degradation Lene Clausen1, Amelie Stein1,*, Martin Grønbæk-Thygesen1, Lasse Nygaard1, Cecilie L. Søltoft1, Sofie V. Nielsen1, Michael Lisby1, Tommer Ravid2, Kresten Lindorff-Larsen1,* and Rasmus Hartmann-Petersen1,* Running title: Birt-Hogg-Dubé syndrome is a protein misfolding disease Keywords: protein folding, protein quality control, proteasome, ubiquitin, BHD, FLCN 1: The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark. 2: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. *Corresponding authors: A.S. ([email protected]), K.L.-L. ([email protected]) and R.H.-P. ([email protected]). 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.30.015248; this version posted March 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Germline mutations in the folliculin (FLCN) tumor suppressor gene are linked to Birt-Hogg-Dubé (BHD) syndrome, a dominantly inherited genetic disease characterized by predisposition to fibrofolliculomas, lung cysts, and renal cancer.
    [Show full text]