Download PDF
Semin Respir Crit Care Med 2020; 41(02): 247-255
DOI: 10.1055/s-0040-1708500
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

New Developments in the Pathogenesis of Pulmonary Cysts in Birt–Hogg–Dubé Syndrome

John C. Kennedy
1   Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
2   Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts
,
Damir Khabibullin
1   Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
,
Yoseph Boku
1   Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
,
Wei Shi
3   Department of Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
,
Elizabeth P. Henske
1   Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
› Author Affiliations
Further Information

Publication History

Publication Date:
12 April 2020 (online)

    Permissions and Reprints

Abstract

Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in Folliculin gene (FLCN). BHD is characterized by lower lobe-predominant pulmonary cysts with risk of pneumothorax, benign skin tumors (fibrofolliculomas), and renal cell carcinoma, often of an unusual chromophobe/oncocytic hybrid histology. The FLCN protein functions in multiple signaling and metabolic pathways including positive regulation of mechanistic target of rapamycin complex 1 (mTORC1) activity via FLCN's GTPase (GAP) activity for Rag C, positive regulation of Wnt signaling (in mesenchymal cells), and negative regulation of TFE3 nuclear localization. Therefore, FLCN-deficient cells are predicted to have reduced mTORC1 and Wnt activity and enhanced TFE3 activity. Folliculin also has functions in autophagy, mitochondrial biogenesis, cell-cell adhesion, 5′ AMP activated protein kinase activity, and other pathways. The specific contributions of these pathways to the lung manifestations of BHD are largely unknown. This review is focused on the pulmonary manifestations of BHD, highlighting selected recent advances in elucidating the cellular functions of FLCN and current hypotheses related to the pathogenesis of cystic lung disease in BHD, including the “stretch hypothesis.” We also discuss important knowledge gaps in the field, including the genetic, cellular and physical mechanisms of cyst pathogenesis, and the timing of cyst initiation, which may occur during lung development.

Keywords

Birt–Hogg–Dubé syndrome - Folliculin - pulmonary cysts - pneumothorax
 

  • References

  • 1 Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977; 113 (12) 1674-1677
    CrossrefPubMedGoogle Scholar
  • 2 Toro JR, Glenn G, Duray P. , et al. Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia. Arch Dermatol 1999; 135 (10) 1195-1202
    PubMedGoogle Scholar
  • 3 Hornstein OP, Knickenberg M. Perifollicular fibromatosis cutis with polyps of the colon--a cutaneo-intestinal syndrome sui generis. Arch Dermatol Res 1975; 253 (02) 161-175
    CrossrefPubMedGoogle Scholar
  • 4 Schulz T, Hartschuh W. Birt-Hogg-Dubé syndrome and Hornstein-Knickenberg syndrome are the same. Different sectioning technique as the cause of different histology. J Cutan Pathol 1999; 26 (01) 55-61
    CrossrefPubMedGoogle Scholar
  • 5 Happle R. Hornstein-Birt-Hogg-Dubé syndrome: a renaming and reconsideration. Am J Med Genet A 2012; 158A (06) 1247-1251
    CrossrefPubMedGoogle Scholar
  • 6 Gupta N, Sunwoo BY, Kotloff RM. Birt-Hogg-Dubé syndrome. Clin Chest Med 2016; 37 (03) 475-486
    CrossrefPubMedGoogle Scholar
  • 7 Goldenberg P. An update on common chromosome microdeletion and microduplication syndromes. Pediatr Ann 2018; 47 (05) e198-e203
    CrossrefPubMedGoogle Scholar
  • 8 Dardour L, Verleyen P, Lesage K, Holvoet M, Devriendt K. Bilateral renal tumors in an adult man with Smith-Magenis syndrome: the role of the FLCN gene. Eur J Med Genet 2016; 59 (10) 499-501
    CrossrefPubMedGoogle Scholar
  • 9 Smith ACM, Fleming LR, Piskorski AM, Amin A, Phorphutkul C, delaMonte S, Stopa E, Introne W, Vilboux T, Duncan F, Pellegrino J, Braddock B, Middelton LA, Vocke C, Linehan WM. Deletion of 17p11.2 encompasses FLCN with increased risk of Birt-Hogg-Dubé in Smith Magenis syndrome: recommendation for cancer screening. Poster session. San Diego: American Society of Human Genetics Meeting; 2014
    Google Scholar
  • 10 Perkins T, Rosenberg JM, Le Coz C. , et al. Smith-Magenis syndrome patients often display antibody deficiency but not other immune pathologies. J Allergy Clin Immunol Pract 2017; 5 (05) 1344-1350 .e3
    CrossrefPubMedGoogle Scholar
  • 11 Goh ES, Perez IC, Canales CP. , et al. Definition of a critical genetic interval related to kidney abnormalities in the Potocki-Lupski syndrome. Am J Med Genet A 2012; 158A (07) 1579-1588
    CrossrefPubMedGoogle Scholar
  • 12 Tong Y, Schneider JA, Coda AB, Hata TR, Cohen PR. Birt-Hogg-Dubé syndrome: a review of dermatological manifestations and other symptoms. Am J Clin Dermatol 2018; 19 (01) 87-101
    CrossrefPubMedGoogle Scholar
  • 13 Burnier and Rejsek: Fibromes sous-cutanes peripilaires multiples du cou, Bull. Soc. franç. dermat. et syph. 32:242, 1925
    PubMed
  • 14 Riegert-Johnson DLBL, Hefferon T. , et al , Eds. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2009
  • 15 Toro JR, Pautler SE, Stewart L. , et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 2007; 175 (10) 1044-1053
    CrossrefPubMedGoogle Scholar
  • 16 Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 2015; 12 (10) 558-569
    CrossrefPubMedGoogle Scholar
  • 17 Furuya M, Yao M, Tanaka R. , et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome. Clin Genet 2016; 90 (05) 403-412
    CrossrefPubMedGoogle Scholar
  • 18 Ren HZ, Zhu CC, Yang C. , et al. Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax. Clin Genet 2008; 74 (02) 178-183
    CrossrefPubMedGoogle Scholar
  • 19 Lee JH, Jeon MJ, Song JS. , et al. Birt-Hogg-Dubé syndrome in Korean: clinicoradiologic features and long term follow-up. Korean J Intern Med (Korean Assoc Intern Med) 2019; 34 (04) 830-840
    CrossrefPubMedGoogle Scholar
  • 20 Schmidt LS, Nickerson ML, Warren MB. , et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet 2005; 76 (06) 1023-1033
    CrossrefPubMedGoogle Scholar
  • 21 Schmidt LS, Linehan WM. FLCN: the causative gene for Birt-Hogg-Dubé syndrome. Gene 2018; 640: 28-42
    CrossrefPubMedGoogle Scholar
  • 22 Benusiglio PR, Giraud S, Deveaux S. , et al; French National Cancer Institute Inherited Predisposition to Kidney Cancer Network. Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis 2014; 9: 163
    CrossrefPubMedGoogle Scholar
  • 23 Schneider M, Dinkelborg K, Xiao X. , et al. Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion. Fam Cancer 2018; 17 (01) 135-139
    CrossrefPubMedGoogle Scholar
  • 24 Maher ER. Hereditary renal cell carcinoma syndromes: diagnosis, surveillance and management. World J Urol 2018; 36 (12) 1891-1898
    CrossrefPubMedGoogle Scholar
  • 25 Carlo MI, Hakimi AA, Stewart GD. , et al. Familial kidney cancer: implications of new syndromes and molecular insights. Eur Urol 2019; 76 (06) 754-764
    CrossrefPubMedGoogle Scholar
  • 26 Linehan WM, Schmidt LS, Crooks DR. , et al. The metabolic basis of kidney cancer. Cancer Discov 2019; 9 (08) 1006-1021
    CrossrefPubMedGoogle Scholar
  • 27 Pavlovich CP, Walther MM, Eyler RA. , et al. Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Pathol 2002; 26 (12) 1542-1552
    CrossrefPubMedGoogle Scholar
  • 28 Gupta N, Kopras EJ, Henske EP. , et al. Spontaneous pneumothoraces in patients with Birt-Hogg-Dubé syndrome. Ann Am Thorac Soc 2017; 14 (05) 706-713
    CrossrefPubMedGoogle Scholar
  • 29 Zbar B, Alvord WG, Glenn G. , et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 2002; 11 (04) 393-400
    PubMedGoogle Scholar
  • 30 Johannesma PC, van de Beek I, van der Wel JW. , et al. Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt-Hogg-Dubé syndrome. Springerplus 2016; 5 (01) 1506
    CrossrefPubMedGoogle Scholar
  • 31 Escalon JG, Richards JC, Koelsch T, Downey GP, Lynch DA. Isolated cystic lung disease: an algorithmic approach to distinguishing Birt-Hogg-Dubé syndrome, lymphangioleiomyomatosis, and lymphocytic interstitial pneumonia. AJR Am J Roentgenol 2019; 1-5 . 10.2214/AJR.18.20920
    PubMedGoogle Scholar
  • 32 Furuya M, Nakatani Y. Pathology of Birt-Hogg-Dubé syndrome: a special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review. Pathol Int 2019; 69 (01) 1-12
    CrossrefPubMedGoogle Scholar
  • 33 Geilswijk M, Bendstrup E, Madsen MG, Sommerlund M, Skytte AB. Childhood pneumothorax in Birt-Hogg-Dubé syndrome: a cohort study and review of the literature. Mol Genet Genomic Med 2018; 6 (03) 332-338
    CrossrefPubMedGoogle Scholar
  • 34 Demir M, Çobanoğlu N. An 18-year-old man with recurrent pneumothorax since he was 10-year-old. Pediatr Pulmonol 2016; 51 (12) E41-E43
    CrossrefPubMedGoogle Scholar
  • 35 Bessis D, Giraud S, Richard S. A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt-Hogg-Dubé syndrome. Br J Dermatol 2006; 155 (05) 1067-1069
    CrossrefPubMedGoogle Scholar
  • 36 Sundaram S, Tasker AD, Morrell NW. Familial spontaneous pneumothorax and lung cysts due to a Folliculin exon 10 mutation. Eur Respir J 2009; 33 (06) 1510-1512
    CrossrefPubMedGoogle Scholar
  • 37 Johannesma PC, Houweling AC, van Waesberghe JH. , et al. The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: a hypothesis. Respirology 2014; 19 (08) 1248-1250
    CrossrefPubMedGoogle Scholar
  • 38 Ayo DS, Aughenbaugh GL, Yi ES, Hand JL, Ryu JH. Cystic lung disease in Birt-Hogg-Dube syndrome. Chest 2007; 132 (02) 679-684
    CrossrefPubMedGoogle Scholar
  • 39 Tobino K, Gunji Y, Kurihara M. , et al. Characteristics of pulmonary cysts in Birt-Hogg-Dubé syndrome: thin-section CT findings of the chest in 12 patients. Eur J Radiol 2011; 77 (03) 403-409
    CrossrefPubMedGoogle Scholar
  • 40 Skolnik K, Tsai WH, Dornan K, Perrier R, Burrowes PW, Davidson WJ. Birt-Hogg-Dubé syndrome: a large single family cohort. Respir Res 2016; 17: 22
    CrossrefPubMedGoogle Scholar
  • 41 Tomassetti S, Carloni A, Chilosi M. , et al. Pulmonary features of Birt-Hogg-Dubé syndrome: cystic lesions and pulmonary histiocytoma. Respir Med 2011; 105 (05) 768-774
    CrossrefPubMedGoogle Scholar
  • 42 Tobino K, Hirai T, Johkoh T. , et al. Differentiation between Birt-Hogg-Dubé syndrome and lymphangioleiomyomatosis: quantitative analysis of pulmonary cysts on computed tomography of the chest in 66 females. Eur J Radiol 2012; 81 (06) 1340-1346
    CrossrefPubMedGoogle Scholar
  • 43 Johannesma PC, Reinhard R, Kon Y. , et al; Amsterdam BHD working group. Prevalence of Birt-Hogg-Dubé syndrome in patients with apparently primary spontaneous pneumothorax. Eur Respir J 2015; 45 (04) 1191-1194
    CrossrefPubMedGoogle Scholar
  • 44 Li CW, Li MH, Li JX, Tao RJ, Xu JF, Cao WJ. Pulmonary Langerhans cell histiocytosis: analysis of 14 patients and literature review. J Thorac Dis 2016; 8 (06) 1283-1289
    CrossrefPubMedGoogle Scholar
  • 45 Fabre A, Borie R, Debray MP, Crestani B, Danel C. Distinguishing the histological and radiological features of cystic lung disease in Birt-Hogg-Dubé syndrome from those of tobacco-related spontaneous pneumothorax. Histopathology 2014; 64 (05) 741-749
    CrossrefPubMedGoogle Scholar
  • 46 Sahn SA, Heffner JE. Spontaneous pneumothorax. N Engl J Med 2000; 342 (12) 868-874
    CrossrefPubMedGoogle Scholar
  • 47 Baumann MH, Strange C, Heffner JE. , et al; AACP Pneumothorax Consensus Group. Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest 2001; 119 (02) 590-602
    CrossrefPubMedGoogle Scholar
  • 48 Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse cystic lung disease. Part II. Am J Respir Crit Care Med 2015; 192 (01) 17-29
    CrossrefPubMedGoogle Scholar
  • 49 Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse cystic lung disease. Part I. Am J Respir Crit Care Med 2015; 191 (12) 1354-1366
    CrossrefPubMedGoogle Scholar
  • 50 Gupta N, Langenderfer D, McCormack FX, Schauer DP, Eckman MH. Chest computed tomographic image screening for cystic lung diseases in patients with spontaneous pneumothorax is cost effective. Ann Am Thorac Soc 2017; 14 (01) 17-25
    CrossrefPubMedGoogle Scholar
  • 51 Lippert HL, Lund O, Blegvad S, Larsen HV. Independent risk factors for cumulative recurrence rate after first spontaneous pneumothorax. Eur Respir J 1991; 4 (03) 324-331
    PubMedGoogle Scholar
  • 52 Liu Y, Xing H, Huang Y, Meng S, Wang J. Familial spontaneous pneumothorax: importance of screening for Birt–Hogg–Dubé syndrome. Eur J Cardiothorac Surg 2019; 57 (01) 39-45
    PubMedGoogle Scholar
  • 53 Johannesma PCJM, van der Wel MA, van Waesberghe J, van Moorselaar J, Menko F, Postmus P. Management of spontaneous pneumothorax in patients with or without Birt–Hogg–Dubé syndrome. Eur Respir J 2014; 44: 752
    PubMedGoogle Scholar
  • 54 Hoshika Y, Kataoka H, Kurihara M. , et al. Features of pneumothorax and risk of air travel in Birt-Hogg-Dube syndrome. Am J Respir Crit Care Med 2012; 185: A4438
    PubMedGoogle Scholar
  • 55 Pradella LM, Lang M, Kurelac I. , et al. Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. Eur J Hum Genet 2013; 21 (10) 1169-1172
    PubMedGoogle Scholar
  • 56 Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 2000; 43 (06) 1120-1122
    CrossrefPubMedGoogle Scholar
  • 57 Lindor NM, Kasperbauer J, Lewis JE, Pittelkow M. Birt-Hogg-Dube syndrome presenting as multiple oncocytic parotid tumors. Hered Cancer Clin Pract 2012; 10 (01) 13
    CrossrefPubMedGoogle Scholar
  • 58 Nahorski MS, Lim DH, Martin L. , et al. Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet 2010; 47 (06) 385-390
    CrossrefPubMedGoogle Scholar
  • 59 Furuya M, Tanaka R, Okudela K. , et al. Pulmonary neoplasms in patients with Birt-Hogg-Dubé syndrome: histopathological features and genetic and somatic events. PLoS One 2016; 11 (03) e0151476
    CrossrefPubMedGoogle Scholar
  • 60 Escuissato DL, de Almeida Teixeira BC, Warszwiak D, Zanetti G, Marchiori E. Renal tumor associated with pulmonary cysts: Birt-Hogg-Dubé syndrome. QJM 2014; 107 (10) 851-852
    CrossrefPubMedGoogle Scholar
  • 61 Toro JR, Wei MH, Glenn GM. , et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet 2008; 45 (06) 321-331
    CrossrefPubMedGoogle Scholar
  • 62 Khoo SK, Giraud S, Kahnoski K. , et al; J KSGSKKC. Clinical and genetic studies of Birt-Hogg-Dubé syndrome. J Med Genet 2002; 39 (12) 906-912
    CrossrefPubMedGoogle Scholar
  • 63 Liu K, Xu W, Tian X. , et al. Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants. Orphanet J Rare Dis 2019; 14 (01) 223
    CrossrefPubMedGoogle Scholar
  • 64 2019. at http://www.LOVD.nl/FLCN
    PubMed
  • 65 Vocke CD, Yang Y, Pavlovich CP. , et al. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst 2005; 97 (12) 931-935
    CrossrefPubMedGoogle Scholar
  • 66 Petit CS, Roczniak-Ferguson A, Ferguson SM. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol 2013; 202 (07) 1107-1122
    CrossrefPubMedGoogle Scholar
  • 67 Hartman TR, Nicolas E, Klein-Szanto A. , et al. The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis. Oncogene 2009; 28 (13) 1594-1604
    CrossrefPubMedGoogle Scholar
  • 68 Baba M, Hong SB, Sharma N. , et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 2006; 103 (42) 15552-15557
    CrossrefPubMedGoogle Scholar
  • 69 Khabibullin D, Medvetz DA, Pinilla M. , et al. Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiol Rep 2014; 2 (08) 2
    PubMedGoogle Scholar
  • 70 Nahorski MS, Seabra L, Straatman-Iwanowska A. , et al. Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Hum Mol Genet 2012; 21 (24) 5268-5279
    CrossrefPubMedGoogle Scholar
  • 71 Goncharova EA, Goncharov DA, James ML. , et al. Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK. Cell Reports 2014; 7 (02) 412-423
    CrossrefPubMedGoogle Scholar
  • 72 Baba M, Furihata M, Hong SB. , et al. Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst 2008; 100 (02) 140-154
    CrossrefPubMedGoogle Scholar
  • 73 Cash TP, Gruber JJ, Hartman TR, Henske EP, Simon MC. Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated transcription. Oncogene 2011; 30 (22) 2534-2546
    CrossrefPubMedGoogle Scholar
  • 74 Chen J, Futami K, Petillo D. , et al. Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. PLoS One 2008; 3 (10) e3581
    CrossrefPubMedGoogle Scholar
  • 75 Hasumi Y, Baba M, Ajima R. , et al. Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 2009; 106 (44) 18722-18727
    CrossrefPubMedGoogle Scholar
  • 76 Hasumi H, Baba M, Hasumi Y. , et al. Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. J Natl Cancer Inst 2012; 104 (22) 1750-1764
    CrossrefPubMedGoogle Scholar
  • 77 Hong SB, Oh H, Valera VA. , et al. Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling. Mol Cancer 2010; 9: 160
    CrossrefPubMedGoogle Scholar
  • 78 Hudon V, Sabourin S, Dydensborg AB. , et al. Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin. J Med Genet 2010; 47 (03) 182-189
    CrossrefPubMedGoogle Scholar
  • 79 Luijten MN, Basten SG, Claessens T. , et al. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum Mol Genet 2013; 22 (21) 4383-4397
    CrossrefPubMedGoogle Scholar
  • 80 Takagi Y, Kobayashi T, Shiono M. , et al. Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene 2008; 27 (40) 5339-5347
    CrossrefPubMedGoogle Scholar
  • 81 Bastola P, Stratton Y, Kellner E. , et al. Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy. PLoS One 2013; 8 (07) e70030
    CrossrefPubMedGoogle Scholar
  • 82 Preston RS, Philp A, Claessens T. , et al. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene 2011; 30 (10) 1159-1173
    CrossrefPubMedGoogle Scholar
  • 83 Tsun ZY, Bar-Peled L, Chantranupong L. , et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell 2013; 52 (04) 495-505
    CrossrefPubMedGoogle Scholar
  • 84 van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, Henske EP. The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe. J Biol Chem 2007; 282 (34) 24583-24590
    CrossrefPubMedGoogle Scholar
  • 85 Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, Smith A. Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3. Cell 2013; 153 (02) 335-347
    CrossrefPubMedGoogle Scholar
  • 86 Dunlop EA, Seifan S, Claessens T. , et al. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy 2014; 10 (10) 1749-1760
    CrossrefPubMedGoogle Scholar
  • 87 Gaur K, Li J, Wang D. , et al. The Birt-Hogg-Dubé tumor suppressor Folliculin negatively regulates ribosomal RNA synthesis. Hum Mol Genet 2013; 22 (02) 284-299
    CrossrefPubMedGoogle Scholar
  • 88 Hong SB, Oh H, Valera VA, Baba M, Schmidt LS, Linehan WM. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS One 2010; 5 (12) e15793
    CrossrefPubMedGoogle Scholar
  • 89 Lim TH, Fujikane R, Sano S. , et al. Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated base mismatch in DNA. DNA Repair (Amst) 2012; 11 (03) 259-266
    CrossrefPubMedGoogle Scholar
  • 90 Liu W, Chen Z, Ma Y, Wu X, Jin Y, Hou S. Genetic characterization of the Drosophila Birt-Hogg-Dubé syndrome gene. PLoS One 2013; 8 (06) e65869
    CrossrefPubMedGoogle Scholar
  • 91 Martínez-Carreres L, Puyal J, Leal-Esteban LC. , et al. CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival. Cancer Res 2019; 79 (20) 5245-5259
    CrossrefPubMedGoogle Scholar
  • 92 Piao X, Kobayashi T, Wang L. , et al. Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway. Biochem Biophys Res Commun 2009; 389 (01) 16-21
    CrossrefPubMedGoogle Scholar
  • 93 Wang L, Kobayashi T, Piao X. , et al. Serine 62 is a phosphorylation site in folliculin, the Birt-Hogg-Dubé gene product. FEBS Lett 2010; 584 (01) 39-43
    CrossrefPubMedGoogle Scholar
  • 94 Laviolette LA, Wilson J, Koller J. , et al. Human folliculin delays cell cycle progression through late S and G2/M-phases: effect of phosphorylation and tumor associated mutations. PLoS One 2013; 8 (07) e66775
    CrossrefPubMedGoogle Scholar
  • 95 Collodet C, Foretz M, Deak M. , et al. AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR. FASEB J 2019; 33 (11) 12374-12391
    CrossrefPubMedGoogle Scholar
  • 96 El-Houjeiri L, Possik E, Vijayaraghavan T. , et al. The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance. Cell Reports 2019; 26 (13) 3613-3628.e6
    CrossrefPubMedGoogle Scholar
  • 97 Lapierre LR, De Magalhaes Filho CD, McQuary PR. , et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun 2013; 4: 2267
    CrossrefPubMedGoogle Scholar
  • 98 Possik E, Jalali Z, Nouët Y. , et al. Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS Genet 2014; 10 (04) e1004273
    CrossrefPubMedGoogle Scholar
  • 99 Meng J, Ferguson SM. GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. J Cell Biol 2018; 217 (08) 2765-2776
    CrossrefPubMedGoogle Scholar
  • 100 Bar-Peled L, Chantranupong L, Cherniack AD. , et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 2013; 340 (6136): 1100-1106
    CrossrefPubMedGoogle Scholar
  • 101 Shen K, Huang RK, Brignole EJ. , et al. Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature 2018; 556 (7699): 64-69
    CrossrefPubMedGoogle Scholar
  • 102 Nookala RK, Langemeyer L, Pacitto A. , et al. Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open Biol 2012; 2 (08) 120071
    CrossrefPubMedGoogle Scholar
  • 103 Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM. Cryo-EM structure of the human FLCN-FNIP2-Rag-Ragulator Complex. Cell 2019; 179 (06) 1319-1329.e8
    CrossrefPubMedGoogle Scholar
  • 104 Lawrence RE, Fromm SA, Fu Y. , et al. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science 2019; 366 (6468): 971-977
    CrossrefPubMedGoogle Scholar
  • 105 Kennedy JC, Khabibullin D, Hougard T, Nijmeh J, Shi W, Henske EP. Loss of FLCN inhibits canonical WNT signaling via TFE3. Hum Mol Genet 2019; 28 (19) 3270-3281
    CrossrefPubMedGoogle Scholar
  • 106 Goss AM, Tian Y, Tsukiyama T. , et al. Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Dev Cell 2009; 17 (02) 290-298
    CrossrefPubMedGoogle Scholar
  • 107 Wada S, Neinast M, Jang C. , et al. The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes Dev 2016; 30 (22) 2551-2564
    CrossrefPubMedGoogle Scholar
  • 108 Mathieu J, Detraux D, Kuppers D. , et al. Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency. Nat Commun 2019; 10 (01) 632
    CrossrefPubMedGoogle Scholar
  • 109 Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 2012; 8 (06) 903-914
    CrossrefPubMedGoogle Scholar
  • 110 Roczniak-Ferguson A, Petit CS, Froehlich F. , et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 2012; 5 (228) ra42
    PubMedGoogle Scholar
  • 111 Villegas F, Lehalle D, Mayer D. , et al. Lysosomal signaling licenses embryonic stem cell differentiation via inactivation of Tfe3. Cell Stem Cell 2019; 24 (02) 257-270.e8
    CrossrefPubMedGoogle Scholar
  • 112 Zemirli N, Boukhalfa A, Dupont N, Botti J, Codogno P, Morel E. The primary cilium protein folliculin is part of the autophagy signaling pathway to regulate epithelial cell size in response to fluid flow. Cell Stress 2019; 3 (03) 100-109
    CrossrefPubMedGoogle Scholar
  • 113 Zhao L, Ji X, Zhang X, Li L, Jin Y, Liu W. FLCN is a novel Rab11A-interacting protein that is involved in the Rab11A-mediated recycling transport. J Cell Sci 2018; 131 (24) 131
    CrossrefPubMedGoogle Scholar
  • 114 Haley R, Wang Y, Zhou Z. The small GTPase RAB-35 defines a third pathway that is required for the recognition and degradation of apoptotic cells. PLoS Genet 2018; 14 (08) e1007558
    CrossrefPubMedGoogle Scholar
  • 115 Haley R, Zhou Z. The small GTPase RAB-35 facilitates the initiation of phagosome maturation and acts as a robustness factor for apoptotic cell clearance. Small GTPases 2019; 14 (08) 1-14
    PubMedGoogle Scholar
  • 116 Baba M, Endoh M, Ma W. , et al. Folliculin regulates osteoclastogenesis through metabolic regulation. J Bone Miner Res 2018; 33 (10) 1785-1798
    CrossrefPubMedGoogle Scholar
  • 117 Li J, Wada S, Weaver LK, Biswas C, Behrens EM, Arany Z. Myeloid Folliculin balances mTOR activation to maintain innate immunity homeostasis. JCI Insight 2019; 5: 5
    PubMedGoogle Scholar
  • 118 Chen J, Huang D, Rubera I. , et al. Disruption of tubular Flcn expression as a mouse model for renal tumor induction. Kidney Int 2015; 88 (05) 1057-1069
    CrossrefPubMedGoogle Scholar
  • 119 Hasumi Y, Baba M, Hasumi H. , et al. Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation. Hum Mol Genet 2014; 23 (21) 5706-5719
    CrossrefPubMedGoogle Scholar
  • 120 Medvetz DA, Khabibullin D, Hariharan V. , et al. Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PLoS One 2012; 7 (11) e47842
    CrossrefPubMedGoogle Scholar