Folliculin variants linked to Birt-Hogg-Dubé syndrome are targeted for proteasomal degradation

Autoři: Lene Clausen aff001;  Amelie Stein aff001;  Martin Grønbæk-Thygesen aff001;  Lasse Nygaard aff001;  Cecilie L. Søltoft aff001;  Sofie V. Nielsen aff001;  Michael Lisby aff001;  Tommer Ravid aff002;  Kresten Lindorff-Larsen aff001;  Rasmus Hartmann-Petersen aff001
Působiště autorů: The Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark aff001;  Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel aff002
Vyšlo v časopise: Folliculin variants linked to Birt-Hogg-Dubé syndrome are targeted for proteasomal degradation. PLoS Genet 16(11): e32767. doi:10.1371/journal.pgen.1009187
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009187


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. Most BHD-linked FLCN variants include large deletions and splice site aberrations predicted to cause loss of function. The mechanisms by which missense variants and short in-frame deletions in FLCN trigger disease are unknown. Here, we present an integrated computational and experimental study that reveals that the majority of such disease-causing FLCN variants cause loss of function due to proteasomal degradation of the encoded FLCN protein, rather than directly ablating FLCN function. Accordingly, several different single-site FLCN variants are present at strongly reduced levels in cells. In line with our finding that FLCN variants are protein quality control targets, several are also highly insoluble and fail to associate with the FLCN-binding partners FNIP1 and FNIP2. The lack of FLCN binding leads to rapid proteasomal degradation of FNIP1 and FNIP2. Half of the tested FLCN variants are mislocalized in cells, and one variant (ΔE510) forms perinuclear protein aggregates. A yeast-based stability screen revealed that the deubiquitylating enzyme Ubp15/USP7 and molecular chaperones regulate the turnover of the FLCN variants. Lowering the temperature led to a stabilization of two FLCN missense proteins, and for one (R362C), function was re-established at low temperature. In conclusion, we propose that most BHD-linked FLCN missense variants and small in-frame deletions operate by causing misfolding and degradation of the FLCN protein, and that stabilization and resulting restoration of function may hold therapeutic potential of certain disease-linked variants. Our computational saturation scan encompassing both missense variants and single site deletions in FLCN may allow classification of rare FLCN variants of uncertain clinical significance.

Klíčová slova:

Autophagic cell death – Crystal structure – Immunoprecipitation – Proteasomes – Protein folding – Transfection – Uracils – Yeast


1. Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature. 2011;475:324–332. doi: 10.1038/nature10317 21776078

2. Kriegenburg F, Ellgaard L, Hartmann-Petersen R. Molecular chaperones in targeting misfolded proteins for ubiquitin-dependent degradation. FEBS J. 2012;279:532–542. doi: 10.1111/j.1742-4658.2011.08456.x 22177318

3. Jones RD, Gardner RG. Protein quality control in the nucleus. Curr Opin Cell Biol. 2016;40:81–89. doi: 10.1016/ 27015023

4. Esser C, Alberti S, Hohfeld J. Cooperation of molecular chaperones with the ubiquitin/proteasome system. Biochim Biophys Acta. 2004;1695:171–188. doi: 10.1016/j.bbamcr.2004.09.020 15571814

5. Sontag EM, Vonk WI, Frydman J. Sorting out the trash: the spatial nature of eukaryotic protein quality control. Curr Opin Cell Biol. 2014;26C:139–146. doi: 10.1016/ 24463332

6. Amm I, Sommer T, Wolf DH. Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system. Biochim Biophys Acta. 2014;1843:182–196. doi: 10.1016/j.bbamcr.2013.06.031 23850760

7. Shiber A, Ravid T. Chaperoning proteins for destruction: diverse roles of Hsp70 chaperones and their co-chaperones in targeting misfolded proteins to the proteasome. Biomolecules. 2014;4:704–724.

8. Kevei E, Pokrzywa W, Hoppe T. Repair or destruction-an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis. FEBS Lett. 2017;591:2616–2635. doi: 10.1002/1873-3468.12750 28699655

9. Geffen Y, Appleboim A, Gardner RG, Friedman N, Sadeh R, Ravid T. Mapping the Landscape of a Eukaryotic Degronome. Mol Cell. 2016;63:1055–1065. doi: 10.1016/j.molcel.2016.08.005 27618491

10. Maurer MJ, Spear ED, Yu AT, Lee EJ, Shahzad S, Michaelis S. Degradation Signals for Ubiquitin-Proteasome Dependent Cytosolic Protein Quality Control (CytoQC) in Yeast. G3 (Bethesda). 2016;6:1853–1866. doi: 10.1534/g3.116.027953 27172186

11. Nielsen SV, Stein A, Dinitzen AB, Papaleo E, Tatham MH, Poulsen EG et al. Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations. PLoS Genet. 2017;13:e1006739. doi: 10.1371/journal.pgen.1006739 28422960

12. Scheller R, Stein A, Nielsen SV, Marin FI, Gerdes AM, Di MM et al. Toward mechanistic models for genotype-phenotype correlations in phenylketonuria using protein stability calculations. Hum Mutat. 2019;40:444–457. doi: 10.1002/humu.23707 30648773

13. Abildgaard AB, Stein A, Nielsen SV, Schultz-Knudsen K, Papaleo E, Shrikhande A et al. Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. Elife. 2019;8. doi: 10.7554/eLife.49138 31697235

14. Gardner RG, Nelson ZW, Gottschling DE. Degradation-mediated protein quality control in the nucleus. Cell. 2005;120:803–815. doi: 10.1016/j.cell.2005.01.016 15797381

15. Kriegenburg F, Jakopec V, Poulsen EG, Nielsen SV, Roguev A, Krogan N et al. A chaperone-assisted degradation pathway targets kinetochore proteins to ensure genome stability. PLoS Genet. 2014;10:e1004140. doi: 10.1371/journal.pgen.1004140 24497846

16. Kampmeyer C, Karakostova A, Schenstrom SM, Abildgaard AB, Lauridsen AM, Jourdain I et al. The exocyst subunit Sec3 is regulated by a protein quality control pathway. J Biol Chem. 2017;292:15240–15253. doi: 10.1074/jbc.M117.789867 28765280

17. Meacham GC, Patterson C, Zhang W, Younger JM, Cyr DM. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol. 2001;3:100–105. doi: 10.1038/35050509 11146634

18. Ahner A, Nakatsukasa K, Zhang H, Frizzell RA, Brodsky JL. Small heat-shock proteins select deltaF508-CFTR for endoplasmic reticulum-associated degradation. Mol Biol Cell. 2007;18:806–814. doi: 10.1091/mbc.e06-05-0458 17182856

19. Arora S, Huwe PJ, Sikder R, Shah M, Browne AJ, Lesh R et al. Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods. Cancer Biol Ther. 2017;18:519–533. doi: 10.1080/15384047.2017.1326439 28494185

20. McCafferty CL, Sergeev YV. In silico Mapping of Protein Unfolding Mutations for Inherited Disease. Sci Rep. 2016;6:37298. doi: 10.1038/srep37298 27905547

21. Kumar V, Rahman S, Choudhry H, Zamzami MA, Sarwar JM, Islam A et al. Computing disease-linked SOD1 mutations: deciphering protein stability and patient-phenotype relations. Sci Rep. 2017;7:4678. doi: 10.1038/s41598-017-04950-9 28680046

22. Wagih O, Galardini M, Busby BP, Memon D, Typas A, Beltrao P. A resource of variant effect predictions of single nucleotide variants in model organisms. Mol Syst Biol. 2018;14:e8430.

23. Beaver SK, Mesa-Torres N, Pey AL, Timson DJ. NQO1: A target for the treatment of cancer and neurological diseases, and a model to understand loss of function disease mechanisms. Biochim Biophys Acta Proteins Proteom. 2019;1867:663–676. doi: 10.1016/j.bbapap.2019.05.002 31091472

24. Caswell RC, Owens MM, Gunning AC, Ellard S, Wright CF. Using Structural Analysis In Silico to Assess the Impact of Missense Variants in MEN1. J Endocr Soc. 2019;3:2258–2275. doi: 10.1210/js.2019-00260 31737856

25. Iqbal S, Jespersen JB, Perez-Palma E, May P, Hoksza D, Heyne HO et al. Insights into protein structural, physicochemical, and functional consequences of missense variants in 1,330 disease-associated human genes. bioRxiv. 2019;693259.

26. Tang N, Sandahl T, Ott P, Kepp KP. Benchmarking Computational Methods for Estimating the Pathogenicity of Wilson's Disease Mutations bioRxiv 2019;780924:

27. Jepsen MM, Fowler DM, Hartmann-Petersen R, Stein A, Lindorff-Larsen K. Classifying disease-associated variants using measures of protein activity and stability. bioRxiv. 2019;688234.

28. Tiberti M, Terkelsen T, Cremers TC, Di Marco M, da Piedade I, Maiani E et al. MutateX: an automated pipeline for in-silico saturation mutagenesis of protein structures and structural ensembles. bioRxiv. 2019;824938.

29. Casadio R, Vassura M, Tiwari S, Fariselli P, Luigi MP. Correlating disease-related mutations to their effect on protein stability: a large-scale analysis of the human proteome. Hum Mutat. 2011;32:1161–1170. doi: 10.1002/humu.21555 21853506

30. Pal LR, Moult J. Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies. J Mol Biol. 2015;427:2271–2289.

31. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002;2:157–164. doi: 10.1016/s1535-6108(02)00104-6 12204536

32. Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev. 2002;11:393–400. 11927500

33. Schmidt LS, Linehan WM. FLCN: The causative gene for Birt-Hogg-Dube syndrome. Gene. 2018;640:28–42. doi: 10.1016/j.gene.2017.09.044 28970150

34. Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977;113:1674–1677. 596896

35. Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S et al. Birt-Hogg-Dube syndrome: diagnosis and management. Lancet Oncol. 2009;10:1199–1206. doi: 10.1016/S1470-2045(09)70188-3 19959076

36. Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B et al. Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia Arch Dermatol 1999;135:1195–1202. doi: 10.1001/archderm.135.10.1195 10522666

37. Kovacs D, Kalmar E, Torok Z, Tompa P. Chaperone activity of ERD10 and ERD14, two disordered stress-related plant proteins. Plant Physiol. 2008;147:381–390. doi: 10.1104/pp.108.118208 18359842

38. Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Birt-Hogg-Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene. 2001;20:5239–5242. doi: 10.1038/sj.onc.1204703 11526515

39. Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR et al. Birt-Hogg-Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet. 2001;69:876–882. doi: 10.1086/323744 11533913

40. Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA et al. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal tumors. J Natl Cancer Inst. 2005;97:931–935. doi: 10.1093/jnci/dji154 15956655

41. Yang Y, Padilla-Nash HM, Vira MA, Abu-Asab MS, Val D, Worrell R et al. The UOK 257 cell line: a novel model for studies of the human Birt-Hogg-Dube gene pathway. Cancer Genet Cytogenet. 2008;180:100–109. doi: 10.1016/j.cancergencyto.2007.10.010 18206534

42. Okimoto K, Sakurai J, Kobayashi T, Mitani H, Hirayama Y, Nickerson ML et al. A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Proc Natl Acad Sci U S A. 2004;101:2023–2027. doi: 10.1073/pnas.0308071100 14769940

43. Togashi Y, Kobayashi T, Momose S, Ueda M, Okimoto K, Hino O. Transgenic rescue from embryonic lethality and renal carcinogenesis in the Nihon rat model by introduction of a wild-type Bhd gene. Oncogene. 2006;25:2885–2889.

44. Lingaas F, Comstock KE, Kirkness EF, Sorensen A, Aarskaug T, Hitte C et al. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Hum Mol Genet. 2003;12:3043–3053. doi: 10.1093/hmg/ddg336 14532326

45. Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, Southon E 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;100:140–154.

46. Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ et al. Birt-Hogg-Dube renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression. BMC Med Genomics. 2010;3:59.

47. 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:e15793. doi: 10.1371/journal.pone.0015793 21209915

48. Napolitano G, Di MC, Esposito A, de Araujo MEG, Pece S, Bertalot G et al. A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. Nature. 2020. doi: 10.1038/s41586-020-2444-0 32612235

49. Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X et al. Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Hum Mol Genet. 2012;21:5268–5279. doi: 10.1093/hmg/dds378 22965878

50. Bar-Peled L, Sabatini DM. Regulation of mTORC1 by amino acids. Trends Cell Biol. 2014;24:400–406. doi: 10.1016/j.tcb.2014.03.003 24698685

51. Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52:495–505.

52. Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C et al. The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat Commun. 2016;7:12037. doi: 10.1038/ncomms12037 27353360

53. Sager RA, Woodford MR, Backe SJ, Makedon AM, Baker-Williams AJ, DiGregorio BT et al. Post-translational Regulation of FNIP1 Creates a Rheostat for the Molecular Chaperone Hsp90. Cell Rep. 2019;26:1344–1356. doi: 10.1016/j.celrep.2019.01.018 30699359

54. Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montano B, Donaldson JC, Blaszczyk BK et al. Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. Open Biol. 2012;2:120071. doi: 10.1098/rsob.120071 22977732

55. Wu X, Bradley MJ, Cai Y, Kummel D, De La Cruz EM, Barr FA et al. Insights regarding guanine nucleotide exchange from the structure of a DENN-domain protein complexed with its Rab GTPase substrate. Proc Natl Acad Sci U S A. 2011;108:18672–18677. doi: 10.1073/pnas.1110415108 22065758

56. Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, Barr FA. Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. J Cell Biol. 2010;191:367–381. doi: 10.1083/jcb.201008051 20937701

57. 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;179:1319–1329. doi: 10.1016/j.cell.2019.10.036 31704029

58. Lawrence RE, Fromm SA, Fu Y, Yokom AL, Kim DJ, Thelen AM et al. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 2019;366:971–977. doi: 10.1126/science.aax0364 31672913

59. Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A 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;103:15552–15557. doi: 10.1073/pnas.0603781103 17028174

60. Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M et al. Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene. 2008;415:60–67. doi: 10.1016/j.gene.2008.02.022 18403135

61. Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G et al. Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene. 2008;27:5339–5347. doi: 10.1038/onc.2008.261 18663353

62. Hasumi H, Baba M, Hasumi Y, Lang M, Huang Y, Oh HF et al. Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. Proc Natl Acad Sci U S A. 2015;112:E1624–E1631. doi: 10.1073/pnas.1419502112 25775561

63. Chen J, Futami K, Petillo D, Peng J, Wang P, Knol J et al. Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia. PLoS One. 2008;3:e3581.

64. Sager RA, Woodford MR, Shapiro O, Mollapour M, Bratslavsky G. Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis. Oncotarget. 2018;9:22220–22229. doi: 10.18632/oncotarget.25164 29774133

65. Nahorski MS, Reiman A, Lim DH, Nookala RK, Seabra L, Lu X et al. Birt Hogg-Dube syndrome-associated FLCN mutations disrupt protein stability Hum Mutat 2011;32:921–929. doi: 10.1002/humu.21519 21538689

66. Matreyek KA, Starita LM, Stephany JJ, Martin B, Chiasson MA, Gray VE et al. Multiplex assessment of protein variant abundance by massively parallel sequencing Nat Genet 2018;50:874–882. doi: 10.1038/s41588-018-0122-z 29785012

67. Roscoe BP, Thayer KM, Zeldovich KB, Fushman D, Bolon DN. Analyses of the effects of all ubiquitin point mutants on yeast growth rate. J Mol Biol. 2013;425:1363–1377.

68. Stein A, Fowler DM, Hartmann-Petersen R, Lindorff-Larsen K. Biophysical and Mechanistic Models for Disease-Causing Protein Variants. Trends Biochem Sci. 2019;44:575–588. doi: 10.1016/j.tibs.2019.01.003 30712981

69. Gonzalez CE, Roberts P, Ostermeier M. Fitness Effects of Single Amino Acid Insertions and Deletions in TEM-1 beta-Lactamase. J Mol Biol. 2019;431:2320–2330. doi: 10.1016/j.jmb.2019.04.030 31034887

70. Arpino JA, Reddington SC, Halliwell LM, Rizkallah PJ, Jones DD. Random single amino acid deletion sampling unveils structural tolerance and the benefits of helical registry shift on GFP folding and structure. Structure. 2014;22:889–898. doi: 10.1016/j.str.2014.03.014 24856363

71. Jones DD. Triplet nucleotide removal at random positions in a target gene: the tolerance of TEM-1 beta-lactamase to an amino acid deletion. Nucleic Acids Res. 2005;33:e80.

72. Banerjee A, Levy Y, Mitra P. Analyzing Change in Protein Stability Associated with Single Point Deletions in a Newly Defined Protein Structure Database. J Proteome Res. 2019;18:1402–1410. doi: 10.1021/acs.jproteome.9b00048 30735617

73. Park H, Bradley P, Greisen P, Jr., Liu Y, Mulligan VK, Kim DE et al. Simultaneous Optimization of Biomolecular Energy Functions on Features from Small Molecules and Macromolecules. J Chem Theory Comput. 2016;12:6201–6212. doi: 10.1021/acs.jctc.6b00819 27766851

74. Alford RF, Leaver-Fay A, Jeliazkov JR, O'Meara MJ, DiMaio FP, Park H et al. The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design. J Chem Theory Comput. 2017;13:3031–3048. doi: 10.1021/acs.jctc.7b00125 28430426

75. Jackson EL, Spielman SJ, Wilke CO. Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein. PLoS One. 2017;12:e0164905. doi: 10.1371/journal.pone.0164905 28369116

76. Mathiassen SG, Larsen IB, Poulsen EG, Madsen CT, Papaleo E, Lindorff-Larsen K et al. A Two-step Protein Quality Control Pathway for a Misfolded DJ-1 Variant in Fission Yeast. J Biol Chem. 2015;290:21141–21153. doi: 10.1074/jbc.M115.662312 26152728

77. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRxiv. 2019;531210:

78. Shiber A, Breuer W, Brandeis M, Ravid T. Ubiquitin conjugation triggers misfolded protein sequestration into quality control foci when Hsp70 chaperone levels are limiting. Mol Biol Cell. 2013;24:2076–2087. doi: 10.1091/mbc.E13-01-0010 23637465

79. Le Goff X, Chesnel F, Delalande O, Couturier A, Dreano S, Le Goff C. et al. Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel-Lindau tumor suppressor protein. J Cell Sci. 2016;129:2638–2650. doi: 10.1242/jcs.184846 27179072

80. Westhoff B, Chapple JP, van der Spuy J, Hohfeld J, Cheetham ME. HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome. Curr Biol. 2005;15:1058–1064. doi: 10.1016/j.cub.2005.04.058 15936278

81. Bartram MP, Mishra T, Reintjes N, Fabretti F, Gharbi H, Adam AC et al. Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. BMC Med Genet. 2017;18:53. doi: 10.1186/s12881-017-0416-5 28499369

82. Bard JAM, Goodall EA, Greene ER, Jonsson E, Dong KC, Martin A. Structure and Function of the 26S Proteasome. Annu Rev Biochem. 2018;87:697–724. doi: 10.1146/annurev-biochem-062917-011931 29652515

83. Winzeler EA, Shoemaker DD, Astromoff A, Liang H, Anderson K, Andre B et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science. 1999;285:901–906. doi: 10.1126/science.285.5429.901 10436161

84. Kim RQ, Sixma TK. Regulation of USP7: A High Incidence of E3 Complexes. J Mol Biol. 2017;429:3395–3408. doi: 10.1016/j.jmb.2017.05.028 28591556

85. Landrum MJ, Chitipiralla S, Brown GR, Chen C, Gu B, Hart J et al. ClinVar: improvements to accessing data. Nucleic Acids Res. 2020;48:D835–D844. doi: 10.1093/nar/gkz972 31777943

86. Chai Y, Koppenhafer SL, Shoesmith SJ, Perez MK, Paulson HL. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet. 1999;8:673–682. doi: 10.1093/hmg/8.4.673 10072437

87. Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell. 2009;138:389–403. doi: 10.1016/j.cell.2009.04.042 19615732

88. Maertens GN, El Messaoudi-Aubert S, Elderkin S, Hiom K, Peters G. Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor. EMBO J. 2010;29:2553–2565. doi: 10.1038/emboj.2010.129 20601937

89. Hao YH, Fountain MD Jr., Fon TK, Xia F, Bi W, Kang SH et al. USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder. Mol Cell. 2015;59:956–969. doi: 10.1016/j.molcel.2015.07.033 26365382

90. Cummins JM, Rago C, Kohli M, Kinzler KW, Lengauer C, Vogelstein B. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature. 2004;428:1. doi: 10.1038/nature02501 15058298

91. Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004;13:879–886. doi: 10.1016/s1097-2765(04)00157-1 15053880

92. Turnbull AP, Ioannidis S, Krajewski WW, Pinto-Fernandez A, Heride C, Martin ACL et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature. 2017;550:481–486. doi: 10.1038/nature24451 29045389

93. Reverdy C, Conrath S, Lopez R, Planquette C, Atmanene C, Collura V et al. Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme Chem Biol 2012;19:467–477.

94. Samant RS, Livingston CM, Sontag EM, Frydman J. Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control. Nature. 2018;563:407–411. doi: 10.1038/s41586-018-0678-x 30429547

95. Theodoraki MA, Nillegoda NB, Saini J, Caplan AJ. A network of ubiquitin ligases is important for the dynamics of misfolded protein aggregates in yeast. J Biol Chem. 2012;287:23911–23922. doi: 10.1074/jbc.M112.341164 22593585

96. Gowda NK, Kandasamy G, Froehlich MS, Dohmen RJ, Andreasson C. Hsp70 nucleotide exchange factor Fes1 is essential for ubiquitin-dependent degradation of misfolded cytosolic proteins. Proc Natl Acad Sci U S A. 2013;110:5975–5980. doi: 10.1073/pnas.1216778110 23530227

97. Kandasamy G, Andreasson C. Hsp70-Hsp110 chaperones deliver ubiquitin-dependent and -independent substrates to the 26S proteasome for proteolysis in yeast. J Cell Sci. 2018;131. doi: 10.1242/jcs.210948 29507114

98. Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Hohfeld J et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol. 2001;3:93–96. doi: 10.1038/35050618 11146632

99. Fang NN, Chan GT, Zhu M, Comyn SA, Persaud A, Deshaies RJ et al. Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress. Nat Cell Biol. 2014;16:1227–1237. doi: 10.1038/ncb3054 25344756

100. Yanagitani K, Juszkiewicz S, Hegde RS. UBE2O is a quality control factor for orphans of multiprotein complexes. Science. 2017;357:472–475. doi: 10.1126/science.aan0178 28774922

101. McShane E, Sin C, Zauber H, Wells JN, Donnelly N, Wang X et al. Kinetic Analysis of Protein Stability Reveals Age-Dependent Degradation. Cell. 2016;167:803–815.

102. Nagashima K, Fukushima H, Shimizu K, Yamada A, Hidaka M, Hasumi H et al. Nutrient-induced FNIP degradation by SCFbeta-TRCP regulates FLCN complex localization and promotes renal cancer progression. Oncotarget. 2017;8:9947–9960. doi: 10.18632/oncotarget.14221 28039480

103. Hasumi H, Hasumi Y, Baba M, Nishi H, Furuya M, Vocke CD et al. H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation Hum Mol Genet. 2017;26:354–366.

104. Van GF, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809 Proc Natl Acad Sci U S A. 2011;108:18843–18848. doi: 10.1073/pnas.1105787108 21976485

105. Yang C, Huntoon K, Ksendzovsky A, Zhuang Z, Lonser RR. Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. Cell Rep. 2013;3:52–59.

106. Joerger AC, Fersht AR. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Annu Rev Biochem. 2016;85:375–404. doi: 10.1146/annurev-biochem-060815-014710 27145840

107. Kampmeyer C, Nielsen SV, Clausen L, Stein A, Gerdes AM, Lindorff-Larsen K et al. Blocking protein quality control to counter hereditary cancers. Genes Chromosomes Cancer. 2017;56:823–831. doi: 10.1002/gcc.22487 28779490

108. Gietz RD, Woods RA. Transformation of yeast by lithium acetate/single-stranded carrier DNA/polyethylene glycol method Methods Enzymol. 2002;350:87–96. doi: 10.1016/s0076-6879(02)50957-5 12073338

109. Cox JS, Chapman RE, Walter P. The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane Mol Biol Cell. 1997;8:1805–1814. doi: 10.1091/mbc.8.9.1805 9307975

110. Tong AH, Boone C. High-Throughput Strain Construction and Systematic Synthetic Lethal Screening in Saccharomyces cerevisiae. Methods in Microbiology. 2007;36:369–386.

111. Webb B, Sali A. Comparative Protein Structure Modeling Using MODELLER Curr Protoc Protein Sci. 2016;86:2.

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PLOS Genetics

2020 Číslo 11

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