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The role of deubiquitinating enzymes in spermatogenesis

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Abstract

Spermatogenesis is a complex process through which spermatogonial stem cells undergo mitosis, meiosis, and cell differentiation to generate mature spermatozoa. During this process, male germ cells experience several translational modifications. One of the major post-translational modifications in eukaryotes is the ubiquitination of proteins, which targets proteins for degradation; this enables control of the expression of enzymes and structural proteins during spermatogenesis. It has become apparent that ubiquitination plays a key role in regulating every stage of spermatogenesis starting from gonocytes to differentiated spermatids. It is understood that, where there is ubiquitination, deubiquitination by deubiquitinating enzymes (DUBs) also exists to counterbalance the ubiquitination process in a reversible manner. Normal spermatogenesis is dependent on the balanced actions of ubiquitination and deubiquitination. This review highlights the current knowledge of the role of DUBs and their essential regulatory contribution to spermatogenesis, especially during progression into meiotic phase, acrosome biogenesis, quality sperm production, and apoptosis of germ cells.

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Abbreviations

DUBs:

Deubiquitinating enzymes

UPS:

Ubiquitin proteasome system

UCH:

Ubiquitin C-terminal hydrolases

USP:

Ubiquitin-specific processing proteases

JAMM:

Jab1/Pab1/MPN domain-containing metalloenzymes

OTU:

Otu-domain ubiquitin aldehyde-binding proteins

MCPIPs:

Monocyte chemotactic protein-induced proteases

MIT:

Microtubule interacting and transport domain

AZF:

Azoospermia factor

AR:

Androgen receptor

ax:

Ataxia

SNPs:

Single nucleotide polymorphism

CYLD:

Cylindromatosis

RIP1:

Receptor-interacting protein 1

References

  1. Amerik AY, Hochstrasser M (2004) Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta 1695:189–207

    Article  CAS  PubMed  Google Scholar 

  2. Sigismund S, Polo S, Di Fiore PP (2004) Signaling through monoubiquitination. Curr Top Microbiol Immunol 286:149–185

    CAS  PubMed  Google Scholar 

  3. Sun L, Chen ZJ (2004) The novel functions of ubiquitination in signaling. Curr Opin Cell Biol 16(2):119–126. doi:10.1016/j.ceb.2004.02.005

    Article  CAS  PubMed  Google Scholar 

  4. Sadowski M, Suryadinata R, Tan AR, Roesley SN, Sarcevic B (2012) Protein monoubiquitination and polyubiquitination generate structural diversity to control distinct biological processes. IUBMB Life 64(2):136–142. doi:10.1002/iub.589

    Article  CAS  PubMed  Google Scholar 

  5. Ramanathan HN, Ye Y (2012) Cellular strategies for making monoubiquitin signals. Crit Rev Biochem Mol Biol 47(1):17–28. doi:10.3109/10409238.2011.620943

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229. doi:10.1146/annurev-biochem-060310-170328

    Article  CAS  PubMed  Google Scholar 

  7. Komander D (2009) The emerging complexity of protein ubiquitination. Biochem Soc Trans 37(Pt 5):937–953. doi:10.1042/BST0370937

    Article  CAS  PubMed  Google Scholar 

  8. Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78:363–397. doi:10.1146/annurev.biochem.78.082307.091526

    Article  CAS  PubMed  Google Scholar 

  9. Baek KH (2006) Cytokine-regulated protein degradation by the ubiquitination system. Curr Protein Pept Sci 7:171–177

    Article  CAS  PubMed  Google Scholar 

  10. Baek KH, Kim MS, Kim YS, Shin JM, Choi KH (2004) DUB-1A, a novel subfamily member of deubiquitinating enzyme, is polyubiquitinated and cytokine inducible in B-lymphocytes. J Biol Chem 279:2368–2376

    Article  CAS  PubMed  Google Scholar 

  11. Lim KH, Ramakrishna S, Baek KH (2013) Molecular mechanisms and functions of cytokine-inducible deubiquitinating enzymes. Cytokine Growth Factor Rev 24(5):427–431. doi:10.1016/j.cytogfr.2013.05.007

    Article  CAS  PubMed  Google Scholar 

  12. Ramakrishna S, Kim KS, Baek KH (2014) Posttranslational modifications of defined embryonic reprogramming transcription factors. Cell Reprogramm 16(2):108–120. doi:10.1089/cell.2013.0077

    Article  CAS  Google Scholar 

  13. Ramakrishna S, Suresh B, Baek KH (2011) The role of deubiquitinating enzymes in apoptosis. Cell Mol Life Sci 68(1):15–26. doi:10.1007/s00018-010-0504-6

    Article  CAS  PubMed  Google Scholar 

  14. Ramakrishna S, Suresh B, Baek KH (2015) Biological functions of hyaluronan and cytokine-inducible deubiquitinating enzymes. Biochim Biophys Acta 1855(1):83–91. doi:10.1016/j.bbcan.2014.11.006

    CAS  PubMed  Google Scholar 

  15. Hess RA, Renato de Franca L (2008) Spermatogenesis and cycle of the seminiferous epithelium. Adv Exp Med Biol 636:1–15. doi:10.1007/978-0-387-09597-4_1

    Article  PubMed  Google Scholar 

  16. Heller CH, Clermont Y (1964) Kinetics of the germinal epithelium in man. Recent Prog Horm Res 20:545–575

    CAS  PubMed  Google Scholar 

  17. Misell LM, Holochwost D, Boban D, Santi N, Shefi S, Hellerstein MK, Turek PJ (2006) A stable isotope-mass spectrometric method for measuring human spermatogenesis kinetics in vivo. J Urol 175(1):242–246. doi:10.1016/S0022-5347(05)00053-4 (discussion 246)

    Article  CAS  PubMed  Google Scholar 

  18. Schulze C (1979) Morphological characteristics of the spermatogonial stem cells in man. Cell Tissue Res 198(2):191–199

    Article  CAS  PubMed  Google Scholar 

  19. Clermont Y (1972) Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Physiol Rev 52(1):198–236

    CAS  PubMed  Google Scholar 

  20. de Rooij DG, Russell LD (2000) All you wanted to know about spermatogonia but were afraid to ask. J Androl 21(6):776–798

    PubMed  Google Scholar 

  21. de Rooij DG (2001) Proliferation and differentiation of spermatogonial stem cells. Reproduction 121(3):347–354

    Article  PubMed  Google Scholar 

  22. Tegelenbosch RA, de Rooij DG (1993) A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F1 hybrid mouse. Mutat Res 290(2):193–200

    Article  CAS  PubMed  Google Scholar 

  23. Bose R, Manku G, Culty M, Wing SS (2014) Ubiquitin-proteasome system in spermatogenesis. Adv Exp Med Biol 759:181–213. doi:10.1007/978-1-4939-0817-2_9

    Article  CAS  PubMed  Google Scholar 

  24. Lin H, Keriel A, Morales CR, Bedard N, Zhao Q, Hingamp P, Lefrancois S, Combaret L, Wing SS (2000) Divergent N-terminal sequences target an inducible testis deubiquitinating enzyme to distinct subcellular structures. Mol Cell Biol 20(17):6568–6578

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Manku G, Wing SS, Culty M (2012) Expression of the ubiquitin proteasome system in neonatal rat gonocytes and spermatogonia: role in gonocyte differentiation. Biol Reprod 87(2):44. doi:10.1095/biolreprod.112.099143

    Article  PubMed  Google Scholar 

  26. Bedard N, Yang Y, Gregory M, Cyr DG, Suzuki J, Yu X, Chian RC, Hermo L, O’Flaherty C, Smith CE, Clarke HJ, Wing SS (2011) Mice lacking the USP2 deubiquitinating enzyme have severe male subfertility associated with defects in fertilization and sperm motility. Biol Reprod 85(3):594–604. doi:10.1095/biolreprod.110.088542

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Naviglio S, Mattecucci C, Matoskova B, Nagase T, Nomura N, Di Fiore PP, Draetta GF (1998) UBPY: a growth-regulated human ubiquitin isopeptidase. EMBO J 17(12):3241–3250. doi:10.1093/emboj/17.12.3241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Gnesutta N, Ceriani M, Innocenti M, Mauri I, Zippel R, Sturani E, Borgonovo B, Berruti G, Martegani E (2001) Cloning and characterization of mouse UBPy, a deubiquitinating enzyme that interacts with the ras guanine nucleotide exchange factor CDC25(Mm)/Ras-GRF1. J Biol Chem 276(42):39448–39454. doi:10.1074/jbc.M103454200

    Article  CAS  PubMed  Google Scholar 

  29. Mizuno E, Kobayashi K, Yamamoto A, Kitamura N, Komada M (2006) A deubiquitinating enzyme UBPY regulates the level of protein ubiquitination on endosomes. Traffic 7(8):1017–1031. doi:10.1111/j.1600-0854.2006.00452.x

    Article  CAS  PubMed  Google Scholar 

  30. Niendorf S, Oksche A, Kisser A, Lohler J, Prinz M, Schorle H, Feller S, Lewitzky M, Horak I, Knobeloch KP (2007) Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo. Mol Cell Biol 27(13):5029–5039. doi:10.1128/MCB.01566-06

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Berruti G, Martegani E (2001) MSJ-1, a mouse testis-specific DnaJ protein, is highly expressed in haploid male germ cells and interacts with the testis-specific heat shock protein Hsp70-2. Biol Reprod 65(2):488–495

    Article  CAS  PubMed  Google Scholar 

  32. Berruti G, Martegani E (2002) mUBPy and MSJ-1, a deubiquitinating enzyme and a molecular chaperone specifically expressed in testis, associate with the acrosome and centrosome in mouse germ cells. Ann N Y Acad Sci 973:5–7

    Article  CAS  PubMed  Google Scholar 

  33. Berruti G, Martegani E (2005) The deubiquitinating enzyme mUBPy interacts with the sperm-specific molecular chaperone MSJ-1: the relation with the proteasome, acrosome, and centrosome in mouse male germ cells. Biol Reprod 72(1):14–21. doi:10.1095/biolreprod.104.030866

    Article  CAS  PubMed  Google Scholar 

  34. Meccariello R, Cobellis G, Berruti G, Junier MP, Ceriani M, Boilee S, Pierantoni R, Fasano S (2002) Mouse sperm cell-specific DnaJ first homologue: an evolutionarily conserved protein for spermiogenesis. Biol Reprod 66(5):1328–1335

    Article  CAS  PubMed  Google Scholar 

  35. Chianese R, Scarpa D, Berruti G, Cobellis G, Pierantoni R, Fasano S, Meccariello R (2010) Expression and localization of the deubiquitinating enzyme mUBPy in wobbler mouse testis during spermiogenesis. Gen Comp Endocrinol 166(2):289–295. doi:10.1016/j.ygcen.2009.09.014

    Article  CAS  PubMed  Google Scholar 

  36. Berruti G, Ripolone M, Ceriani M (2010) USP8, a regulator of endosomal sorting, is involved in mouse acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Biol Reprod 82(5):930–939. doi:10.1095/biolreprod.109.081679

    Article  CAS  PubMed  Google Scholar 

  37. Paiardi C, Pasini ME, Gioria M, Berruti G (2011) Failure of acrosome formation and globozoospermia in the wobbler mouse, a Vps54 spontaneous recessive mutant. Spermatogenesis 1(1):52–62. doi:10.4161/spmg.1.1.14698

    Article  PubMed Central  PubMed  Google Scholar 

  38. Krausz C, Forti G, McElreavey K (2003) The Y chromosome and male fertility and infertility. Int J Androl 26(2):70–75

    Article  PubMed  Google Scholar 

  39. Sun C, Skaletsky H, Birren B, Devon K, Tang Z, Silber S, Oates R, Page DC (1999) An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet 23(4):429–432. doi:10.1038/70539

    Article  CAS  PubMed  Google Scholar 

  40. Brown GM, Furlong RA, Sargent CA, Erickson RP, Longepied G, Mitchell M, Jones MH, Hargreave TB, Cooke HJ, Affara NA (1998) Characterisation of the coding sequence and fine mapping of the human DFFRY gene and comparative expression analysis and mapping to the Sxrb interval of the mouse Y chromosome of the Dffry gene. Hum Mol Genet 7(1):97–107

    Article  CAS  PubMed  Google Scholar 

  41. Ferlin A, Arredi B, Speltra E, Cazzadore C, Selice R, Garolla A, Lenzi A, Foresta C (2007) Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab 92(3):762–770. doi:10.1210/jc.2006-1981

    Article  CAS  PubMed  Google Scholar 

  42. Krausz C, Degl’Innocenti S, Nuti F, Morelli A, Felici F, Sansone M, Varriale G, Forti G (2006) Natural transmission of USP9Y gene mutations: a new perspective on the role of AZFa genes in male fertility. Hum Mol Genet 15(18):2673–2681. doi:10.1093/hmg/ddl198

    Article  CAS  PubMed  Google Scholar 

  43. Luddi A, Margollicci M, Gambera L, Serafini F, Cioni M, De Leo V, Balestri P, Piomboni P (2009) Spermatogenesis in a man with complete deletion of USP9Y. N Engl J Med 360(9):881–885. doi:10.1056/NEJMoa0806218

    Article  CAS  PubMed  Google Scholar 

  44. Hu M, Li P, Song L, Jeffrey PD, Chenova TA, Wilkinson KD, Cohen RE, Shi Y (2005) Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. EMBO J 24(21):3747–3756. doi:10.1038/sj.emboj.7600832

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. D’Amato CJ, Hicks SP (1965) Neuropathologic alterations in the ataxia (paralytic) mouse. Arch Pathol 80(6):604–612

    PubMed  Google Scholar 

  46. Vaden JH, Bhattacharyya BJ, Chen PC, Watson JA, Marshall AG, Phillips SE, Wilson JA, King GD, Miller RJ, Wilson SM (2015) Ubiquitin-specific protease 14 regulates c-Jun N-terminal kinase signaling at the neuromuscular junction. Mol Neurodegener 10(1):3. doi:10.1186/1750-1326-10-3

    Article  PubMed Central  PubMed  Google Scholar 

  47. Crimmins S, Sutovsky M, Chen PC, Huffman A, Wheeler C, Swing DA, Roth K, Wilson J, Sutovsky P, Wilson S (2009) Transgenic rescue of ataxia mice reveals a male-specific sterility defect. Dev Biol 325(1):33–42. doi:10.1016/j.ydbio.2008.09.021

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Zhang J, Tian H, Huo YW, Zhou DX, Wang HX, Wang LR, Zhang QY, Qiu SD (2009) The expression of Usp26 gene in mouse testis and brain. Asian J Androl 11(4):478–483. doi:10.1038/aja.2009.31

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Dirac AM, Bernards R (2010) The deubiquitinating enzyme USP26 is a regulator of androgen receptor signaling. Mol Cancer Res 8(6):844–854. doi:10.1158/1541-7786.MCR-09-0424

    Article  CAS  PubMed  Google Scholar 

  50. Wang PJ, McCarrey JR, Yang F, Page DC (2001) An abundance of X-linked genes expressed in spermatogonia. Nat Genet 27(4):422–426. doi:10.1038/86927

    Article  PubMed  Google Scholar 

  51. Lin YW, Hsu TH, Yen PH (2011) Localization of ubiquitin specific protease 26 at blood-testis barrier and near Sertoli cell-germ cell interface in mouse testes. Int J Androl 34(5 Pt 2):e368–e377. doi:10.1111/j.1365-2605.2010.01130.x

    Article  CAS  PubMed  Google Scholar 

  52. Stouffs K, Tournaye H, Liebaers I, Lissens W (2009) Male infertility and the involvement of the X chromosome. Hum Reprod Update 15(6):623–637. doi:10.1093/humupd/dmp023

    Article  CAS  PubMed  Google Scholar 

  53. Lee IW, Kuan LC, Lin CH, Pan HA, Hsu CC, Tsai YC, Kuo PL, Teng YN (2008) Association of USP26 haplotypes in men in Taiwan, China with severe spermatogenic defect. Asian J Androl 10(6):896–904. doi:10.1111/j.1745-7262.2008.00439.x

    Article  CAS  PubMed  Google Scholar 

  54. Paduch DA, Mielnik A, Schlegel PN (2005) Novel mutations in testis-specific ubiquitin protease 26 gene may cause male infertility and hypogonadism. Reprod Biomed Online 10(6):747–754

    Article  PubMed  Google Scholar 

  55. Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I (2005) Possible role of USP26 in patients with severely impaired spermatogenesis. Eur J Hum Genet 13(3):336–340. doi:10.1038/sj.ejhg.5201335

    Article  CAS  PubMed  Google Scholar 

  56. Ravel C, El Houate B, Chantot S, Lourenco D, Dumaine A, Rouba H, Bandyopadahyay A, Radhakrishna U, Das B, Sengupta S, Mandelbaum J, Siffroi JP, McElreavey K (2006) Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26. Mol Hum Reprod 12(10):643–646. doi:10.1093/molehr/gal063

    Article  CAS  PubMed  Google Scholar 

  57. Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I (2006) Alterations of the USP26 gene in Caucasian men. Int J Androl 29(6):614–617. doi:10.1111/j.1365-2605.2006.00708.x

    Article  CAS  PubMed  Google Scholar 

  58. Ribarski I, Lehavi O, Yogev L, Hauser R, Bar-Shira Maymon B, Botchan A, Paz G, Yavetz H, Kleiman SE (2009) USP26 gene variations in fertile and infertile men. Hum Reprod 24(2):477–484. doi:10.1093/humrep/den374

    Article  CAS  PubMed  Google Scholar 

  59. Aston KI, Krausz C, Laface I, Ruiz-Castane E, Carrell DT (2010) Evaluation of 172 candidate polymorphisms for association with oligozoospermia or azoospermia in a large cohort of men of European descent. Hum Reprod 25(6):1383–1397. doi:10.1093/humrep/deq081

    Article  CAS  PubMed  Google Scholar 

  60. Zhang W, Liu T, Mi YJ, Yue LD, Wang JM, Liu DW, Yan J, Tian QB (2015) Evidence from enzymatic and meta-analyses does not support a direct association between USP26 gene variants and male infertility. Andrology 3(2):271–279. doi:10.1111/andr.295

    Article  CAS  PubMed  Google Scholar 

  61. Valero R, Marfany G, Gonzalez-Angulo O, Gonzalez-Gonzalez G, Puelles L, Gonzalez-Duarte R (1999) USP25, a novel gene encoding a deubiquitinating enzyme, is located in the gene-poor region 21q11.2. Genomics 62(3):395–405. doi:10.1006/geno.1999.6025

    Article  CAS  PubMed  Google Scholar 

  62. Kim YK, Kim YS, Yoo KJ, Lee HJ, Lee DR, Yeo CY, Baek KH (2007) The expression of Usp42 during embryogenesis and spermatogenesis in mouse. Gene Expr Patterns 7(1–2):143–148. doi:10.1016/j.modgep.2006.06.006

    Article  CAS  PubMed  Google Scholar 

  63. Suresh B, Ramakrishna S, Lee HJ, Choi JH, Kim JY, Ahn WS, Baek KH (2010) K48- and K63-linked polyubiquitination of deubiquitinating enzyme USP44. Cell Biol Int 34(8):799–808. doi:10.1042/CBI20090144

    Article  CAS  PubMed  Google Scholar 

  64. Wilkinson KD, Lee KM, Deshpande S, Duerksen-Hughes P, Boss JM, Pohl J (1989) The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 246(4930):670–673

    Article  CAS  PubMed  Google Scholar 

  65. Kwon J (2007) The new function of two ubiquitin C-terminal hydrolase isozymes as reciprocal modulators of germ cell apoptosis. Exp Anim 56(2):71–77

    Article  CAS  PubMed  Google Scholar 

  66. Kwon J, Wang YL, Setsuie R, Sekiguchi S, Sakurai M, Sato Y, Lee WW, Ishii Y, Kyuwa S, Noda M, Wada K, Yoshikawa Y (2004) Developmental regulation of ubiquitin C-terminal hydrolase isozyme expression during spermatogenesis in mice. Biol Reprod 71(2):515–521. doi:10.1095/biolreprod.104.027565

    Article  CAS  PubMed  Google Scholar 

  67. Luo J, Megee S, Dobrinski I (2009) Asymmetric distribution of UCH-L1 in spermatogonia is associated with maintenance and differentiation of spermatogonial stem cells. J Cell Physiol 220(2):460–468. doi:10.1002/jcp.21789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Jervis KM, Robaire B (2001) Dynamic changes in gene expression along the rat epididymis. Biol Reprod 65(3):696–703

    Article  CAS  PubMed  Google Scholar 

  69. Wang YL, Liu W, Sun YJ, Kwon J, Setsuie R, Osaka H, Noda M, Aoki S, Yoshikawa Y, Wada K (2006) Overexpression of ubiquitin carboxyl-terminal hydrolase L1 arrests spermatogenesis in transgenic mice. Mol Reprod Dev 73(1):40–49. doi:10.1002/mrd.20364

    Article  CAS  PubMed  Google Scholar 

  70. Kwon J, Mochida K, Wang YL, Sekiguchi S, Sankai T, Aoki S, Ogura A, Yoshikawa Y, Wada K (2005) Ubiquitin C-terminal hydrolase L-1 is essential for the early apoptotic wave of germinal cells and for sperm quality control during spermatogenesis. Biol Reprod 73(1):29–35. doi:10.1095/biolreprod.104.037077

    Article  CAS  PubMed  Google Scholar 

  71. Welch JP, Wells RS, Kerr CB (1968) Ancell-Spiegler cylindromas (turban tumours) and Brooke-Fordyce trichoepitheliomas: evidence for a single genetic entity. J Med Genet 5(1):29–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Young AL, Kellermayer R, Szigeti R, Teszas A, Azmi S, Celebi JT (2006) CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet 70(3):246–249. doi:10.1111/j.1399-0004.2006.00667.x

    Article  CAS  PubMed  Google Scholar 

  73. Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, Jones C, Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans DG, Schrander-Stumpel C, Beemer FA, van Den Ouweland A, Halley D, Delpech B, Cleveland MG, Leigh I, Leisti J, Rasmussen S (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25(2):160–165. doi:10.1038/76006

    Article  CAS  PubMed  Google Scholar 

  74. Blake PW, Toro JR (2009) Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat 30(7):1025–1036. doi:10.1002/humu.21024

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Mathis BJ, Lai Y, Qu C, Janicki JS, Cui T (2015) CYLD-mediated signaling and diseases. Curr Drug Targets 16(4):284–294

    Article  CAS  PubMed  Google Scholar 

  76. Massoumi R (2011) CYLD: a deubiquitination enzyme with multiple roles in cancer. Future Oncol 7(2):285–297. doi:10.2217/fon.10.187

    Article  CAS  PubMed  Google Scholar 

  77. Hovelmeyer N, Wunderlich FT, Massoumi R, Jakobsen CG, Song J, Worns MA, Merkwirth C, Kovalenko A, Aumailley M, Strand D, Bruning JC, Galle PR, Wallach D, Fassler R, Waisman A (2007) Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD. J Exp Med 204(11):2615–2627. doi:10.1084/jem.20070318

    Article  PubMed Central  PubMed  Google Scholar 

  78. Lim JH, Stirling B, Derry J, Koga T, Jono H, Woo CH, Xu H, Bourne P, Ha UH, Ishinaga H, Xu H, Andalibi A, Feng XH, Zhu H, Huang Y, Zhang W, Weng X, Yan C, Yin Z, Briles DE, Davis RJ, Flavell RA, Li JD (2007) Tumor suppressor CYLD regulates acute lung injury in lethal Streptococcus pneumoniae infections. Immunity 27(2):349–360. doi:10.1016/j.immuni.2007.07.011

    Article  CAS  PubMed  Google Scholar 

  79. Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC (2006) Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7(4):411–417. doi:10.1038/ni1315

    Article  CAS  PubMed  Google Scholar 

  80. Trompouki E, Tsagaratou A, Kosmidis SK, Dolle P, Qian J, Kontoyiannis DL, Cardoso WV, Mosialos G (2009) Truncation of the catalytic domain of the cylindromatosis tumor suppressor impairs lung maturation. Neoplasia 11(5):469–476

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Zhang J, Stirling B, Temmerman ST, Ma CA, Fuss IJ, Derry JM, Jain A (2006) Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J Clin Investig 116(11):3042–3049. doi:10.1172/JCI28746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R (2006) Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125(4):665–677. doi:10.1016/j.cell.2006.03.041

    Article  CAS  PubMed  Google Scholar 

  83. Wright A, Reiley WW, Chang M, Jin W, Lee AJ, Zhang M, Sun SC (2007) Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev Cell 13(5):705–716. doi:10.1016/j.devcel.2007.09.007

    Article  CAS  PubMed  Google Scholar 

  84. Print CG, Loveland KL (2000) Germ cell suicide: new insights into apoptosis during spermatogenesis. BioEssays : news and reviews in molecular, cellular and developmental biology 22(5):423–430. doi:10.1002/(SICI)1521-1878(200005)22:5<423:AID-BIES4>3.0.CO;2-0

    Article  CAS  Google Scholar 

  85. Kwon J, Kikuchi T, Setsuie R, Ishii Y, Kyuwa S, Yoshikawa Y (2003) Characterization of the testis in congenitally ubiquitin carboxy-terminal hydrolase-1 (Uch-L1) defective (gad) mice. Exp Anim 52(1):1–9

    Article  CAS  PubMed  Google Scholar 

  86. Osawa Y, Wang YL, Osaka H, Aoki S, Wada K (2001) Cloning, expression, and mapping of a mouse gene, Uchl4, highly homologous to human and mouse Uchl3. Biochem Biophys Res Commun 283(3):627–633. doi:10.1006/bbrc.2001.4841

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank all of Suri’s laboratory members for their helpful discussions. This study was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIP) (No. 2012M3A9B4028738).

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    Authors and Affiliations

    1. Graduate School of Biomedical Science and Engineering, Hanyang University, Seongdong-gu, Seoul, South Korea

      Bharathi Suresh, Kye-Seong Kim & Suresh Ramakrishna

    2. Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea

      Junwon Lee

    3. Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, South Korea

      Seok-Ho Hong

    4. College of Medicine, Hanyang University, Seoul, South Korea

      Kye-Seong Kim & Suresh Ramakrishna

    Authors
    1. Bharathi Suresh
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    2. Junwon Lee
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    3. Seok-Ho Hong
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    4. Kye-Seong Kim
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    5. Suresh Ramakrishna
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    Corresponding authors

    Correspondence to Kye-Seong Kim or Suresh Ramakrishna.

    Additional information

    B. Suresh and J. Lee contributed equally to this work.

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    Suresh, B., Lee, J., Hong, SH. et al. The role of deubiquitinating enzymes in spermatogenesis. Cell. Mol. Life Sci. 72, 4711–4720 (2015). https://doi.org/10.1007/s00018-015-2030-z

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    • DOI: https://doi.org/10.1007/s00018-015-2030-z

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