Accumulation of Glucosylceramide in the Absence of the Beta-Glucosidase GBA2 Alters Cytoskeletal Dynamics

English version České info

During mammalian spermatogenesis, sperm with a head and a tail are formed from a round cell. This process is tightly regulated and involves the close interaction of somatic Sertoli cells and germ cells. Accumulation of the glycosphingolipid glucosylceramide in the absence of the beta-glucosidase GBA2 has been proposed to disturb sperm development, leading to morphological defects. However, the underlying mechanism is not known. Here, we demonstrate that accumulation of glucosylceramide in GBA2 knockout-mice controls the dynamics of the actin and microtubule cytoskeleton, which are crucial for sperm development. In particular, cytoskeletal structures at the interface between Sertoli and germ cells are disorganized, leading to malformation of the sperm head and a defect in acrosome formation. In summary, we provide mechanistic insights into how glucosylceramide controls cellular signaling and dysregulation of this essential glycosphingolipid leads to male infertility.

Vyšlo v časopise: Accumulation of Glucosylceramide in the Absence of the Beta-Glucosidase GBA2 Alters Cytoskeletal Dynamics. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005063
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005063

Souhrn

Zdroje

1. Yildiz Y, Matern H, Thompson B, Allegood JC, Warren RL, et al. (2006) Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J Clin Invest 116: 2985–2994. 17080196

2. Dam AH, Feenstra I, Westphal JR, Ramos L, van Golde RJ, et al. (2007) Globozoospermia revisited. Hum Reprod Update 13: 63–75. 17008355

3. Funaki T, Kon S, Tanabe K, Natsume W, Sato S, et al. (2013) The Arf GAP SMAP2 is necessary for organized vesicle budding from the trans-Golgi network and subsequent acrosome formation in spermiogenesis. Mol Biol Cell 24: 2633–2644. doi: 10.1091/mbc.E13-05-0234 23864717

4. Heimann P, Laage S, Jockusch H (1991) Defect of sperm assembly in a neurological mutant of the mouse, wobbler (WR). Differentiation 47: 77–83. 1955109

5. Kang-Decker N, Mantchev GT, Juneja SC, McNiven MA, van Deursen JM (2001) Lack of acrosome formation in Hrb-deficient mice. Science 294: 1531–1533. 11711676

6. Moreno RD, Palomino J, Schatten G (2006) Assembly of spermatid acrosome depends on microtubule organization during mammalian spermiogenesis. Dev Biol 293: 218–227. 16540102

7. 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: 52–62. 21866276

8. Pierre V, Martinez G, Coutton C, Delaroche J, Yassine S, et al. (2012) Absence of Dpy19l2, a new inner nuclear membrane protein, causes globozoospermia in mice by preventing the anchoring of the acrosome to the nucleus. Development 139: 2955–2965. doi: 10.1242/dev.077982 22764053

9. Xiao N, Kam C, Shen C, Jin W, Wang J, et al. (2009) PICK1 deficiency causes male infertility in mice by disrupting acrosome formation. J Clin Invest 119: 802–812. doi: 10.1172/JCI36230 19258705

10. Yao R, Ito C, Natsume Y, Sugitani Y, Yamanaka H, et al. (2002) Lack of acrosome formation in mice lacking a Golgi protein, GOPC. ProcNatlAcadSci USA 99: 11211–11216. 12149515

11. Kierszenbaum AL, Rivkin E, Tres LL (2003) Acroplaxome, an F-actin-keratin-containing plate, anchors the acrosome to the nucleus during shaping of the spermatid head. Mol Biol Cell 14: 4628–4640. 14551252

12. Abou-Haila A, Tulsiani DR (2000) Mammalian sperm acrosome: formation, contents, and function. Arch Biochem Biophys 379: 173–182. 10898932

13. Moreno RD, Alvarado CP (2006) The mammalian acrosome as a secretory lysosome: new and old evidence. Mol Reprod Dev 73: 1430–1434. 16894549

14. Escalier D, Silvius D, Xu X (2003) Spermatogenesis of mice lacking CK2alpha': failure of germ cell survival and characteristic modifications of the spermatid nucleus. Mol Reprod Dev 66: 190–201. 12950107

15. Fujihara Y, Satouh Y, Inoue N, Isotani A, Ikawa M, et al. (2012) SPACA1-deficient male mice are infertile with abnormally shaped sperm heads reminiscent of globozoospermia. Development 139: 3583–3589. doi: 10.1242/dev.081778 22949614

16. Xu X, Toselli PA, Russell LD, Seldin DC (1999) Globozoospermia in mice lacking the casein kinase II alpha' catalytic subunit. Nat Genet 23: 118–121. 10471512

17. Guttman JA, Takai Y, Vogl AW (2004) Evidence that tubulobulbar complexes in the seminiferous epithelium are involved with internalization of adhesion junctions. Biol Reprod 71: 548–559. 15084482

18. Russell L, Clermont Y (1976) Anchoring device between Sertoli cells and late spermatids in rat seminiferous tubules. Anat Rec 185: 259–278. 937734

19. Xiao X, Yang WX (2007) Actin-based dynamics during spermatogenesis and its significance. J Zhejiang Univ Sci B 8: 498–506. 17610330

20. Mruk DD, Cheng CY (2004) Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 25: 747–806. 15466940

21. Young JS, Guttman JA, Vaid KS, Vogl AW (2009) Tubulobulbar complexes are intercellular podosome-like structures that internalize intact intercellular junctions during epithelial remodeling events in the rat testis. Biol Reprod 80: 162–174. doi: 10.1095/biolreprod.108.070623 18799754

22. Russell LD (1979) Spermatid-Sertoli tubulobulbar complexes as devices for elimination of cytoplasm from the head region late spermatids of the rat. Anat Rec 194: 233–246. 464324

23. Kierszenbaum AL, Rivkin E, Tres LL (2007) Molecular biology of sperm head shaping. Soc Reprod Fertil Suppl 65: 33–43. 17644953

24. Bellve AR, Millette CF, Bhatnagar YM, O'Brien DA (1977) Dissociation of the mouse testis and characterization of isolated spermatogenic cells. J Histochem Cytochem 25: 480–494. 893996

25. Rabionet M, van der Spoel AC, Chuang CC, von Tumpling-Radosta B, Litjens M, et al. (2008) Male germ cells require polyenoic sphingolipids with complex glycosylation for completion of meiosis: a link to ceramide synthase-3. J Biol Chem 283: 13357–13369. doi: 10.1074/jbc.M800870200 18308723

26. Kierszenbaum AL (2004) Polycystins: what polycystic kidney disease tells us about sperm. Mol Reprod Dev 67: 385–388. 14991728

27. Mruk DD, Cheng CY (2004) Cell-cell interactions at the ectoplasmic specialization in the testis. Trends Endocrinol Metab 15: 439–447. 15519891

28. Meistrich ML, Trostle-Weige PK, Russell LD (1990) Abnormal manchette development in spermatids of azh/azh mutant mice. Am J Anat 188: 74–86. 2346121

29. Russell LD, Russell JA, MacGregor GR, Meistrich ML (1991) Linkage of manchette microtubules to the nuclear envelope and observations of the role of the manchette in nuclear shaping during spermiogenesis in rodents. Am J Anat 192: 97–120. 1759685

30. Nayernia K, Vauti F, Meinhardt A, Cadenas C, Schweyer S, et al. (2003) Inactivation of a testis-specific Lis1 transcript in mice prevents spermatid differentiation and causes male infertility. J Biol Chem 278: 48377–48385. 13129914

31. Akhmanova A, Mausset-Bonnefont AL, van Cappellen W, Keijzer N, Hoogenraad CC, et al. (2005) The microtubule plus-end-tracking protein CLIP-170 associates with the spermatid manchette and is essential for spermatogenesis. Genes Dev 19: 2501–2515. 16230537

32. Kierszenbaum AL (2001) Spermatid manchette: plugging proteins to zero into the sperm tail. Mol Reprod Dev 59: 347–349. 11468770

33. Wolosewick JJ, Bryan JH (1977) Ultrastructural characterization of the manchette microtubules in the seminiferous epithelium of the mouse. Am J Anat 150: 301–331. 920632

34. Tarsounas M, Pearlman RE, Moens PB (2001) CLIP-50 immunolocalization during mouse spermiogenesis suggests a role in shaping the sperm nucleus. Dev Biol 236: 400–410. 11476580

35. Sperry AO (2012) The dynamic cytoskeleton of the developing male germ cell. Biol Cell 104: 297–305. doi: 10.1111/boc.201100102 22276751

36. Moreno RD, Ramalho-Santos J, Sutovsky P, Chan EK, Schatten G (2000) Vesicular traffic and golgi apparatus dynamics during mammalian spermatogenesis: implications for acrosome architecture. Biol Reprod 63: 89–98. 10859246

37. Heasman SJ, Ridley AJ (2008) Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 9: 690–701. doi: 10.1038/nrm2476 18719708

38. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279: 509–514. 9438836

39. Machesky LM, Hall A (1996) Rho: a connection between membrane receptor signalling and the cytoskeleton. Trends Cell Biol 6: 304–310. 15157438

40. Nobes CD, Hall A (1995) Rho, rac and cdc42 GTPases: regulators of actin structures, cell adhesion and motility. Biochem Soc Trans 23: 456–459. 8566347

41. Ridley AJ, Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70: 389–399. 1643657

42. Van Aelst L, D'Souza-Schorey C (1997) Rho GTPases and signaling networks. Genes Dev 11: 2295–2322. 9308960

43. Efimov A, Schiefermeier N, Grigoriev I, Ohi R, Brown MC, et al. (2008) Paxillin-dependent stimulation of microtubule catastrophes at focal adhesion sites. J Cell Sci 121: 196–204. doi: 10.1242/jcs.012666 18187451

44. Waterman-Storer CM, Worthylake RA, Liu BP, Burridge K, Salmon ED (1999) Microtubule growth activates Rac1 to promote lamellipodial protrusion in fibroblasts. Nat Cell Biol 1: 45–50. 10559863

45. Korschen HG, Yildiz Y, Raju DN, Schonauer S, Bonigk W, et al. (2013) The non-lysosomal beta-glucosidase GBA2 is a non-integral membrane-associated protein at the endoplasmic reticulum (ER) and Golgi. J Biol Chem 288: 3381–3393. doi: 10.1074/jbc.M112.414714 23250757

46. van Meer G, Wolthoorn J, Degroote S (2003) The fate and function of glycosphingolipid glucosylceramide. Philos Trans R Soc Lond B Biol Sci 358: 869–873. 12803919

47. Sezgin E, Kaiser HJ, Baumgart T, Schwille P, Simons K, et al. (2012) Elucidating membrane structure and protein behavior using giant plasma membrane vesicles. Nat Protoc 7: 1042–1051. doi: 10.1038/nprot.2012.059 22555243

48. Weber G, Farris FJ (1979) Synthesis and spectral properties of a hydrophobic fluorescent probe: 6-propionyl-2-(dimethylamino)naphthalene. Biochemistry 18: 3075–3078. 465454

49. Parasassi T, Gratton E (1995) Membrane lipid domains and dynamics as detected by Laurdan fluorescence. J Fluoresc 5: 59–69. doi: 10.1007/BF00718783 24226612

50. Park SS, Kim MO, Yun SP, Ryu JM, Park JH, et al. (2013) C(16)-Ceramide-induced F-actin regulation stimulates mouse embryonic stem cell migration: involvement of N-WASP/Cdc42/Arp2/3 complex and cofilin-1/alpha-actinin. Biochim Biophys Acta 1831: 350–360. doi: 10.1016/j.bbalip.2012.09.005 22989773

51. Groves JT, Kuriyan J (2010) Molecular mechanisms in signal transduction at the membrane. Nat Struct Mol Biol 17: 659–665. doi: 10.1038/nsmb.1844 20495561

52. Meiri KF (2004) Membrane/cytoskeleton communication. Subcell Biochem 37: 247–282. 15376624

53. Fooksman DR, Shaikh SR, Boyle S, Edidin M (2009) Cutting edge: phosphatidylinositol 4,5-bisphosphate concentration at the APC side of the immunological synapse is required for effector T cell function. J Immunol 182: 5179–5182. doi: 10.4049/jimmunol.0801797 19380760

54. Khuong TM, Habets RL, Slabbaert JR, Verstreken P (2010) WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling. Proc Natl Acad Sci U S A 107: 17379–17384. doi: 10.1073/pnas.1001794107 20844206

55. Hakomori S, Handa K, Iwabuchi K, Yamamura S, Prinetti A (1998) New insights in glycosphingolipid function: "glycosignaling domain," a cell surface assembly of glycosphingolipids with signal transducer molecules,involved in cell adhesion coupled with signaling. Glycobiology 8: xi–xix. 9840984

56. Coskun U, Grzybek M, Drechsel D, Simons K (2011) Regulation of human EGF receptor by lipids. Proc Natl Acad Sci U S A 108: 9044–9048. doi: 10.1073/pnas.1105666108 21571640

57. van der Poel S, Wolthoorn J, van den Heuvel D, Egmond M, Groux-Degroote S, et al. (2011) Hyperacidification of trans-Golgi network and endo/lysosomes in melanocytes by glucosylceramide-dependent V-ATPase activity. Traffic 12: 1634–1647. doi: 10.1111/j.1600-0854.2011.01263.x 21810155

58. Gillot I, Jehl-Pietri C, Gounon P, Luquet S, Rassoulzadegan M, et al. (2005) Germ cells and fatty acids induce translocation of CD36 scavenger receptor to the plasma membrane of Sertoli cells. J Cell Sci 118: 3027–3035. 15972317

59. van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9: 112–124. doi: 10.1038/nrm2330 18216768

60. Reichelt J, Breiden B, Sandhoff K, Magin TM (2004) Loss of keratin 10 is accompanied by increased sebocyte proliferation and differentiation. Eur J Cell Biol 83: 747–759. 15679119

61. Yildiz Y, Hoffmann P, Vom Dahl S, Breiden B, Sandhoff R, et al. (2013) Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease. Orphanet J Rare Dis 8: 151. doi: 10.1186/1750-1172-8-151 24070122

62. Wewer V, Dombrink I, vom Dorp K, Dormann P (2011) Quantification of sterol lipids in plants by quadrupole time-of-flight mass spectrometry. J Lipid Res 52: 1039–1054. doi: 10.1194/jlr.D013987 21382968

63. Ginkel C, Hartmann D, vom Dorp K, Zlomuzica A, Farwanah H, et al. (2012) Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J Biol Chem 287: 41888–41902. doi: 10.1074/jbc.M112.413500 23074226