Skip to main content

Advertisement

Log in

Unravelling Secretion in Cryptococcus neoformans: More than One Way to Skin a Cat

  • Published:
Mycopathologia Aims and scope Submit manuscript

Abstract

Secretion pathways in fungi are essential for the maintenance of cell wall architecture and for the export of a number of virulence factors. In the fungal pathogen, Cryptococcus neoformans, much evidence supports the existence of more than one route taken by secreted molecules to reach the cell periphery and extracellular space, and a significant degree of crosstalk between conventional and non-conventional secretion routes. The need for such complexity may be due to differences in the nature of the exported cargo, the spatial and temporal requirements for constitutive and non-constitutive protein secretion, and/or as a means of compensating for the extra burden on the secretion machinery imposed by the elaboration of the polysaccharide capsule. This review focuses on the role of specific components of the C. neoformans secretion machinery in protein and/or polysaccharide export, including Sec4, Sec6, Sec14, Golgi reassembly and stacking protein and extracellular exosome-like vesicles. We also address what is known about traffic of the lipid, glucosylceramide, a target of therapeutic antibodies and an important regulator of C. neoformans pathogenicity, and the role of signalling pathways in the regulation of secretion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Zaragoza O, Rodrigues ML, De Jesus M, Frases S, Dadachova E, Casadevall A. The capsule of the fungal pathogen Cryptococcus neoformans. Adv Appl Microbiol. 2009;68:133–216. doi:10.1016/S0065-2164(09)01204-0.

    Article  PubMed  CAS  Google Scholar 

  2. Rodrigues ML, Casadevall A, Zaragoza O. The architecture and antigenic composition of the polysaccharide capsule. In: Joseph Heitman TK, Kwon-Chung J, Perfect J, Casadevall A, editors. Cryptococcus: from human pathogen to model yeast. American Society for Microbiology; 2011. p. 43–54.

  3. Cox GM, Mukherjee J, Cole GT, Casadevall A, Perfect JR. Urease as a virulence factor in experimental cryptococcosis. Infect Immun. 2000;68(2):443–8.

    Article  PubMed  CAS  Google Scholar 

  4. Chayakulkeeree M, Johnston SA, Oei JB, Lev S, Williamson PR, Wilson CF, et al. SEC14 is a specific requirement for secretion of phospholipase B1 and pathogenicity of Cryptococcus neoformans. Mol Microbiol. 2011;80(4):1088–101. doi:10.1111/j.1365-2958.2011.07632.x.

    Article  PubMed  CAS  Google Scholar 

  5. Cox GM, McDade HC, Chen SC, Tucker SC, Gottfredsson M, Wright LC, et al. Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans. Mol Microbiol. 2001;39(1):166–75. doi:10.1046/j.1365-2958.2001.02236.x.

    Google Scholar 

  6. Djordjevic JT, Del Poeta M, Sorrell TC, Turner KM, Wright LC. Secretion of cryptococcal phospholipase B1 (PLB1) is regulated by a glycosylphosphatidylinositol (GPI) anchor. Biochem J. 2005;389(Pt 3):803–12. doi:10.1042/BJ20050063.

    PubMed  CAS  Google Scholar 

  7. Eisenman HC, Frases S, Nicola AM, Rodrigues ML, Casadevall A. Vesicle-associated melanization in Cryptococcus neoformans. Microbiology. 2009;155(Pt 12):3860–7. doi:10.1099/mic.0.032854-0.

    Article  PubMed  CAS  Google Scholar 

  8. Panepinto J, Komperda K, Frases S, Park YD, Djordjevic JT, Casadevall A, et al. Sec6-dependent sorting of fungal extracellular exosomes and laccase of Cryptococcus neoformans. Mol Microbiol. 2009;71(5):1165–76. doi:10.1111/j.1365-2958.2008.06588.x.

    Article  PubMed  CAS  Google Scholar 

  9. Salas SD, Bennett JE, Kwon-Chung KJ, Perfect JR, Williamson PR. Effect of the laccase gene CNLAC1, on virulence of Cryptococcus neoformans. J Exp Med. 1996;184(2):377–86.

    Article  PubMed  CAS  Google Scholar 

  10. Williamson PR. Laccase and melanin in the pathogenesis of Cryptococcus neoformans. Front Biosci. 1997;2:e99–107.

    PubMed  CAS  Google Scholar 

  11. Levitz SM, Specht CA. The molecular basis for the immunogenicity of Cryptococcus neoformans mannoproteins. FEMS Yeast Res. 2006;6(4):513–24. doi:10.1111/j.1567-1364.2006.00071.x.

    Article  PubMed  CAS  Google Scholar 

  12. Eigenheer RA, Jin Lee Y, Blumwald E, Phinney BS, Gelli A. Extracellular glycosylphosphatidylinositol-anchored mannoproteins and proteases of Cryptococcus neoformans. FEMS Yeast Res. 2007;7(4):499–510. doi:10.1111/j.1567-1364.2006.00198.x.

    Article  PubMed  CAS  Google Scholar 

  13. Reese AJ, Doering TL. Cell wall alpha-1, 3-glucan is required to anchor the Cryptococcus neoformans capsule. Mol Microbiol. 2003;50(4):1401–9. doi:10.1046/j.1365-2958.2003.03780.x.

  14. Gilbert NM, Donlin MJ, Gerik KJ, Specht CA, Djordjevic JT, Wilson CF, et al. KRE genes are required for beta-1, 6-glucan synthesis, maintenance of capsule architecture and cell wall protein anchoring in Cryptococcus neoformans. Mol Microbiol. 2010;76(2):517–34. doi:10.1111/j.1365-2958.2010.07119.x.

    Article  PubMed  CAS  Google Scholar 

  15. Hruskova-Heidingsfeldova O. Secreted proteins of Candida albicans. Front Biosci. 2008;13:7227–42. doi:10.2741/3224.

  16. Schekman R. Lasker basic medical research award. SEC mutants and the secretory apparatus. Nat Med. 2002;8(10):1055–8. doi:10.1038/nm769.

    Article  PubMed  CAS  Google Scholar 

  17. Kmetzsch L, Joffe LS, Staats CC, de Oliveira DL, Fonseca FL, Cordero RJ, et al. Role for Golgi reassembly and stacking protein (GRASP) in polysaccharide secretion and fungal virulence. Mol Microbiol. 2011;81:206–18. doi:10.1111/j.1365-2958.2011.07686.x.

    Article  PubMed  CAS  Google Scholar 

  18. Rodrigues ML, Nimrichter L, Oliveira DL, Frases S, Miranda K, Zaragoza O, et al. Vesicular polysaccharide export in Cryptococcus neoformans is a eukaryotic solution to the problem of fungal trans-cell wall transport. Eukaryot Cell. 2007;6(1):48–59. doi:10.1128/EC.00318-06.

    Article  PubMed  CAS  Google Scholar 

  19. Yoneda A, Doering TL. A eukaryotic capsular polysaccharide is synthesized intracellularly and secreted via exocytosis. Mol Biol Cell. 2006;17(12):5131–40. doi:10.1091/mbc.E06-08-0701.

    Article  PubMed  CAS  Google Scholar 

  20. Doms RW, Russ G, Yewdell JW. Brefeldin A redistributes resident and itinerant Golgi proteins to the endoplasmic reticulum. J Cell Biol. 1989;109(1):61–72.

    Article  PubMed  CAS  Google Scholar 

  21. Mehul B, Hughes RC. Plasma membrane targeting, vesicular budding and release of galectin 3 from the cytoplasm of mammalian cells during secretion. J Cell Sci. 1997;110(Pt 10):1169–78.

    PubMed  CAS  Google Scholar 

  22. Muesch A, Hartmann E, Rohde K, Rubartelli A, Sitia R, Rapoport TA. A novel pathway for secretory proteins? Trends Biochem Sci. 1990;15(3):86–8.

    Article  PubMed  CAS  Google Scholar 

  23. Rubartelli A, Bajetto A, Allavena G, Wollman E, Sitia R. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem. 1992;267(34):24161–4.

    PubMed  CAS  Google Scholar 

  24. Rubartelli A, Bajetto A, Bonifaci N, Di Blas E, Solito E, Sitia R. A novel way to get out of the cell. Cytotechnology. 1993;11(Suppl 1):S37–40.

    Article  CAS  Google Scholar 

  25. Chang HC, Samaniego F, Nair BC, Buonaguro L, Ensoli B. HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS. 1997;11(12):1421–31.

    Article  PubMed  CAS  Google Scholar 

  26. Rubartelli A, Sitia R. Interleukin 1 beta and thioredoxin are secreted through a novel pathway of secretion. Biochem Soc Trans. 1991;19(2):255–9.

    PubMed  CAS  Google Scholar 

  27. Ferro-Novick S, Novick P, Field C, Schekman R. Yeast secretory mutants that block the formation of active cell surface enzymes. J Cell Biol. 1984;98(1):35–43.

    Article  PubMed  CAS  Google Scholar 

  28. Novick P, Field C, Schekman R. Identification of 23 complementation groups required for post-translational events in the yeast secretory pathway. Cell. 1980;21(1):205–15. doi:10.1016/0092-8674(80)90128-2.

    Google Scholar 

  29. Novick P, Schekman R. Export of major cell surface proteins is blocked in yeast secretory mutants. J Cell Biol. 1983;96(2):541–7.

    Article  PubMed  CAS  Google Scholar 

  30. Novick P, Schekman R. Secretion and cell-surface growth are blocked in a temperature-sensitive mutant of Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 1979;76(4):1858–62.

    Article  PubMed  CAS  Google Scholar 

  31. Bankaitis VA, Malehorn DE, Emr SD, Greene R. The Saccharomyces cerevisiae SEC14 gene encodes a cytosolic factor that is required for transport of secretory proteins from the yeast Golgi complex. J Cell Biol. 1989;108(4):1271–81.

    Article  PubMed  CAS  Google Scholar 

  32. Siafakas AR, Sorrell TC, Wright LC, Wilson C, Larsen M, Boadle R, et al. Cell wall-linked cryptococcal phospholipase B1 is a source of secreted enzyme and a determinant of cell wall integrity. J Biol Chem. 2007;282(52):37508–14. doi:10.1074/jbc.M707913200.

    Article  PubMed  CAS  Google Scholar 

  33. Chen SC, Wright LC, Golding JC, Sorrell TC. Purification and characterization of secretory phospholipase B, lysophospholipase and lysophospholipase/transacylase from a virulent strain of the pathogenic fungus Cryptococcus neoformans. Biochem J. 2000;347(Pt 2):431–9.

    Article  PubMed  CAS  Google Scholar 

  34. Chen SC, Wright LC, Santangelo RT, Muller M, Moran VR, Kuchel PW, et al. Identification of extracellular phospholipase B, lysophospholipase, and acyltransferase produced by Cryptococcus neoformans. Infect Immun. 1997;65(2):405–11.

    PubMed  CAS  Google Scholar 

  35. Ganendren R, Carter E, Sorrell T, Widmer F, Wright L. Phospholipase B activity enhances adhesion of Cryptococcus neoformans to a human lung epithelial cell line. Microbes Infect. 2006;8(4):1006–15. doi:10.1016/j.micinf.2005.10.018.

    Article  PubMed  CAS  Google Scholar 

  36. Noverr MC, Cox GM, Perfect JR, Huffnagle GB. Role of PLB1 in pulmonary inflammation and cryptococcal eicosanoid production. Infect Immun. 2003;71(3):1538–47.

    Article  PubMed  CAS  Google Scholar 

  37. Santangelo R, Zoellner H, Sorrell T, Wilson C, Donald C, Djordjevic J, et al. Role of extracellular phospholipases and mononuclear phagocytes in dissemination of cryptococcosis in a murine model. Infect Immun. 2004;72(4):2229–39.

    Article  PubMed  CAS  Google Scholar 

  38. Zhu X, Gibbons J, Garcia-Rivera J, Casadevall A, Williamson PR. Laccase of Cryptococcus neoformans is a cell wall-associated virulence factor. Infect Immun. 2001;69(9):5589–96.

    Article  PubMed  CAS  Google Scholar 

  39. Pukkila-Worley R, Gerrald QD, Kraus PR, Boily MJ, Davis MJ, Giles SS, et al. Transcriptional network of multiple capsule and melanin genes governed by the Cryptococcus neoformans cyclic AMP cascade. Eukaryot Cell. 2005;4(1):190–201. doi:10.1128/EC.4.1.190-201.2005.

    Article  PubMed  CAS  Google Scholar 

  40. Waterman SR, Hacham M, Panepinto J, Hu G, Shin S, Williamson PR. Cell wall targeting of laccase of Cryptococcus neoformans during infection of mice. Infect Immun. 2007;75(2):714–22. doi:10.1128/IAI.01351-06.

    Article  PubMed  CAS  Google Scholar 

  41. Staib F, Grave B, Altmann L, Mishra SK, Abel T, Blisse A. Epidemiology of Cryptococcus neoformans. Mycopathologia. 1978;65(1–3):73–6.

    Article  PubMed  CAS  Google Scholar 

  42. Staib F, Mishra SK, Able T, Blisse A. Growth of Cryptococcus neoformans on uric acid agar. Zentralbl Bakteriol Orig A. 1976;236(2–3):374–85.

    PubMed  CAS  Google Scholar 

  43. Shi M, Li SS, Zheng C, Jones GJ, Kim KS, Zhou H, et al. Real-time imaging of trapping and urease-dependent transmigration of Cryptococcus neoformans in mouse brain. J Clin Invest. 2010;120(5):1683–93. doi:10.1172/JCI41963.

    Article  PubMed  CAS  Google Scholar 

  44. Lee IR, Chow EW, Morrow CA, Djordjevic JT, Fraser JA. Nitrogen metabolite repression of metabolism and virulence in the human fungal pathogen Cryptococcus neoformans. Genetics. 2011;188(2):309–23. doi:10.1534/genetics.111.128538.

    Article  PubMed  CAS  Google Scholar 

  45. Canteros CE, Rodero L, Rivas MC, Davel G. A rapid urease test for presumptive identification of Cryptococcus neoformans. Mycopathologia. 1996;136(1):21–3.

    Article  PubMed  CAS  Google Scholar 

  46. Hotzel H, Kielstein P, Blaschke-Hellmessen R, Wendisch J, Bar W. Phenotypic and genotypic differentiation of several human and avian isolates of Cryptococcus neoformans. Mycoses. 1998;41(9–10):389–96.

    Article  PubMed  CAS  Google Scholar 

  47. Rodrigues ML, Nakayasu ES, Oliveira DL, Nimrichter L, Nosanchuk JD, Almeida IC, et al. Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence. Eukaryot Cell. 2008;7(1):58–67. doi:10.1128/EC.00370-07.

    Article  PubMed  CAS  Google Scholar 

  48. Staubach S, Razawi H, Hanisch FG. Proteomics of MUC1-containing lipid rafts from plasma membranes and exosomes of human breast carcinoma cells MCF-7. Proteomics. 2009;9(10):2820–35. doi:10.1002/pmic.200800793.

    Article  PubMed  CAS  Google Scholar 

  49. Stahl PD, Barbieri MA. Multivesicular bodies and multivesicular endosomes: the “ins and outs” of endosomal traffic. Sci STKE. 2002;2002(141):pe32. doi:10.1126/stke.2002.141.pe32.

    Article  PubMed  Google Scholar 

  50. Siafakas AR, Wright LC, Sorrell TC, Djordjevic JT. Lipid rafts in Cryptococcus neoformans concentrate the virulence determinants phospholipase B1 and Cu/Zn superoxide dismutase. Eukaryot Cell. 2006;5(3):488–98. doi:10.1128/EC.5.3.488-498.2006.

    Article  PubMed  CAS  Google Scholar 

  51. Turner KM, Wright LC, Sorrell TC, Djordjevic JT. N-linked glycosylation sites affect secretion of cryptococcal phospholipase B1, irrespective of glycosylphosphatidylinositol anchoring. Biochim Biophys Acta. 2006;1760(10):1569–79. doi:10.1016/j.bbagen.2006.07.002.

    Article  PubMed  CAS  Google Scholar 

  52. Djordjevic J (2011) Role of phospholipases in fungal fitness, pathogenicity and drug development-lessons from cryptococcus neoformans. Front Microbiol 1. doi:10.3389/fmicb.2010.00125.

  53. Chayakulkeeree M, Sorrell TC, Siafakas AR, Wilson CF, Pantarat N, Gerik KJ, et al. Role and mechanism of phosphatidylinositol-specific phospholipase C in survival and virulence of Cryptococcus neoformans. Mol Microbiol. 2008;69(4):809–26. doi:10.1111/j.1365-2958.2008.06310.x.

    PubMed  CAS  Google Scholar 

  54. Xie Z, Fang M, Bankaitis VA. Evidence for an intrinsic toxicity of phosphatidylcholine to Sec14p-dependent protein transport from the yeast Golgi complex. Mol Biol Cell. 2001;12(4):1117–29.

    PubMed  CAS  Google Scholar 

  55. Curwin AJ, Fairn GD, McMaster CR. Phospholipid transfer protein Sec14 is required for trafficking from endosomes and regulates distinct trans-Golgi export pathways. J Biol Chem. 2009;284(11):7364–75. doi:10.1074/jbc.M808732200.

    Article  PubMed  CAS  Google Scholar 

  56. Bankaitis VA, Mousley CJ, Schaaf G. The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling. Trends Biochem Sci. 2010;35(3):150–60. doi:10.1016/j.tibs.2009.10.008.

    Article  PubMed  CAS  Google Scholar 

  57. Li X, Routt SM, Xie Z, Cui X, Fang M, Kearns MA, et al. Identification of a novel family of nonclassic yeast phosphatidylinositol transfer proteins whose function modulates phospholipase D activity and Sec14p-independent cell growth. Mol Biol Cell. 2000;11(6):1989–2005.

    PubMed  CAS  Google Scholar 

  58. Monteoliva L, Sanchez M, Pla J, Gil C, Nombela C. Cloning of Candida albicans SEC14 gene homologue coding for a putative essential function. Yeast. 1996;12(11):1097–105. doi:10.1002/(SICI)1097-0061(19960915)12:11<1097:AID-YEA990>3.0.CO;2-E.

    Article  PubMed  CAS  Google Scholar 

  59. Chrisman CJ, Albuquerque P, Guimaraes AJ, Nieves E, Casadevall A. Phospholipids trigger Cryptococcus neoformans capsular enlargement during interactions with amoebae and macrophages. PLoS Pathog. 2011;7(5):e1002047. doi:10.1371/journal.ppat.1002047.

    Article  PubMed  CAS  Google Scholar 

  60. De Jesus M, Nicola AM, Rodrigues ML, Janbon G, Casadevall A. Capsular localization of the Cryptococcus neoformans polysaccharide component galactoxylomannan. Eukaryot Cell. 2009;8(1):96–103. doi:10.1128/EC.00331-08.

    Article  PubMed  Google Scholar 

  61. Eng RH, Bishburg E, Smith SM, Kapila R. Cryptococcal infections in patients with acquired immune deficiency syndrome. Am J Med. 1986;81(1):19–23. doi:0002-9343(86)90176-2.

    Article  PubMed  CAS  Google Scholar 

  62. Feldmesser M, Tucker S, Casadevall A. Intracellular parasitism of macrophages by Cryptococcus neoformans. Trends Microbiol. 2001;9(6):273–8. doi:S0966-842X(01)02035-2.

    Article  PubMed  CAS  Google Scholar 

  63. Salminen A, Novick PJ. A ras-like protein is required for a post-Golgi event in yeast secretion. Cell. 1987;49(4):527–38. doi:0092-8674(87)90455-7.

    Article  PubMed  CAS  Google Scholar 

  64. Yoneda A, Doering TL. An unusual organelle in Cryptococcus neoformans links luminal pH and capsule biosynthesis. Fungal Genet Biol. 2009;46(9):682–7. doi:10.1016/j.fgb.2009.05.001.

    Article  PubMed  CAS  Google Scholar 

  65. Hu G, Steen BR, Lian T, Sham AP, Tam N, Tangen KL, et al. Transcriptional regulation by protein kinase A in Cryptococcus neoformans. PLoS Pathog. 2007;3(3):e42. doi:10.1371/journal.ppat.0030042.

    Article  PubMed  Google Scholar 

  66. Nickel W. Pathways of unconventional protein secretion. Curr Opin Biotechnol. 2010;21(5):621–6. doi:10.1016/j.copbio.2010.06.004.

    Article  PubMed  CAS  Google Scholar 

  67. Nickel W, Rabouille C. Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol. 2009;10(2):148–55. doi:10.1038/nrm2617.

    Article  PubMed  CAS  Google Scholar 

  68. Cabral M, Anjard C, Malhotra V, Loomis WF, Kuspa A. Unconventional secretion of AcbA in Dictyostelium discoideum through a vesicular intermediate. Eukaryot Cell. 2010;9(7):1009–17. doi:10.1128/EC.00337-09.

    Article  PubMed  CAS  Google Scholar 

  69. Duran JM, Anjard C, Stefan C, Loomis WF, Malhotra V. Unconventional secretion of Acb1 is mediated by autophagosomes. J Cell Biol. 2010;188(4):527–36. doi:10.1083/jcb.200911154.

    Article  PubMed  CAS  Google Scholar 

  70. Kinseth MA, Anjard C, Fuller D, Guizzunti G, Loomis WF, Malhotra V. The Golgi-associated protein GRASP is required for unconventional protein secretion during development. Cell. 2007;130(3):524–34. doi:10.1016/j.cell.2007.06.029.

    Article  PubMed  CAS  Google Scholar 

  71. Manjithaya R, Anjard C, Loomis WF, Subramani S. Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation. J Cell Biol. 2010;188(4):537–46. doi:10.1083/jcb.200911149.

    Article  PubMed  CAS  Google Scholar 

  72. Schotman H, Karhinen L, Rabouille C. dGRASP-mediated noncanonical integrin secretion is required for Drosophila epithelial remodeling. Dev Cell. 2008;14(2):171–82. doi:10.1016/j.devcel.2007.12.006.

    Article  PubMed  CAS  Google Scholar 

  73. Vinke FP, Grieve AG, Rabouille C. The multiple facets of the Golgi reassembly stacking proteins. Biochem J. 2011;433(3):423–33. doi:10.1042/BJ20101540.

    Article  PubMed  CAS  Google Scholar 

  74. Behnia R, Barr FA, Flanagan JJ, Barlowe C, Munro S. The yeast orthologue of GRASP65 forms a complex with a coiled-coil protein that contributes to ER to Golgi traffic. J Cell Biol. 2007;176(3):255–61. doi:10.1083/jcb.200607151.

    Article  PubMed  CAS  Google Scholar 

  75. Oliveira DL, Nakayasu ES, Joffe LS, Guimaraes AJ, Sobreira TJ, Nosanchuk JD, et al. Characterization of yeast extracellular vesicles: evidence for the participation of different pathways of cellular traffic in vesicle biogenesis. PLoS One. 2010;5(6):e11113. doi:10.1371/journal.pone.0011113.

    Article  PubMed  Google Scholar 

  76. Kmetzsch L, Joffe LS, Staats CC, Oliveira DL, Nimrichter L, Cordero RJ, et al. Golgi reassembly and stacking protein is required for Cryptococcus neoformans virulence and polysaccharide secretion. In: 8th international conference on cryptococcus and cryptococcosis. Charleston, USA; 2011. p. 87.

  77. Cabral M, Anjard C, Malhotra V, Loomis WF, Kuspa A. Unconventional secretion of AcbA in Dictyostelium discoideum through a vesicular intermediate. Eukaryot Cell. 2010;9:1009–17. doi:10.1128/EC.00337-09.

    Article  PubMed  CAS  Google Scholar 

  78. Cox RA, Best GK. Cell wall composition of two strains of Blastomyces dermatitidis exhibiting differences in virulence for mice. Infect Immun. 1972;5(4):449–53.

    PubMed  CAS  Google Scholar 

  79. Schneider EF, Barran LR, Wood PJ, Siddiqui IR. Cell wall of Fusarium sulphureum. II. Chemical composition of the conidial and chlamydospore walls. Can J Microbiol. 1977;23(6):763–9.

    Article  PubMed  CAS  Google Scholar 

  80. Kechichian TB, Shea J, Del Poeta M. Depletion of alveolar macrophages decreases the dissemination of a glucosylceramide-deficient mutant of Cryptococcus neoformans in immunodeficient mice. Infect Immun. 2007;75(10):4792–8. doi:10.1128/IAI.00587-07.

    Article  PubMed  CAS  Google Scholar 

  81. Rhome R, Singh A, Kechichian T, Drago M, Morace G, Luberto C, et al. Surface localization of glucosylceramide during Cryptococcus neoformans infection allows targeting as a potential antifungal. PLoS One. 2011;6(1):e15572. doi:10.1371/journal.pone.0015572.

    Article  PubMed  CAS  Google Scholar 

  82. Rittershaus PC, Kechichian TB, Allegood JC, Merrill AH Jr, Hennig M, Luberto C, et al. Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans. J Clin Invest. 2006;116(6):1651–9. doi:10.1172/JCI27890.

    Article  PubMed  CAS  Google Scholar 

  83. Rodrigues ML, Shi L, Barreto-Bergter E, Nimrichter L, Farias SE, Rodrigues EG, et al. Monoclonal antibody to fungal glucosylceramide protects mice against lethal Cryptococcus neoformans infection. Clin Vaccin Immunol. 2007;14(10):1372–6. doi:10.1128/CVI.00202-07.

    Article  CAS  Google Scholar 

  84. Rodrigues ML, Travassos LR, Miranda KR, Franzen AJ, Rozental S, de Souza W, et al. Human antibodies against a purified glucosylceramide from Cryptococcus neoformans inhibit cell budding and fungal growth. Infect Immun. 2000;68(12):7049–60.

    Article  PubMed  CAS  Google Scholar 

  85. Nimrichter L, Rodrigues ML, Rodrigues EG, Travassos LR. The multitude of targets for the immune system and drug therapy in the fungal cell wall. Microbes Infect. 2005;7(4):789–98. doi:10.1016/j.micinf.2005.03.002.

    Article  PubMed  CAS  Google Scholar 

  86. Oliveira DL, Nakayasu ES, Joffe LS, Guimaraes AJ, Sobreira TJ, Nosanchuk JD, et al. Biogenesis of extracellular vesicles in yeast: many questions with few answers. Commun Integr Biol. 2010;3(6):533–5. doi:10.4161/cib.3.6.12756.

    Article  PubMed  Google Scholar 

  87. Casadevall A, Nosanchuk JD, Williamson P, Rodrigues ML. Vesicular transport across the fungal cell wall. Trends Microbiol. 2009;17(4):158–62. doi:10.1016/j.tim.2008.12.005.

    Article  PubMed  CAS  Google Scholar 

  88. Nosanchuk JD, Nimrichter L, Casadevall A, Rodrigues ML. A role for vesicular transport of macromolecules across cell walls in fungal pathogenesis. Commun Integr Biol. 2008;1(1):37–9.

    Article  PubMed  CAS  Google Scholar 

  89. Rodrigues ML, Nimrichter L, Oliveira DL, Nosanchuk JD, Casadevall A. Vesicular trans-cell wall transport in fungi: a mechanism for the delivery of virulence-associated macromolecules? Lipid Insights. 2008;2:27–40.

    PubMed  CAS  Google Scholar 

  90. Feldmesser M, Kress Y, Casadevall A. Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection. Microbiology. 2001;147(Pt 8):2355–65.

    PubMed  CAS  Google Scholar 

  91. Garcia-Rivera J, Chang YC, Kwon-Chung KJ, Casadevall A. Cryptococcus neoformans CAP59 (or Cap59p) is involved in the extracellular trafficking of capsular glucuronoxylomannan. Eukaryot Cell. 2004;3(2):385–92.

    Article  PubMed  CAS  Google Scholar 

  92. Oliveira DL, Nimrichter L, Miranda K, Frases S, Faull KF, Casadevall A, et al. Cryptococcus neoformans cryoultramicrotomy and vesicle fractionation reveals an intimate association between membrane lipids and glucuronoxylomannan. Fungal Genet Biol. 2009;46(12):956–63. doi:10.1016/j.fgb.2009.09.001.

    Article  PubMed  CAS  Google Scholar 

  93. Albuquerque PC, Nakayasu ES, Rodrigues ML, Frases S, Casadevall A, Zancope-Oliveira RM, et al. Vesicular transport in Histoplasma capsulatum: an effective mechanism for trans-cell wall transfer of proteins and lipids in ascomycetes. Cell Microbiol. 2008;10(8):1695–710. doi:10.1111/j.1462-5822.2008.01160.x.

    Article  PubMed  CAS  Google Scholar 

  94. Vallejo MC, Matsuo AL, Ganiko L, Medeiros LC, Miranda K, Silva LS, et al. The pathogenic fungus Paracoccidioides brasiliensis exports extracellular vesicles containing highly immunogenic alpha-Galactosyl epitopes. Eukaryot Cell. 2010;10(3):343–51. doi:10.1128/EC.00227-10.

    Article  Google Scholar 

  95. Wolf JM, Casadevall A. Extracellular Cryptococcus neoformans vesicles are stable after isolation but not in serum. In: 8th international conference on cryptococcus and cryptococcosis. Charleston, USA: Medical University of South Carolina; 2011. p. 34.

  96. Kozubowski L, Lee SC, Heitman J. Signalling pathways in the pathogenesis of Cryptococcus. Cell Microbiol. 2009;11(3):370–80. doi:10.1111/j.1462-5822.2008.01273.x.

    Article  PubMed  CAS  Google Scholar 

  97. Hu G, Hacham M, Waterman SR, Panepinto J, Shin S, Liu X, et al. PI3K signaling of autophagy is required for starvation tolerance and virulence of Cryptococcus neoformans. J Clin Invest. 2008;118(3):1186–97. doi:10.1172/JCI32053.

    Article  PubMed  CAS  Google Scholar 

  98. Alspaugh JA, Perfect JR, Heitman J. Signal transduction pathways regulating differentiation and pathogenicity of Cryptococcus neoformans. Fungal Genet Biol. 1998;25(1):1–14. doi:10.1006/fgbi.1998.1079.

    Article  PubMed  CAS  Google Scholar 

  99. Pukkila-Worley R, Alspaugh JA. Cyclic AMP signaling in Cryptococcus neoformans. FEMS Yeast Res. 2004;4(4–5):361–7. doi:S1567135603002411.

    Article  PubMed  CAS  Google Scholar 

  100. D’Souza CA, Alspaugh JA, Yue C, Harashima T, Cox GM, Perfect JR, et al. Cyclic AMP-dependent protein kinase controls virulence of the fungal pathogen Cryptococcus neoformans. Mol Cell Biol. 2001;21(9):3179–91. doi:10.1128/MCB.21.9.3179-3191.2001.

    Article  PubMed  Google Scholar 

  101. Odom A, Muir S, Lim E, Toffaletti DL, Perfect J, Heitman J. Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J. 1997;16(10):2576–89. doi:10.1093/emboj/16.10.2576.

    Article  PubMed  CAS  Google Scholar 

  102. Fox DS, Djordjevic JT, Sorrel T. Signaling cascades and enzymes as Cryptococcus virulence factors In: Joseph Heitman TK, Kwon-Chung J, Perfect J, Casadevall A, editors. Cryptococcus: from human pathogen to model yeast. American Society for Microbiology; 2011. p. 217-34.

  103. Piper RC, Katzmann DJ. Biogenesis and function of multivesicular bodies. Annu Rev Cell Dev Biol. 2007;23:519–47. doi:10.1146/annurev.cellbio.23.090506.123319.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

MLR is supported by grants from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil), Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, Brazil) and Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil). We are thankful to Professors Arturo, Casadevall, Tania Sorrell, Josh Nosanchuk, Rosana Puccia and Leonardo Nimrichter for many discussions and suggestions within the secretion field and Stephen Schibeci (Westmead Millennium Institute, University of Sydney) for proofreading this review. Work on secretion mechanisms performed in the laboratory of JTD is supported by a project grant (632634) from the National Health and Medical Research Council of Australia (NHMRC).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marcio L. Rodrigues.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodrigues, M.L., Djordjevic, J.T. Unravelling Secretion in Cryptococcus neoformans: More than One Way to Skin a Cat. Mycopathologia 173, 407–418 (2012). https://doi.org/10.1007/s11046-011-9468-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11046-011-9468-9

Keywords

Navigation