Applied Microbiology and Biotechnology

, Volume 86, Issue 2, pp 403–417 | Cite as

Engineering of protein secretion in yeast: strategies and impact on protein production

  • Alimjan Idiris
  • Hideki Tohda
  • Hiromichi Kumagai
  • Kaoru Takegawa
Mini-Review

Abstract

Yeasts combine the ease of genetic manipulation and fermentation of a microorganism with the capability to secrete and modify foreign proteins according to a general eukaryotic scheme. Their rapid growth, microbiological safety, and high-density fermentation in simplified medium have a high impact particularly in the large-scale industrial production of foreign proteins, where secretory expression is important for simplifying the downstream protein purification process. However, secretory expression of heterologous proteins in yeast is often subject to several bottlenecks that limit yield. Thus, many studies on yeast secretion systems have focused on the engineering of the fermentation process, vector systems, and host strains. Recently, strain engineering by genetic modification has been the most useful and effective method for overcoming the drawbacks in yeast secretion pathways. Such an approach is now being promoted strongly by current post-genomic technology and system biology tools. However, engineering of the yeast secretion system is complicated by the involvement of many cross-reacting factors. Tight interdependence of each of these factors makes genetic modification difficult. This indicates the necessity of developing a novel systematic modification strategy for genetic engineering of the yeast secretion system. This mini-review focuses on recent strategies and their advantages for systematic engineering of yeast strains for effective protein secretion.

Keywords

Yeast secretion system Secretion pathway Protein folding Membrane trafficking Protease Glycosylation 

Notes

Acknowledgments

This work was supported by funds from the Ministry of Economy, Trade and Industry (METI) as a part of the project “Development of a Technological Infrastructure for Industrial Bioprocesses on Research and Development of New Industrial Science and Technology Frontiers” entrusted by the New Energy and Industrial Technology Development Organization (NEDO).

References

  1. Aalto MK, Ronne H, Keränen S (1993) Yeast syntaxins Sso1p and Sso2p belong to a family of related membrane proteins that function in vesicular transport. EMBO J 12:4095–4104Google Scholar
  2. Ahn JO, Choi ES, Lee HW, Hwang SH, Kim CS, Jang HW, Haam SJ, Jung JK (2004) Enhanced secretion of Bacillus tearothermophilus L1 lipase in Saccharomyces cerevisiae by translational fusion to cellulose-binding domain. Appl Microbiol Biotechnol 64:833–839Google Scholar
  3. Anelli T, Sitia R (2008) Protein quality control in the early secretory pathway. EMBO J 27:315–327Google Scholar
  4. Banta LM, Robinson JS, Klionsky DJ, Emr SD (1988) Organelle assembly in yeast: characterization of yeast mutants defective in vacuolar biogenesis and protein sorting. J Cell Biol 107:1369–1383Google Scholar
  5. Bao WG, Fukuhara H (2001) Secretion of human proteins from yeast: stimulation by duplication of polyubiquitin and protein disulfide isomerase genes in Kluyveromyces lactis. Gene 272:103–110Google Scholar
  6. Berndt U, Oellerer S, Zhang Y, Johnson AE, Rospert S (2009) A signal-anchor sequence stimulates signal recognition particle binding to ribosomes from inside the exit tunnel. Proc Natl Acad Sci USA 106:1398–1403Google Scholar
  7. Böer E, Gellissin G, Kunze G (2005) Arxula adeninivorans. In: Gellisson G (ed) Production of recombinant proteins—novel microbial and eukaryotic expression systems. Wiley-VCH, Weinheim, pp 89–110Google Scholar
  8. Böer E, Steinborn G, Kunze G, Gellissen G (2007) Yeast expression platforms. Appl Microbiol Biotechnol 77:513–523Google Scholar
  9. Bonander N, Hedfalk K, Larsson C, Mostad P, Chang C, Gustafsson L, Bill RM (2005) Design of improved membrane protein production experiments: quantitation of the host response. Protein Sci 14:1729–1740Google Scholar
  10. Bonander N, Darby RA, Grgic L, Bora N, Wen J, Brogna S, Poyner DR, O’Neill MA, Bill RM (2009) Altering the ribosomal subunit ratio in yeast maximizes recombinant protein yield. Microb Cell Fact 8:10Google Scholar
  11. Bonangelino CJ, Chavez EM, Bonifacino JS (2002) Genomic screen for vacuolar protein sorting genes in Saccharomyces cerevisiae. Mol Biol Cell 13:2486–2501Google Scholar
  12. Brake AJ, Merryweather JP, Coit DG, Heberlein UA, Masiarz FR, Mullenbach GT, Urdea MS, Valenzuela P, Barr PJ (1984) Alpha-factor-directed synthesis and secretion of mature foreign proteins in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 81:4642–4646Google Scholar
  13. Bretthauer RK (2003) Genetic engineering of Pichia pastoris to humanize N-glycosylation of proteins. Trends Biotechnol 21:459–462Google Scholar
  14. Burd CG, Babst M, Emr SD (1998) Novel pathways, membrane coats and PI kinase regulation in yeast lysosomal trafficking. Semin Cell Dev Biol 9:527–533Google Scholar
  15. Butz JA, Niebauer RT, Robinson AS (2003) Co-expression of molecular chaperones does not improve the heterologous expression of mammalian G-protein coupled receptor expression in yeast. Biotechnol Bioeng 84:292–304Google Scholar
  16. Chen Y, Pioli D, Piper PW (1994) Overexpression of the gene for polyubiquitin in yeast confers increased secretion of a human leucocyte protease inhibitor. Biotechnology (N Y) 12:819–823Google Scholar
  17. Chiba Y, Akeboshi H (2009) Glycan engineering and production of ‘humanized’ glycoprotein in yeast cells. Biol Pharm Bull 32:786–795Google Scholar
  18. Chiba Y, Suzuki M, Yoshida S, Yoshida A, Ikenaga H, Takeuchi M, Jigami Y, Ichishima E (1998) Production of human compatible high mannose-type (Man5GlcNAc2) sugar chains in Saccharomyces cerevisiae. J Biol Chem 273:26298–26304Google Scholar
  19. Chigira Y, Oka T, Okajima T, Jigami Y (2008) Engineering of a mammalian O-glycosylation pathway in the yeast Saccharomyces cerevisiae: production of O-fucosylated epidermal growth factor domains. Glycobiology 18:303–314Google Scholar
  20. Chow TY, Ash JJ, Dignard D, Thomas DY (1992) Screening and identification of a gene, PSE-1, that affects protein secretion in Saccharomyces cerevisiae. J Cell Sci 101:709–719Google Scholar
  21. Chung BH, Park KS (1998) Simple approach to reducing proteolysis during the secretory production of human parathyroid hormone in Saccharomyces cerevisiae. Biotechnol Bioeng 57:245–249Google Scholar
  22. Conibear E, Stevens TH (1998) Multiple sorting pathways between the late Golgi and the vacuole in yeast. Biochim Biophys Acta 1404:211–230Google Scholar
  23. Copley KS, Alm SM, Schooley DA, Courchesne WE (1998) Expression, processing and secretion of a proteolytically sensitive insect diuretic hormone by Saccharomyces cerevisiae requires the use of a yeast strain lacking genes encoding the Yap3 and Mkc7 endoproteases found in the secretory pathway. Biochem J 330:1333–1340Google Scholar
  24. Damasceno LM, Anderson KA, Ritter G, Cregg JM, Old LJ, Batt CA (2006) Cooverexpression of chaperones for enhanced secretion of a single-chain antibody fragment in Pichia pastoris. Appl Microbiol Biotechnol 56:157–164Google Scholar
  25. Darsow T, Katzmann DJ, Cowles CR, Emr SD (2001) Vps41p function in the alkaline phosphatase pathway requires homo-oligomerization and interaction with AP-3 through two distinct domains. Mol Biol Cell 12:37–51Google Scholar
  26. Dobson CM (2004) Principles of protein folding, misfolding and aggregation. Semin Cell Dev Biol 15:3–16Google Scholar
  27. Eiden-Plach A, Zagorc T, Heintel T, Carius Y, Breinig F, Schmitt MJ (2004) Viral preprotoxin signal sequence allows efficient secretion of green fluorescent protein by Candida glabrata, Pichia pastoris, Saccharomyces cerevisiae, and Schizosaccharomyces pombe. Appl Environ Microbiol 70:961–966Google Scholar
  28. Ellgaard L, Helenius A (2003) Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Bio 4:181–191Google Scholar
  29. Enfors SO (1992) Control of in vivo proteolysis in the production of recombinant proteins. Trends Biotechnol 10:310–315Google Scholar
  30. Fuller RS, Brake AJ, Thorner J (1989) Intracellular targeting and structural conservation of a prohormone-processing endoprotease. Science 246:482–486Google Scholar
  31. Gasser B, Sauer M, Maurer M, Stadlmayr G, Mattanovich D (2007) Transcriptomics-based identification of novel factors enhancing heterologous protein secretion in yeasts. Appl Environ Microbiol 73:6499–6507Google Scholar
  32. Gasser B, Saloheimo M, Rinas U, Dragosits M, Rodríguez-Carmona E, Baumann K, Giuliani M, Parrilli E, Branduardi P, Lang C, Porro D, Ferrer P, Tutino ML, Mattanovich D, Villaverde A (2009) Protein folding and conformational stress in microbial cells producing recombinant proteins: a host comparative overview. Microb Cell Fact 7:11Google Scholar
  33. Gellissen G (2000) Heterologous protein production in methylotrophic yeasts. Appl Microbiol Biotechnol 54:741–750Google Scholar
  34. Gellissen G, Hollenberg CP (1997) Application of yeasts in gene expression studies: a comparison of Saccharomyces cerevisiae, Hansenula polymorpha and Kluyveromyces lactis—a review. Gene 190:87–97Google Scholar
  35. Gellissen G, Kunze G, Gaillardin C, Cregg JM, Berardi E, Veenhuis M, van der Klei I (2005a) New yeast expression platforms based on methylotrophic Hansenula polymorpha and Pichia pastoris and on dimorphic Arxula adeninivorans and Yarrowia lipolytica—a comparison. FEMS Yeast Res 5:1079–1096Google Scholar
  36. Gellissin G, Strasser AWM, Suckow M (2005b) Key and criteria to the selection of an expression system. In: Gellissen G (ed) Production of recombinant proteins—novel microbial and eukaryotic expression systems. Wiley-VCH, Weinheim, pp 1–5Google Scholar
  37. Gemmill TR, Trimble RB (1999) Overview of N- and O-linked oligosaccharide structures found in various yeast species. Biochim Biophys Acta 1426:227–237Google Scholar
  38. Gerngross TU (2004) Advances in the production of human therapeutic proteins in yeasts and filamentous fungi. Nat Biotechnol 22:1409–1414Google Scholar
  39. Giga-Hama Y (1997) Fission yeast Schizosaccharomyces pombe: an attractive host for heterologous protein production. In: Giga-Hama Y, Kumagai H (eds) Foreign gene expression in fission yeast Schizosaccharomyces pombe. Springer, Berlin, pp 3–28Google Scholar
  40. Giga-Hama Y, Kumagai H (1999) Expression system for foreign genes using the fission yeast: Schizosaccharomyces pombe. Biotechnol Appl Biochem 30:235–244Google Scholar
  41. Giga-Hama Y, Tohda H, Okada H, Owada MK, Okayama H, Kumagai H (1994) High level expression of human lipocortin I in the fission yeast Schizosaccharomyces pombe using a novel expression vector. Bio/Technology (N Y) 12:400–404Google Scholar
  42. Giga-Hama Y, Tohda H, Takegawa K, Kumagai H (2007) Schizosaccharomyces pombe minimum genome factory. Biotechnol Appl Biochem 46:147–155Google Scholar
  43. Gleeson MA, White CE, Meininger DP, Komives EA (1998) Generation of protease-deficient strains and their use in heterologous protein expression. Methods Mol Biol 103:81–94Google Scholar
  44. Gonzalez-Lopez CI, Szabo R, Blanchin-Roland S, Gaillardin C (2002) Genetic control of extracellular protease synthesis in the yeast Yarrowia lipolytica. Genetics 160:417–427Google Scholar
  45. Greene JJ (2004) Host cell compatibility in protein expression. In: Balbas P, Lorence A (eds) Recombinant gene expression. Springer, New York, pp 3–14Google Scholar
  46. Gross E, Kastner D, Kaiser C, Fass D (2004) Structure of Ero1p, source of disulfide bonds for oxidative protein folding in the cell. Cell 117:601–610Google Scholar
  47. Halic M, Beckmann R (2005) The signal recognition particle and its interactions during protein targeting. Curr Opin Struct Biol 15:116–125Google Scholar
  48. Hamilton SR, Gerngross TU (2007) Glycosylation engineering in yeast: the advent of fully humanized yeast. Curr Opin Biotechnol 18:387–392Google Scholar
  49. Hamilton SR, Bobrowicz P, Bobrowicz B, Davidson RC, Li H, Mitchell T, Nett JH, Rausch S, Stadheim TA, Wischnewski H, Wildt S, Gerngross TU (2003) Production of complex human glycoproteins in yeast. Science 301:1244–1246Google Scholar
  50. Hamilton SR, Davidson RC, Sethuraman N, Nett JH, Jiang Y, Rios S, Bobrowicz P, Stadheim TA, Li H, Choi BK, Hopkins D, Wischnewski H, Roser J, Mitchell T, Strawbridge RR, Hoopes J, Wildt S, Gerngross TU (2006) Humanization of yeast to produce complex terminally sialylated glycoproteins. Science 313:1441–1443Google Scholar
  51. Harford N, Cabezon T, Colau B, Delisse AM, Rutgers T, De Wilde M (1987) Construction and characterization of a Saccharomyces cerevisiae strain (RIT4376) expressing hepatitis B surface antigen. Postgrad Med J 63:65–70Google Scholar
  52. Harmsen M, Bruyne M, Raué H, Maat J (1996) Overexpression of binding protein and disruption of the PMR1 gene synergistically stimulate secretion of bovine prochymosin but not plant thaumatin in yeast. Appl Microbiol Biotechnol 46:365–370Google Scholar
  53. Holkeri H, Makarow M (1998) Different degradation pathways for heterologous glycoproteins in yeast. FEBS Lett 429:162–166Google Scholar
  54. Hong E, Davidson AR, Kaiser CA (1996) A pathway for targeting soluble misfolded proteins to the yeast vacuole. J Cell Biol 135:623–633Google Scholar
  55. Idiris A, Bi KW, Tohda H, Kumagai H, Giga-Hama Y (2006a) Construction of a protease-deficient strain set for the fission yeast Schizosaccharomyces pombe, useful for effective production of protease-sensitive heterologous proteins. Yeast 23:83–99Google Scholar
  56. Idiris A, Tohda H, Bi KW, Isoai A, Kumagai H, Giga-Hama Y (2006b) Enhanced productivity of protease-sensitive heterologous proteins by disruption of multiple protease genes in the fission yeast Schizosaccharomyces pombe. Appl Microbiol Biotechnol 73:404–420Google Scholar
  57. Idiris A, Tohda H, Sasaki M, Okada K, Kumagai H, Giga-Hama Y, Takegawa K (2010) Enhanced protein secretion from multiprotease-deficient fission yeast by modification of its vacuolar protein sorting pathway. Appl Microbiol Biotechnol 85:667–677Google Scholar
  58. Ikeda Y, Ohashi T, Tanaka N, Takegawa K (2009) Identification and characterization of a gene required for α1, 2-mannose extension in the O-linked glycan synthesis pathway in Schizosaccharomyces pombe. FEMS Yeast Res 9:115–125Google Scholar
  59. Ilgen C, Lin-Cereghino J, Cregg JM (2005) Pichia pastoris. In: Gelisson G (ed) Production of recombinant proteins—novel microbial and eukaryotic expression system. Wiley-VCH, Weinheim, pp 143–162Google Scholar
  60. Inan M, Aryasomayajula D, Sinha J, Meagher MM (2006) Enhancement of protein secretion in Pichia pastoris by overexpression of protein disulfide isomerase. Biotechnol Bioeng 93:771–778Google Scholar
  61. Iwaki T, Hosomi A, Tokudomi S, Kusunoki Y, Fujita Y, Giga-Hama Y, Tanaka N, Takegawa K (2006) Vacuolar protein sorting receptor in Schizosaccharomyces pombe. Microbiology 152:1523–1532Google Scholar
  62. Jones EW (1991) Tackling the protease problem in Saccharomyces cerevisiae. Methods Enzymol 194:429–453Google Scholar
  63. Jønson L, Rehfeld JF, Johnsen AH (2004) Enhanced peptide secretion by gene disruption of CYM1, a novel protease in Saccharomyces cerevisiae. Eur J Biochem 271:4788–4797Google Scholar
  64. Kabani M, Beckerich JM, Gaillardin C (2000) Sls1p stimulates Sec63p-mediated activation of Kar2p in a conformation-dependent manner in the yeast endoplasmic reticulum. Mol Cell Biol 20:6923–6934Google Scholar
  65. Kang HA, Gellissen G (2005) Hansenula polymorpha. In: Gellissen G (ed) Production of recombinant proteins—novel microbial and eukaryotic expression systems. Wiley-VCH, Weinheim, pp 111–142Google Scholar
  66. Kang HA, Kim SJ, Choi ES, Rhee SK, Chung BH (1998) Efficient production of intact human parathyroid hormone in a Saccharomyces cerevisiae mutant deficient in yeast aspartic protease 3 (YAP3). Appl Microbiol Biotechnol 50:187–192Google Scholar
  67. Kang HA, Choi ES, Hong WK, Kim JY, Ko SM, Sohn JH, Rhee SK (2000) Proteolytic stability of recombinant human serum albumin secreted in the yeast Saccharomyces cerevisiae. Appl Microbiol Biotechnol 53:575–582Google Scholar
  68. Kanjou N, Nagao A, Ohmiya Y, Ohgiya S (2007) Yeast mutant with efficient secretion identified by a novel secretory reporter, Cluc. Biochem Biophys Res Commun 358:429–434Google Scholar
  69. Kauffman K, Pridgen E, Fr D, Dhurjati P, Robinson A (2002) Decreased protein expression and intermittent recoveries in BiP levels result from cellular stress during heterologous protein expression in Saccharomyces cerevisiae. Biotechnol Prog 18:942–950Google Scholar
  70. Kida Y, Morimoto F, Sakaguchi M (2007) Two translocating hydrophilic segments of a nascent chain span the ER membrane during multispanning protein topogenesis. J Cell Biol 179:1441–1452Google Scholar
  71. Kida Y, Morimoto F, Sakaguchi M (2009) Signal anchor sequence provides motive force for polypeptide chain translocation through the endoplasmic reticulum membrane. J Biol Chem 284:2861–2866Google Scholar
  72. Kjaerulff S, Jensen MR (2005) Comparison of different signal peptides for secretion of heterologous proteins in fission yeast. Biochem Biophys Res Commun 336:974–982Google Scholar
  73. Klabunde J, Kleebank S, Piontek M, Hollenberg CP, Hellwig S, Degelmann A (2007) Increase of calnexin gene dosage boosts the secretion of heterologous proteins by Hansenula polymorpha. FEMS Yeast Res 7:1168–1180Google Scholar
  74. Klausner RD (1989) Architectural editing: determining the fate of newly synthesized membrane proteins. New Biol 1:3–8Google Scholar
  75. Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5:539–545Google Scholar
  76. Komeda T, Sakai Y, Kato N, Kondo K (2002) Construction of protease-deficient Candida boidinii strains useful for recombinant protein production: cloning and disruption of proteinase A gene (PEP4) and proteinase B gene (PRBI). Biosci Biotechnol Biochem 66:628–631Google Scholar
  77. Lodi T, Neglia B, Donnini C (2005) Secretion of human serum albumin by Kluyveromyces lactis overexpressing KlPDI1 and KlERO1. Appl Environ Microbiol 71:4359–4363Google Scholar
  78. Lombraña M, Moralejo FJ, Pinto R, Martín JF (2004) Modulation of Aspergillus awamori thaumatin secretion by modification of bipA gene expression. Appl Environ Microbiol 70:5145–5152Google Scholar
  79. Macauley-Patrick S, Fazenda ML, McNeil B, Harvey LM (2005) Heterologous protein production using the Pichia pastoris expression system. Yeast 22:249–270Google Scholar
  80. Madzack C, Nicaud J-M, Gaillardin C (2005) Yarrowia lipolytica. In: Gellissin G (ed) Production of recombinant proteins—novel microbial and eukaryotic expression systems. Wiley-VCH, Weinheim, pp 163–189Google Scholar
  81. Marcusson EG, Horazdovsky BF, Cereghino JL, Gharakhanian E, Emr SD (1994) The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell 77:579–586Google Scholar
  82. Martoglio B, Dobberstein B (1998) Signal sequences: more than just greasy peptides. Trends Cell Biol 8:410–415Google Scholar
  83. Mattanovich D, Borth N (2006) Applications of cell sorting in biotechnology. Microb Cell Fact 5:12Google Scholar
  84. Mattanovich D, Gasser B, Hohenblum H, Sauer M (2004) Stress in recombinant protein producing yeasts. J Biotechnol 113:121–135Google Scholar
  85. Melmer G (2005) Biopharmaceuticals and the industrial environment. In: Gellissin G (ed) Production of recombinant proteins—novel microbial and eukaryotic expression system. Wiley-VCH, Weinheim, pp 361–383Google Scholar
  86. Moralejo FJ, Watson AJ, Jeenes DJ, Archer DB, Martín JF (2001) A defined level of protein disulfide isomerase expression is required for optimal secretion of thaumatin by Aspergillus awamori. Mol Genet Genomics 266:246–253Google Scholar
  87. Mormeneo M, Andrés I, Bofill C, Díaz P, Zueco J (2008) Efficient secretion of Bacillus subtilis lipase A in Saccharomyces cerevisiae by translational fusion to the Pir4 cell wall protein. Appl Microbiol Biotechnol 80:437–445Google Scholar
  88. Mukaiyama H, Giga-Hama Y, Tohda H, Takegawa K (2009) Dextran sodium sulfate enhances secretion of recombinant human transferrin in Schizosaccharomyces pombe. Appl Microbiol Biotechnol 85:155–164Google Scholar
  89. Mukaiyama H, Tohda H, Takegawa K (2010) Overexpression of protein disulfide isomerases enhances secretion of recombinant human transferrin in Schizosaccharomyces pombe. Appl Microbiol Biotechnol (in press)Google Scholar
  90. Müller S, Sandal T, Kamp-Hansen P, Dalboge H (1998) Comparison of expression systems in the yeasts Saccharomyces cerevisiae, Hansenula polymorpha, Kluyveromyces lactis. Schizosaccharomyces pombe and Yarrowia lipolytica. Cloning of two novel promoters from Yarrowia lipolytica. Yeast 14:1267–1283Google Scholar
  91. Nagasu T, Shimma Y, Nakanishi Y, Kuromitsu J, Iwama K, Nakayama K, Suzuki K, Jigami Y (1992) Isolation of new temperature-sensitive mutants of Saccharomyces cerevisiae deficient in mannose outer chain elongation. Yeast 8:535–547Google Scholar
  92. Nakanishi-Shindo Y, Nakayama K, Tanaka A, Toda Y, Jigami Y (1993) Structure of the N-linked oligosaccharides that show the complete loss of alpha-1, 6-polymannose outer chain from och1, och1 mnn1, and och1 mnn1 alg3 mutants of Saccharomyces cerevisiae. J Biol Chem 268:26338–26345Google Scholar
  93. Nakashima A, Hasegawa T, Mori S, Ueno M, Tanaka S, Ushimaru T, Sato S, Uritani M (2006) A starvation-specific serine protease gene, isp6 +, is involved in both autophagy and sexual development in Schizosaccharomyces pombe. Curr Genet 49:403–413Google Scholar
  94. Ng DT, Brown JD, Walter P (1996) Signal sequences specify the targeting route to the endoplasmic reticulum membrane. J Cell Biol 134:269–278Google Scholar
  95. Niebauer RT, Robinson AS (2005) Saccharomyces cerevisiae protein expression: from protein production to protein engineering. In: Baneyx F (ed) Protein expression technologies. Horizon, Norwich, pp 253–296Google Scholar
  96. Ohashi T, Takegawa K (2009) N- and O-linked oligosaccharides completely lack galactose residues in the gms1och1 mutant of Schizosaccharomyces pombe. Appl Microbiol Biotechnol (in press)Google Scholar
  97. Oka T, Jigami Y (2006) Reconstruction of de novo pathway for synthesis of UDP-glucuronic acid and UDP-xylose from intrinsic UDP-glucose in Saccharomyces cerevisiae. FEBS J 273:2645–2657Google Scholar
  98. Okada H, Sekiya T, Yokoyama K, Tohda H, Kumagai H, Morikawa Y (1998a) Efficient secretion of Trichoderma reesei cellobiohydrolase II in Schizosaccharomyces pombe and characterization of its products. Appl Microbiol Biotechnol 49:301–308Google Scholar
  99. Okada H, Tada K, Sekiya T, Yokoyama K, Takahashi A, Tohda H, Kumagai H, Morikawa Y (1998b) Molecular characterization and heterologous expression of the gene encoding a low-molecular-mass endoglucanase from Trichoderma reesei QM9414. Appl Environ Microbiol 64:555–563Google Scholar
  100. Palomares LA, Estrada-Mondaca S, Ramirez OT (2004) Production of recombinant proteins: challenges and solutions. In: Balbas P, Lorence A (eds) Recombinant gene expression. Springer, New York, pp 15–52Google Scholar
  101. Payne T, Finnis C, Evans LR, Mead DJ, Avery SV, Archer DB, Sleep D (2008) Modulation of chaperone gene expression in mutagenized Saccharomyces cerevisiae strains developed for recombinant human albumin production results in increased production of multiple heterologous proteins. Appl Environ Microbiol 74:7759–7766Google Scholar
  102. Plath K, Mothes W, Wilkinson BM, Stirling CJ, Rapoport TA (1998) Signal sequence recognition in posttranslational protein transport across the yeast ER membrane. Cell 94:795–807Google Scholar
  103. Porro D, Sauer M, Branduardi P, Mattanovich D (2005) Recombinant protein production in yeasts. Mol Biotechnol 31:245–259Google Scholar
  104. Punt PJ, van Biezen N, Conesa A, Albers A, Mangnus J, van den Hondel C (2002) Filamentous fungi as cell factories for heterologous protein production. Trends Biotechnol 20:200–206Google Scholar
  105. Rader RA (2007) Biopharmaceutical products in the US and European markets, 6th edn. BioPlan Associates, RockvilleGoogle Scholar
  106. Rakestraw JA, Baskaran AR, Wittrup KD (2006) A flow cytometric assay for screening improved heterologous protein secretion in yeast. Biotechnol Prog 22:1200–1208Google Scholar
  107. Rapoport TA (2007) Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature 450:663–669Google Scholar
  108. Raymond CK, Howald-Stevenson I, Vater CA, Stevens TH (1992) Morphological classification of the yeast vacuolar protein sorting mutants: evidence for a prevacuolar compartment in class E vps mutants. Mol Biol Cell 3:1389–1402Google Scholar
  109. Raymond CK, Bukowski T, Holderman SD, Ching AF, Vanaja E, Stamm MR (1998) Development of the methylotrophic yeast Pichia methanolica for the expression of the 65 kilodalton isoform of human glutamate decarboxylase. Yeast 14:11–23Google Scholar
  110. Robinson A, Hines V, Wittrup K (1994) Protein disulfide isomerase overexpression increases secretion of foreign proteins in Saccharomyces cerevisiae. Biotechnology (NY) 12:381–384Google Scholar
  111. Robinson AS, Bockhaus JA, Voegler AC, Wittrup KD (1996) Reduction of BiP levels decreases heterologous protein secretion in Saccharomyces cerevisiae. J Biol Chem 271:10017–10022Google Scholar
  112. Ruohonen L, Toikkanen J, Tieaho V, Outola M, Soderlund H, Keranen S (1997) Enhancement of protein secretion in Saccharomyces cerevisiae by overproduction of Sso protein, a late-acting component of the secretory machinery. Yeast 13:337–351Google Scholar
  113. Sakai Y, Akiyama M, Kondoh H, Shibano Y, Kato N (1996) High-level secretion of fungal glucoamylase using the Candida boidinii gene expression system. Biochim Biophys Acta 1308:81–87Google Scholar
  114. Sauer M, Branduardi P, Gasser B, Valli M, Maurer M, Porro D, Mattanovich D (2004) Differential gene expression in recombinant Pichia pastoris analysed by heterologous DNA microarray hybridisation. Microb Cell Fact 3:17Google Scholar
  115. Schmidt FR (2004) Recombinant expression systems in the pharmaceutical industry. Appl Microbiol Biotechnol 65:363–372Google Scholar
  116. Schröder M (2007) The cellular response to protein unfolding stress. In: Robson GD, van West P, Gadd GM (eds) Exploitation of fungi. British mycological society symposium series, vol 26. Cambridge University Press, Cambridge, pp 117–139Google Scholar
  117. Schröder M (2008) Engineering eukaryotic protein factors. Biotechnol Lett 30:187–196Google Scholar
  118. Schröder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789Google Scholar
  119. Shan SO, Walter P (2005) Co-translational protein targeting by the signal recognition particle. FEBS Lett 579:921–926Google Scholar
  120. Shusta E, Raines R, Plückthun A, Wittrup K (1998) Increasing the secretory capacity of Saccharomyces cerevisiae for production of single-chain antibody fragments. Nat Biotechnol 16:773–777Google Scholar
  121. Shusta EV, Kieke MC, Parke E, Kranz DM, Wittrup KD (1999) Yeast polypeptide fusion surface display levels predict thermal stability and soluble secretion efficiency. J Mol Biol 292:949–956Google Scholar
  122. Siegel RS, Brierley RA (1990) Use of a cell recycle reactor to increase production of a proteolysis-susceptible peptide secreted from recombinant Saccharomyces cerevisiae. Bio/Technology 8:639–643Google Scholar
  123. Sinha J, Plantz BA, Inan M, Meagher MM (2005) Causes of proteolytic degradation of secreted recombinant proteins produced in methylotrophic yeast Pichia pastoris: case study with recombinant ovine interferon-tau. Biotechnol Bioeng 89:102–112Google Scholar
  124. Smith J, Tang B, Robinson A (2004) Protein disulfide isomerase, but not binding protein, overexpression enhances secretion of a nondisulfide-bonded protein in yeast. Biotechnol Bioeng 85:340–350Google Scholar
  125. Steel GJ, Fullerton DM, Tyson JR, Stirling CJ (2004) Coordinated activation of Hsp70 chaperones. Science 303:98–101Google Scholar
  126. Steinborn G, Böer E, Scholz A, Tag K, Kunze G, Gellissen G (2006) Application of a wide-range yeast vector (CoMed™) system to recombinant protein production in dimorphic Arxula adeninivorans, methylotrophic Hansenula polymorpha and other yeasts. Microbial Cell Fact 5:33Google Scholar
  127. Takegawa K, Tokudomi S, Bhuiyan MS, Tabuchi M, Fujita Y, Iwaki T, Utsumi S, Tanaka N (2003) Heterologous expression and characterization of Schizosaccharomyces pombe vacuolar carboxypeptidase Y in Saccharomyces cerevisiae. Curr Genet 42:252–259Google Scholar
  128. Takegawa K, Tohda H, Sasaki M, Idiris A, Ohashi T, Mukaiyama H, Giga-Hama Y, Kumagai H (2009) Production of heterologous proteins using the fission-yeast (Schizosaccharomyces pombe) expression system. Biotechnol Appl Biochem 53:227–235Google Scholar
  129. Travers K, Patil C, Wodicka L, Lockhart D, Weissman J, Walter P (2000) Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101:249–258Google Scholar
  130. Turner BG, Avgerinos GC, Melnick LM, Moir DT (1991) Optimization of pro-urokinase secretion from recombinant Saccharomyces cerevisiae. Biotechnol Bioeng 37:869–875Google Scholar
  131. Tyson JR, Stirling CJ (2000) LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum. EMBO J 19:6440–6452Google Scholar
  132. Valkonen M, Penttilä M, Saloheimo M (2003) Effects of inactivation and constitutive expression of the unfolded-protein response pathway on protein production in the yeast Saccharomyces cerevisiae. Appl Environ Microbiol 69:2065–2072Google Scholar
  133. van der Heide M, Hollenberg C, van der Klei I, Veenhuis M (2002) Overproduction of BiP negatively affects the secretion of Aspergillus niger glucose oxidase by the yeast Hansenula polymorpha. Appl Microbiol Biotechnol 58:487–494Google Scholar
  134. Vida TA, Huyer G, Emr SD (1993) Yeast vacuolar proenzymes are sorted in the late Golgi complex and transported to the vacuole via a prevacuolar endosome-like compartment. J Cell Biol 121:1245–1256Google Scholar
  135. Wentz AE, Shusta EV (2007) A novel high-throughput screen reveals yeast genes that increase secretion of heterologous proteins. Appl Environ Microbiol 73:1189–1198Google Scholar
  136. Wentz AE, Shusta EV (2008) Enhanced secretion of heterologous proteins from yeast by overexpression of ribosomal subunit RPP0. Biotechnol Prog 24:748–756Google Scholar
  137. Werten MW, de Wolf FA (2005) Reduced proteolysis of secreted gelatin and Yps1-mediated α-factor leader processing in a Pichia pastoris kex2 disruptant. Appl Environ Microbiol 71:2310–2317Google Scholar
  138. Wildt S, Gerngross TU (2005) The humanization of N-glycosylation pathways in yeast. Nat Rev Microbiol 3:119–128Google Scholar
  139. Xiao A, Zhou X, Zhou L, Zhang Y (2006) Improvement of cell viability and hirudin production by ascorbic acid in Pichia pastoris fermentation. Appl Microbiol Biotechnol 72:837–844Google Scholar
  140. Yoshida H (2007) ER stress and diseases. FEBS J 274:630–658Google Scholar
  141. Zhang B, Chang A, Kjeldsen TB, Arvan P (2001) Intracellular retention of newly synthesized insulin in yeast is caused by endoproteolytic processing in the Golgi complex. J Cell Biol 153:1187–1198Google Scholar
  142. Zhang W, Zhao HL, Xue C, Xiong XH, Yao XQ, Li XY, Chen HP, Liu ZM (2006) Enhanced secretion of heterologous proteins in Pichia pastoris following overexpression of Saccharomyces cerevisiae chaperone proteins. Biotechnol Prog 22:1090–1095Google Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Alimjan Idiris
    • 1
  • Hideki Tohda
    • 1
  • Hiromichi Kumagai
    • 1
  • Kaoru Takegawa
    • 2
  1. 1.R&D Group, ASPEX Division, Research CenterAsahi Glass Co., Ltd.YokohamaJapan
  2. 2.Laboratory of Applied Microbiology, Graduate School of Bioresource and Bioenvironmental SciencesKyushu UniversityFukuokaJapan

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