Involvement of PDK1, PKC and TOR signalling pathways in basal fluconazole tolerance in Cryptococcus neoformans

Molecular Microbiology

Volumn 84, Issue 1, 2012, Pages 130-146

  Lee, Hyeseung ^a   Khanal Lamichhane, Ami ^a   Garraffo, H Martin ^b   Kwon Chung, Kyung J ^a   Chang, Yun C ^a  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^b NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIAL ENZYME; FLUCONAZOLE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEIN KINASE C; PROTEIN YPK1; SPHINGOLIPID; TARGET OF RAPAMYCIN KINASE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CELL VIABILITY; CONTROLLED STUDY; CRYPTOCOCCUS NEOFORMANS; DRUG TOLERANCE; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; FEMALE; FUNGAL GENE; FUNGAL STRAIN; FUNGAL VIRULENCE; GENE DELETION; GENE MUTATION; HOMEOSTASIS; MOUSE; NONHUMAN; PDK1 GENE; PHENOTYPE; PLASMID; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; SIN1 GENE; WILD TYPE; YPK1 GENE;

ANIMALS; ANTIFUNGAL AGENTS; CRYPTOCOCCUS NEOFORMANS; DRUG RESISTANCE, FUNGAL; FEMALE; FLUCONAZOLE; FUNGAL PROTEINS; GENE DELETION; GENE KNOCKOUT TECHNIQUES; MICE; MICE, INBRED BALB C; PHOSPHORYLATION; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION; SPHINGOLIPIDS; VIRULENCE;

FILOBASIDIELLA NEOFORMANS; MUS;

EID: 84862805988     PISSN: 0950382X     EISSN: 13652958     Source Type: Journal    
DOI: 10.1111/j.1365-2958.2012.08016.x     Document Type: Article

References (91)

1. Abe, F., Usui, K., and Hiraki, T. (2009) Fluconazole modulates membrane rigidity, heterogeneity, and water penetration into the plasma membrane in Saccharomyces cerevisiae. Biochemistry 48: 8494-8504.
2. Akins, R.A. (2005) An update on antifungal targets and mechanisms of resistance in Candida albicans. Med Mycol 43: 285-318.
3. Anderson, J.B., Sirjusingh, C., Parsons, A.B., Boone, C., Wickens, C., Cowen, L.E., and Kohn, L.M. (2003) Mode of selection and experimental evolution of antifungal drug resistance in Saccharomyces cerevisiae. Genetics 163: 1287-1298.
4. Armengou, A., Porcar, C., Mascaro, J., and Garcia-Bragado, F. (1996) Possible development of resistance to fluconazole during suppressive therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 23: 1337-1338.
5. Aronova, S., Wedaman, K., Aronov, P.A., Fontes, K., Ramos, K., Hammock, B.D., and Powers, T. (2008) Regulation of ceramide biosynthesis by TOR complex 2. Cell Metab 7: 148-158.
6. 2+-sensitive csg2Δ mutant. J Biol Chem 273: 30688-30694.
7. Bennett, J.E., Izumikawa, K., and Marr, K.A. (2004) Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother 48: 1773-1777.
8. Berg, J., Clancy, C.J., and Nguyen, M.H. (1998) The hidden danger of primary fluconazole prophylaxis for patients with AIDS. Clin Infect Dis 26: 186-187.
9. Birley, H.D., Johnson, E.M., McDonald, P., Parry, C., Carey, P.B., and Warnock, D.W. (1995) Azole drug resistance as a cause of clinical relapse in AIDS patients with cryptococcal meningitis. Int J STD AIDS 6: 353-355.
10. Brun, S., Berges, T., Poupard, P., Vauzelle-Moreau, C., Renier, G., Chabasse, D., and Bouchara, J. (2004) Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother 48: 1788-1796.
11. Casamayor, A., Torrance, P.D., Kobayashi, T., Thorner, J., and Alessi, D.R. (1999) Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. Curr Biol 9: 186-197.
12. Chang, Y.C., and Kwon-Chung, K.J. (1994) Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence. Mol Cell Biol 14: 4912-4919.
13. Chang, Y.C., Bien, C.M., Lee, H., Espenshade, P.J., and Kwon-Chung, K.J. (2007) Cryptococcus neoformans sterol regulatory element binding protein (Sre1p), a virulence factor that functions in oxygen sensing and sterol homeostasis. Mol Microbiol 64: 614-629.
14. Cowen, L.E. (2008) The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat Rev Microbiol 6: 187-198.
15. Cowen, L.E., and Lindquist, S. (2005) Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309: 2185-2189.
16. Cowen, L.E., and Steinbach, W.J. (2008) Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance. Eukaryot Cell 7: 747-764.
17. Cowen, L.E., Anderson, J.B., and Kohn, L.M. (2002) Evolution of drug resistance in Candida albicans. Annu Rev Microbiol 56: 139-165.
18. Cowen, L.E., Carpenter, A.E., Matangkasombut, O., Fink, G.R., and Lindquist, S. (2006) Genetic architecture of Hsp90-dependent drug resistance. Eukaryot Cell 5: 2184-2188.
19. Cruz, M.C., Cavallo, L.M., Gorlach, J.M., Cox, G., Perfect, J.R., Cardenas, M.E., and Heitman, J. (1999) Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans. Mol Cell Biol 19: 4101-4112.
20. Davidson, R.C., Blankenship, J.R., Kraus, P.R., de Jesus Berrios, M., Hull, C.M., D'Souza, C., etal. (2002) A PCR-based strategy to generate integrative targeting alleles with large regions of homology. Microbiology 148: 2607-2615.
21. Gelperin, D., Horton, L., DeChant, A., Hensold, J., and Lemmon, S.K. (2002) Loss of ypk1 function causes rapamycin sensitivity, inhibition of translation initiation and synthetic lethality in 14-3-3-deficient yeast. Genetics 161: 1453-1464.
22. Gerik, K.J., Donlin, M.J., Soto, C.E., Banks, A.M., Banks, I.R., Maligie, M.A., etal. (2005) Cell wall integrity is dependent on the PKC1 signal transduction pathway in Cryptococcus neoformans. Mol Microbiol 58: 393-408.
23. Gerik, K.J., Bhimireddy, S.R., Ryerse, J.S., Specht, C.A., and Lodge, J.K. (2008) PKC1 is essential for protection against both oxidative and nitrosative stresses, cell integrity, and normal manifestation of virulence factors in the pathogenic fungus Cryptococcus neoformans. Eukaryot Cell 7: 1685-1698.
24. Graub, R., Hilti, N., Niederberger, C., and Schweingruber, M.E. (2003) Ksg1, a homologue of the phosphoinositide-dependent protein kinase 1, controls cell wall integrity in Schizosaccharomyces pombe. J Basic Microbiol 43: 473-482.
25. Hanks, S.K., and Hunter, T. (1995) Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J 9: 576-596.
26. Hartmuth, S., and Petersen, J. (2009) Fission yeast Tor1 functions as part of TORC1 to control mitotic entry through the stress MAPK pathway following nutrient stress. J Cell Sci 122: 1737-1746.
27. Heitman, J., Movva, N.R., and Hall, M.N. (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253: 905-909.
28. Helmerhorst, E.J., Venuleo, C., Sanglard, D., and Oppenheim, F.G. (2006) Roles of cellular respiration, CgCDR1, and CgCDR2 in Candida glabrata resistance to histatin 5. Antimicrob Agents Chemother 50: 1100-1103.
29. Inagaki, M., Schmelzle, T., Yamaguchi, K., Irie, K., Hall, M.N., and Matsumoto, K. (1999) PDK1 homologs activate the Pkc1-mitogen-activated protein kinase pathway in yeast. Mol Cell Biol 19: 8344-8352.
30. Kelly, S.L., Lamb, D.C., Baldwin, B.C., Corran, A.J., and Kelly, D.E. (1997) Characterization of Saccharomyces cerevisiae CYP61, sterol Δ22-desaturase, and inhibition by azole antifungal agents. J Biol Chem 272: 9986-9988.
31. Knighton, D.R., Pearson, R.B., Sowadski, J.M., Means, A.R., Ten Eyck, L.F., Taylor, S.S., and Kemp, B.E. (1992) Structural basis of the intrasteric regulation of myosin light chain kinases. Science 258: 130-135.
32. Kohli, A., Smriti, N., Mukhopadhyay, K., Rattan, A., and Prasad, R. (2002) In vitro low-level resistance to azoles in Candida albicans is associated with changes in membrane lipid fluidity and asymmetry. Antimicrob Agents Chemother 46: 1046-1052.
33. Kojima, K., Bahn, Y.S., and Heitman, J. (2006) Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans. Microbiology 152: 591-604.
34. Kontoyiannis, D.P., Sagar, N., and Hirschi, K.D. (1999) Overexpression of Erg11p by the regulatable GAL1 promoter confers fluconazole resistance in Saccharomyces cerevisiae. Antimicrob Agents Chemother 43: 2798-2800.
35. Kraus, P.R., Fox, D.S., Cox, G.M., and Heitman, J. (2003) The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function. Mol Microbiol 48: 1377-1387.
36. Kuwayama, H., Obara, S., Morio, T., Katoh, M., Urushihara, H., and Tanaka, Y. (2002) PCR-mediated generation of a gene disruption construct without the use of DNA ligase and plasmid vectors. Nucleic Acids Res 30: E2.
37. Kwon-Chung, K.J., and Bennett, J.E. (1992) Medical Mycology. Philadelphia: Lea & Febiger.
38. LaFayette, S.L., Collins, C., Zaas, A.K., Schell, W.A., Betancourt-Quiroz, M., Gunatilaka, A.A., etal. (2010) PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90. PLoS Pathog 6: e1001069.
39. Lamping, E., Monk, B.C., Niimi, K., Holmes, A.R., Tsao, S., Tanabe, K., etal. (2007) Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae. Eukaryot Cell 6: 1150-1165.
40. Lesage, G., and Bussey, H. (2006) Cell wall assembly in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 70: 317-343.
41. Levin, D.E. (2005) Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 69: 262-291.
42. Li, X., Gianoulis, T.A., Yip, K.Y., Gerstein, M., and Snyder, M. (2010) Extensive in vivo metabolite-protein interactions revealed by large-scale systematic analyses. Cell 143: 639-650.
43. Liu, O.W., Chun, C.D., Chow, E.D., Chen, C., Madhani, H.D., and Noble, S.M. (2008) Systematic genetic analysis of virulence in the human fungal pathogen Cryptococcus neoformans. Cell 135: 174-188.
44. Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J.L., Bonenfant, D., etal. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10: 457-468.
45. Luo, G., Gruhler, A., Liu, Y., Jensen, O.N., and Dickson, R.C. (2008) The sphingolipid long-chain base-Pkh1/2-Ypk1/2 signaling pathway regulates eisosome assembly and turnover. J Biol Chem 283: 10433-10444.
46. Lupetti, A., Danesi, R., Campa, M., Tacca, M.D., and Kelly, S. (2002) Molecular basis of resistance to azole antifungals. Trends Mol Med 8: 76-81.
47. Mansfield, B.E., Oltean, H.N., Oliver, B.G., Hoot, S.J., Leyde, S.E., Hedstrom, L., and White, T.C. (2010) Azole drugs are imported by facilitated diffusion in Candida albicans and other pathogenic fungi. PLoS Pathog 6: e1001126.
48. Marichal, P., Koymans, L., Willemsens, S., Bellens, D., Verhasselt, P., Luyten, W., etal. (1999) Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology 145 (Part 10): 2701-2713.
49. Martin, S.W., and Konopka, J.B. (2004) Lipid raft polarization contributes to hyphal growth in Candida albicans. Eukaryot Cell 3: 675-684.
50. Matsuo, T., Kubo, Y., Watanabe, Y., and Yamamoto, M. (2003) Schizosaccharomyces pombe AGC family kinase Gad8p forms a conserved signaling module with TOR and PDK1-like kinases. EMBO J 22: 3073-3083.
51. Matsuo, T., Otsubo, Y., Urano, J., Tamanoi, F., and Yamamoto, M. (2007) Loss of the TOR kinase Tor2 mimics nitrogen starvation and activates the sexual development pathway in fission yeast. Mol Cell Biol 27: 3154-3164.
52. Moffett, S., Brown, D.A., and Linder, M.E. (2000) Lipid-dependent targeting of G proteins into rafts. J Biol Chem 275: 2191-2198.
53. Mondon, P., Petter, R., Amalfitano, G., Luzzati, R., Concia, E., Polacheck, I., and Kwon-Chung, K.J. (1999) Heteroresistance to fluconazole and voriconazole in Cryptococcus neoformans. Antimicrob Agents Chemother 43: 1856-1861.
54. Monk, B.C., Niimi, K., Lin, S., Knight, A., Kardos, T.B., Cannon, R.D., etal. (2005) Surface-active fungicidal d-peptide inhibitors of the plasma membrane proton pump that block azole resistance. Antimicrob Agents Chemother 49: 57-70.
55. Mora, A., Komander, D., van Aalten, D.M., and Alessi, D.R. (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 15: 161-170.
56. Mukhopadhyay, K., Kohli, A., and Prasad, R. (2002) Drug susceptibilities of yeast cells are affected by membrane lipid composition. Antimicrob Agents Chemother 46: 3695-3705.
57. Mukhopadhyay, K., Prasad, T., Saini, P., Pucadyil, T.J., Chattopadhyay, A., and Prasad, R. (2004) Membrane sphingolipid-ergosterol interactions are important determinants of multidrug resistance in Candida albicans. Antimicrob Agents Chemother 48: 1778-1787.
58. Niederberger, C., and Schweingruber, M.E. (1999) A Schizosaccharomyces pombe gene, ksg1, that shows structural homology to the human phosphoinositide-dependent protein kinase PDK1, is essential for growth, mating and sporulation. Mol Gen Genet 261: 177-183.
59. Otsubo, Y., and Yamamato, M. (2008) TOR signaling in fission yeast. Crit Rev Biochem Mol Biol 43: 277-283.
60. Oura, T., and Kajiwara, S. (2008) Disruption of the sphingolipid Δ8-desaturase gene causes a delay in morphological changes in Candida albicans. Microbiology 154: 3795-3803.
61. Oura, T., and Kajiwara, S. (2010) Candida albicans sphingolipid C9-methyltransferase is involved in hyphal elongation. Microbiology 156: 1234-1243.
62. Parsons, A.B., Brost, R.L., Ding, H., Li, Z., Zhang, C., Sheikh, B., etal. (2004) Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways. Nat Biotechnol 22: 62-69.
63. Pasrija, R., Prasad, T., and Prasad, R. (2005) Membrane raft lipid constituents affect drug susceptibilities of Candida albicans. Biochem Soc Trans 33: 1219-1223.
64. Paugam, A., Dupouy-Camet, J., Blanche, P., Gangneux, J., Tourte-Schaefer, C., and Sicard, D. (1994) Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. Clin Infect Dis 19: 975-976.
65. Pearce, L.R., Komander, D., and Alessi, D.R. (2010) The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 11: 9-22.
66. Perfect, J.R., and Casadevall, A. (2002) Cryptococcosis. Infect Dis Clin North Am 16: 837-874, v-vi.
67. Perfect, J.R., and Cox, G.M. (1999) Drug resistance in Cryptococcus neoformans. Drug Resist Updat 2: 259-269.
68. Posteraro, B., Sanguinetti, M., Sanglard, D., Sorda, M.L., Boccia, S., Romano, L., etal. (2003) Identification and characterization of a Cryptococcus neoformans ATP binding cassette (ABC) transporter-encoding gene, CnAFR1, involved in the resistance to fluconazole. Mol Microbiol 47: 357-371.
69. Prasad, T., Saini, P., Gaur, N.A., Vishwakarma, R.A., Khan, L.A., Haq, Q.M., and Prasad, R. (2005) Functional analysis of CaIPT1, a sphingolipid biosynthetic gene involved in multidrug resistance and morphogenesis of Candida albicans. Antimicrob Agents Chemother 49: 3442-3452.
70. Roelants, F.M., Torrance, P.D., Bezman, N., and Thorner, J. (2002) Pkh1 and pkh2 differentially phosphorylate and activate ypk1 and ykr2 and define protein kinase modules required for maintenance of cell wall integrity. Mol Biol Cell 13: 3005-3028.
71. Roelants, F.M., Baltz, A.G., Trott, A.E., Fereres, S., and Thorner, J. (2010) A protein kinase network regulates the function of aminophospholipid flippases. Proc Natl Acad Sci USA 107: 34-39.
72. Sanglard, D., and Odds, F.C. (2002) Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2: 73-85.
73. Sanglard, D., Ischer, F., Calabrese, D., Micheli, M., and Bille, J. (1998) Multiple resistance mechanisms to azole antifungals in yeast clinical isolates. Drug Resist Updat 1: 255-265.
74. Selmecki, A., Forche, A., and Berman, J. (2006) Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313: 367-370.
75. Selmecki, A., Gerami-Nejad, M., Paulson, C., Forche, A., and Berman, J. (2008) An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. Mol Microbiol 68: 624-641.
76. Shapiro, R.S., Robbins, N., and Cowen, L.E. (2011) Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol Mol Biol Rev 75: 213-267.
77. Shea, J.M., and Del Poeta, M. (2006) Lipid signaling in pathogenic fungi. Curr Opin Microbiol 9: 352-358.
78. Sionov, E., Chang, Y.C., Garraffo, H.M., and Kwon-Chung, K.J. (2009) Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob Agents Chemother 53: 2804-2815.
79. Sionov, E., Lee, H., Chang, Y.C., and Kwon-Chung, K.J. (2010) Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog 6: e1000848.
80. Sun, Y., Taniguchi, R., Tanoue, D., Yamaji, T., Takematsu, H., Mori, K., etal. (2000) Sli2 (Ypk1), a homologue of mammalian protein kinase SGK, is a downstream kinase in the sphingolipid-mediated signaling pathway of yeast. Mol Cell Biol 20: 4411-4419.
81. Tabuchi, M., Audhya, A., Parsons, A.B., Boone, C., and Emr, S.D. (2006) The phosphatidylinositol 4, 5-biphosphate and TORC2 binding proteins Slm1 and Slm2 function in sphingolipid regulation. Mol Cell Biol 26: 5861-5875.
82. Toffaletti, D.L., Rude, T.H., Johnston, S.A., Durack, D.T., and Perfect, J.R. (1993) Gene transfer in Cryptococcus neoformans by use of biolistic delivery of DNA. J Bacteriol 175: 1405-1411.
83. Torres, J., Di Como, C.J., Herrero, E., and De La Torre-Ruiz, M.A. (2002) Regulation of the cell integrity pathway by rapamycin-sensitive TOR function in budding yeast. J Biol Chem 277: 43495-43504.
84. Tsai, H.F., Krol, A.A., Sarti, K.E., and Bennett, J.E. (2006) Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother 50: 1384-1392.
85. Vanhaesebroeck, B., and Alessi, D.R. (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346 (Part 3): 561-576.
86. Venkateswarlu, K., Taylor, M., Manning, N.J., Rinaldi, M.G., and Kelly, S.L. (1997) Fluconazole tolerance in clinical isolates of Cryptococcus neoformans. Antimicrob Agents Chemother 41: 748-751.
87. White, T.C., Holleman, S., Dy, F., Mirels, L.F., and Stevens, D.A. (2002) Resistance mechanisms in clinical isolates of Candida albicans. Antimicrob Agents Chemother 46: 1704-1713.
88. Wilkinson, M.G., Pino, T.S., Tournier, S., Buck, V., Martin, H., Christiansen, J., etal. (1999) Sin1: an evolutionarily conserved component of the eukaryotic SAPK pathway. EMBO J 18: 4210-4221.
89. Wu, M., Holowka, D., Craighead, H.G., and Baird, B. (2004) Visualization of plasma membrane compartmentalization with patterned lipid bilayers. Proc Natl Acad Sci USA 101: 13798-13803.
90. Zhao, X., Mehrabi, R., and Xu, J.R. (2007) Mitogen-activated protein kinase pathways and fungal pathogenesis. Eukaryot Cell 6: 1701-1714.
91. Zonios, D.I., and Bennett, J.E. (2008) Update on azole antifungals. Semin Respir Crit Care Med 29: 198-210.