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The Candida albicans Hsp90 Chaperone Network Is Environmentally Flexible and Evolutionarily Divergent

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Book cover The Molecular Chaperones Interaction Networks in Protein Folding and Degradation

Part of the book series: Interactomics and Systems Biology ((INTERACTOM,volume 1))

Abstract

The essential molecular chaperone heat shock protein 90 (Hsp90) is a highly conserved protein hub, which modulates the genotype to phenotype translation in animals, plants, and fungi. In doing so, Hsp90 interacts with up to 10 % of the eukaryotic cell’s proteome. In the leading fungal pathogen of humans, Candida albicans, Hsp90 governs virulence, morphogenesis, and drug resistance. While specific Hsp90 clients have been identified and described, a global overview of Hsp90 interactions in this pathogen remained elusive until recently.

Here, we discuss recent advancements in mapping the C. albicans Hsp90 chaperone network. We describe the first Hsp90 genetic interaction network in C. albicans, discuss its divergence from that of its relative Saccharomyces cerevisiae and illustrate how the network informs our understanding of fungal biology, stress responses and virulence. Deciphering the Hsp90 chaperone network holds great promise for the development of suitable measures to combat fungal drug resistance and counter the ever-increasing number of Candida infections.

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Abbreviations

Hsp90:

Heat shock protein 90

GdA:

Geldanamycin (Hsp90 inhibitor)

GO:

Gene ontology

cAMP:

3’-5’-Cyclic adenosine monophosphate

PKA:

Protein kinase A

MAPK:

Mitogen-activated protein kinase

17-AAG:

17-N-allylamino-17-demethoxygeldanamycin

SGA:

Synthetic genetic array

KDAC:

Lysine deacetylase

PPIs:

Protein-protein interactions

TAP:

Tandem affinity purification

CO2:

Carbon dioxide

RPMI:

Roswell Park Memorial Institute medium

UV:

ultraviolet

Sgt1:

Suppressor of G2 allele of skp1

MALDI ToF:

Matrix-assisted laser desorption/ionization Time of Flight

SAGA:

Spt-Ada-Gcn5-acetyltransferase

UTP-C:

U three proteins complex

CUG:

Cysteine Uracil Guanine

References

  1. Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C (2005) The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 41:1232–1239

    Article  PubMed  Google Scholar 

  2. Zilberberg MD, Shorr AF, Kollef MH (2008) Secular trends in candidemia-related hospitalization in the United States, 2000–2005. Infect Control Hosp Epidemiol 29:978–980

    Article  PubMed  Google Scholar 

  3. Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC (2012) Hidden killers: human fungal infections. Sci Transl Med 4:165rv13

    Article  PubMed  Google Scholar 

  4. Pfaller MA, Diekema DJ (2010) Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36:1–53

    Article  PubMed  Google Scholar 

  5. Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554

    Article  PubMed  Google Scholar 

  6. Lupetti A, Danesi R, Campa M, Del Tacca M, Kelly S (2002) Molecular basis of resistance to azole antifungals. Trends Mol Med 8:76–81

    Article  CAS  PubMed  Google Scholar 

  7. Turner MS, Drew RH, Perfect JR (2006) Emerging echinocandins for treatment of invasive fungal infections. Expert Opin Emerg Drugs 11:231–250

    Article  CAS  PubMed  Google Scholar 

  8. Cowen LE (2013) The fungal Achilles’ heel: targeting Hsp90 to cripple fungal pathogens. Curr Opin Microbiol 16:377–384

    Article  CAS  PubMed  Google Scholar 

  9. Nathan DF, Vos MH, Lindquist S (1997) In vivo functions of the Saccharomyces cerevisiae Hsp90 chaperone. PNAS 94:12949–12956

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Young JC, Moarefi I, Hartl FU (2001) Hsp90: a specialized but essential protein-folding tool. J Cell Biol 154:267–273

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Ali MMU, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW et al (2006) Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440:1013–1017

    Article  CAS  PubMed  Google Scholar 

  12. Li J, Buchner J (2013) Structure, function and regulation of the Hsp90 machinery. Biomed J 36:106–117

    Article  PubMed  Google Scholar 

  13. Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294

    Article  CAS  PubMed  Google Scholar 

  14. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772

    Article  CAS  PubMed  Google Scholar 

  15. Sidera K, Patsavoudi E (20134) Hsp90 inhibitors: current development and potential in cancer therapy. Recent Pat Anticancer Drug Discov; 9(1):1–20

    Google Scholar 

  16. Roe SM, Prodromou C, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 42:260–266

    Article  CAS  PubMed  Google Scholar 

  17. Jarosz DF, Lindquist S (2010) Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330:1820–1824

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Wong KSK, Houry WA (2006) Hsp90 at the crossroads of genetics and epigenetics. Cell Res 16:742–749

    Article  CAS  PubMed  Google Scholar 

  19. Queitsch C, Sangster TA, Lindquist S (2002) Hsp90 as a capacitor of phenotypic variation. Nature 417:618–624

    Article  CAS  PubMed  Google Scholar 

  20. Rutherford SL, Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396:336–342

    Article  CAS  PubMed  Google Scholar 

  21. Cowen LE, Lindquist S (2005) Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309:2185–2189

    Article  CAS  PubMed  Google Scholar 

  22. Johnson JL, Brown C (2009) Plasticity of the Hsp90 chaperone machine in divergent eukaryotic organisms. Cell Stress Chaperon 14:83–94

    Article  CAS  Google Scholar 

  23. Swoboda RK, Bertram G, Budge S, Gooday GW, Gow NA, Brown AJ (1995) Structure and regulation of the HSP90 gene from the pathogenic fungus Candida albicans. Infect Immun 63:4506–4514

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Leach MD, Klipp E, Cowen LE, Brown AJP (2012) Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs. Nat Rev Micro 10:693–704

    Article  CAS  Google Scholar 

  25. Bansal PK, Abdulle R, Kitagawa K (2004) Sgt1 associates with Hsp90: an initial step of assembly of the core kinetochore complex. Mol Cell Biol 24:8069–8079.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Dubacq C, Guerois R, Courbeyrette R, Kitagawa K, Mann C (2002) Sgt1p contributes to cyclic AMP pathway activity and physically interacts with the adenylyl cyclase Cyr1p/Cdc35p in budding yeast. Eukaryot Cell 1:568–582

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Rocha CR, Schröppel K, Harcus D, Marcil A, Dignard D, Taylor BN et al (2001) Signaling through adenylyl cyclase is essential for hyphal growth and virulence in the pathogenic fungus Candida albicans. Mol Biol Cell 12:3631–3643

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Shapiro RS, Robbins N, Cowen LE (2011) Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol Mol Biol Rev 75:213–267

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Shapiro RS, Uppuluri P, Zaas AK, Collins C, Senn H, Perfect JR et al (2009) Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA signaling. Curr Biol 19:621–629

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Flom GA, Langner E, Johnson JL (2012) Identification of an Hsp90 mutation that selectively disrupts cAMP/PKA signaling in Saccharomyces cerevisiae. Curr Biol 58:149–163

    CAS  Google Scholar 

  31. Shapiro RS, Zaas AK, Betancourt-Quiroz M, Perfect JR, Cowen LE (2012) The Hsp90 co-chaperone Sgt1 governs Candida albicans morphogenesis and drug resistance. PLoS ONE 7:e44734

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Cowen LE (2008) The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype. Nat Rev Micro 6:187–198

    Article  CAS  Google Scholar 

  33. White TC (1997) The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans. Antimicrob Agents Chemother 1997;41:1488 −14 94

    Google Scholar 

  34. Cowen LE, Singh SD, Köhler JR, Collins C, Zaas AK, Schell WA et al (2009) Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. PNAS 106:2818–2823

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Robbins N, Uppuluri P, Nett J, Rajendran R, Ramage G, Lopez-Ribot JL et al (2011) Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog 7:e1002257

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Singh SD, Robbins N, Zaas AK, Schell WA, Perfect JR, Cowen LE (2009) Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog 5:e1000532

    Article  PubMed Central  PubMed  Google Scholar 

  37. Singh-Babak SD, Babak T, Diezmann S, Hill JA, Xie JL, Chen Y-L et al (2012) Global analysis of the evolution and mechanism of echinocandin resistance in Candida glabrata. PLoS Pathog 8:e1002718

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Cruz MC, Goldstein AL, Blankenship JR, Del Poeta M, Davis D, Cardenas ME et al (2002) Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J 21:546–559

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Imai J, Yahara I (2000) Role of HSP90 in salt stress tolerance via stabilization and regulation of calcineurin. Mol Cell Biol 20:9262–9270

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. LaFayette SL, Collins C, Zaas AK, Schell WA, Betancourt-Quiroz M, Gunatilaka AAL et al (2010) PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90. PLoS Pathog 6:e1001069

    Article  PubMed Central  PubMed  Google Scholar 

  41. Millson SH, Truman AW, King V, Prodromou C, Pearl LH, Piper PW (2005) A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p). Eukaryot Cell 4:849–860

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Gould CM, Kannan N, Taylor SS, Newton AC (2008) The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase c through a conserved PXXP motif in the c-terminal tail. J Biol Chem 284:4921–4935

    Article  PubMed  Google Scholar 

  43. Tong AHY, Lesage G, Bader GD, Ding H, Xu H, Xin X et al (2004) Global mapping of the yeast genetic interaction network. Science 303:808–813

    Article  CAS  PubMed  Google Scholar 

  44. Dobzhansky T. (1946) Genetics of natural populations. xiii. Recombination and variability in populations of Drosophila pseudoobscura. Genetics 31:269–290

    PubMed Central  Google Scholar 

  45. Giaever G, Chu AM, Ni L, Connelly C, Riles L, Veronneau S et al (2002) Functional profiling of the Saccharomyces cerevisiae genome. Nature 418:387–391

    Article  CAS  PubMed  Google Scholar 

  46. Tischler J, Lehner B, Fraser AG (2008) Evolutionary plasticity of genetic interaction networks. Nat Genet 40:390–391

    Article  CAS  PubMed  Google Scholar 

  47. Zhao R, Davey M, Hsu Y-C, Kaplanek P, Tong A, Parsons AB et al (2005) Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the Hsp90 chaperone. Cell 120:715–727

    Article  CAS  PubMed  Google Scholar 

  48. McClellan AJ, Xia Y, Deutschbauer AM, Davis RW, Gerstein M, Frydman J (2007) Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131:121–135

    Article  CAS  PubMed  Google Scholar 

  49. Franzosa EA, Albanèse V, Frydman J, Xia Y, McClellan AJ (2011) Heterozygous yeast deletion collection screens reveal essential targets of Hsp90. PLoS ONE 6:e28211

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Davis DA, Bruno VM, Loza L, Filler SG (2002) Mitchell AP. Candida albicans Mds3p, a conserved regulator of pH responses and virulence identified through insertional mutagenesis. Genetics 162:1573–1581

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Roemer T, Jiang B, Davison J, Ketela T, Veillette K, Breton A et al (2003) Large-scale essential gene identification in Candida albicans and applications to antifungal drug discovery. Mol Microbiol 50:167–181

    Article  CAS  PubMed  Google Scholar 

  52. Xu D, Jiang B, Ketela T, Lemieux S, Veillette K, Martel N et al (2007) Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albicans. PLoS Pathog 3:e92

    Article  PubMed Central  PubMed  Google Scholar 

  53. Diezmann S, Michaut M, Shapiro RS, Bader GD, Cowen LE (2012) Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry. PLoS Genet 8:e1002562

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Wu P-YJ, Ruhlmann C, Winston F, Schultz P (2004) Molecular architecture of the S. cerevisiae SAGA complex. Mol Cell 15:199–208

    Article  CAS  PubMed  Google Scholar 

  56. Pinna LA (2002) Protein kinase CK2: a challenge to canons. J Cell Sci 115:3873–3878

    Article  CAS  PubMed  Google Scholar 

  57. Perez-Fernandez J, Roman A, Las RDeJ, Bustelo XR, Dosil M (2007) The 90S preribosome is a multimodular structure that is assembled through a hierarchical mechanism. Mol Cell Biol 27:5414–5429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Ota A, Zhang J, Ping P, Han J, Wang Y (2010) Specific regulation of noncanonical p38 activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte. Circ Res 106:1404–1412

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Mollapour M, Tsutsumi S, Truman AW, Xu W, Vaughan CK, Beebe K et al (2011) Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity. Mol Cell 41:672–681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Askew C, Sellam A, Epp E, Mallick J, Hogues H, Mullick A et al (2010) The zinc cluster transcription factor Ahr1p directs Mcm1p regulation of Candida albicans adhesion. Mol Microbiol 79:940–953

    Article  PubMed Central  PubMed  Google Scholar 

  61. Homann OR, Dea J, Noble SM, Johnson AD (2009) A phenotypic profile of the Candida albicans regulatory network. PLoS Genet 5:e1000783

    Article  PubMed Central  PubMed  Google Scholar 

  62. Pijnappel WW, Schaft D, Roguev A, Shevchenko A, Tekotte H, Wilm M et al (2001) The S. cerevisiae SET3 complex includes two histone deacetylases, Hos2 and Hst1, and is a meiotic-specific repressor of the sporulation gene program. Gene Dev 15:2991–3004

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Wang A, Kurdistani SK, Grunstein M (2002) Requirement of Hos2 histone deacetylase for gene activity in yeast. Science 298:1412–1414

    Article  CAS  PubMed  Google Scholar 

  64. Hnisz D, Majer O, Frohner IE, Komnenovic V, Kuchler K (2010) The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans. PLoS Pathog 6:e1000889

    Article  PubMed Central  PubMed  Google Scholar 

  65. Robbins N, Leach MD, Cowen LE (2012) Lysine deacetylases Hda1 and Rpd3 regulate Hsp90 function thereby governing fungal drug resistance. Cell Reports 2:878–888

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Suthram S, Sittler T, Ideker T (2005) The plasmodium protein network diverges from those of other eukaryotes. Nature 438:108–112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Taylor JW, Berbee ML (2006) Dating divergences in the fungal tree of life: review and new analyses. Mycologia 98:838–849

    Article  PubMed  Google Scholar 

  68. Odds FC. (1988) Candida and Candidosis. Elsevier Science Health Science Division, 468 p.

    Google Scholar 

  69. Noble SM, French S, Kohn LA, Chen V, Johnson AD (2010) Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nat Genet 42:590–598

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Santos MA, Tuite MF (1995) The CUG codon is decoded in vivo as serine and not leucine in Candida albicans. Nucleic Acids Res 23:1481–1486

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Hickman MA, Zeng G, Forche A, Hirakawa MP, Abbey D, Harrison BD et al (2013) The “obligate diploid” Candida albicans forms mating-competent haploids. Nature 494:55–59

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Stynen B, Van Dijck P, Tournu HA (2010) CUG codon adapted two-hybrid system for the pathogenic fungus Candida albicans. Nucleic Acids Res 38:e184–e184

    Article  PubMed Central  PubMed  Google Scholar 

  73. Kaneko A, Umeyama T, Hanaoka N, Monk BC, Uehara Y, Niimi M (2004) Tandem affinity purification of the Candida albicans septin protein complex. Yeast 21:1025–1033

    Article  CAS  PubMed  Google Scholar 

  74. Palzer S, Bantel Y, Kazenwadel F, Berg M, Rupp S, Sohn K (2013) An expanded genetic code in Candida albicans to study protein-protein interactions in vivo. Eukaryot Cell 12:816–827.

    Google Scholar 

  75. Gavin A-C, Bösche M, Krause R, Grandi P, Marzioch M, Bauer A et al (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415:141–147

    Article  CAS  PubMed  Google Scholar 

  76. Blackwell C, Brown JD (2009) The application of tandem-affinity purification to Candida albicans. Methods Mol Biol 499:133–148

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Genetics, University of Toronto, 1 Kings College Circle, Medical Sciences Building, Room 4268, M5S 1A8, Toronto, ON, Canada

    Leah E. Cowen

  2. Department of Biology and Biochemistry, University of Bath, Claverton Down, 4 South, BA2 7AY, Bath, UK

    Stephanie Diezmann

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  1. Stephanie Diezmann
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  2. Leah E. Cowen
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Correspondence to Leah E. Cowen .

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Editors and Affiliations

  1. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada

    Walid A. Houry

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Diezmann, S., Cowen, L. (2014). The Candida albicans Hsp90 Chaperone Network Is Environmentally Flexible and Evolutionarily Divergent. In: Houry, W. (eds) The Molecular Chaperones Interaction Networks in Protein Folding and Degradation. Interactomics and Systems Biology, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1130-1_8

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