Advertisement

Candida albicans Ssa: An Hsp70 Homologue and Virulence Factor

  • Sumant Puri
  • Mira Edgerton
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 7)

Abstract

Candida albicans is a member of the normal oral and gut microbiota and is also an opportunistic pathogen causing oral and genital infections in humans. Two of the Hsp70 proteins of this organism, Ssa 1 and Ssa 2, show unusual biological actions, presumably moonlighting actions, which contribute to the interaction of this yeast with its host. Both Ssa 1/2 are found on the outer surface of the fungus and this location provides novel functions for these proteins. It also appears to be an Achilles heel of this fungus. The Hsp70 proteins are highly immunogenic and so the surface location of Ssa 1/2 makes a good immunological target for innate and adaptive immune responses to this organism and also suggests these proteins could be vaccine candidates. Surprisingly, Ssa 1/2 binds to the antifungal peptide Histatin (Hst) 5 and enables this toxic molecule to be taken up by the yeast causing cell death. In spite of these findings, C. albicans lacking Ssa 1, but not Ssa 2, were significantly less virulent in infected mice and this was related to the loss of invasiveness of this fungus. Thus these Hsp70 proteins play unexpected roles in the lifestyle of C. albicans.

Keywords

Heat Shock Protein Hsp70 Protein Heat Shock Response Client Protein Oral Candidiasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Bromuro C, La Valle R, Sandini S, Urbani F, Ausiello CM, Morelli L et al (1998) A 70-kilodalton recombinant heat shock protein of Candida albicans is highly immunogenic and enhances systemic murine candidiasis. Infect Immun 66:2154–2162PubMedGoogle Scholar
  2. Burnie JP, Carter TL, Hodgetts SJ, Matthews RC (2006) Fungal heat-shock proteins in human disease. FEMS Microbiol Rev 30:53–88PubMedCrossRefGoogle Scholar
  3. Chaffin WL, Lopez-Ribot JL, Casanova M, Gozalbo D, Martinez JP (1998) Cell wall and secreted proteins of Candida albicans: identification, function, and expression. Microbiol Mol Biol Rev 62:130–180PubMedGoogle Scholar
  4. 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:e1002562PubMedCrossRefGoogle Scholar
  5. Dubaquie Y, Looser R, Rospert S (1997) Significance of chaperonin 10-mediated inhibition of ATP hydrolysis by chaperonin 60. Proc Natl Acad Sci U S A 94:9011–9016PubMedCrossRefGoogle Scholar
  6. Eroles P, Sentandreu M, Elorza MV, Sentandreu R (1995) Cloning of a DNA fragment encoding part of a 70-kDa heat shock protein of Candida albicans. FEMS Microbiol Lett 128:95–100PubMedCrossRefGoogle Scholar
  7. Gomez FJ, Gomez AM, Deepe GS (1992) An 80-kilodalton antigen from Histoplasma capsulatum that has homology to heat shock protein 70 induces cell-mediated immune responses and protection in mice. Infect Immun 60:2565–2571PubMedGoogle Scholar
  8. Imamura Y, Fujigaki Y, Oomori Y, Usui S, Wang PL (2009) Cooperation of salivary protein histatin 3 with heat shock cognate protein 70 relative to the G1/S transition in human gingival fibroblasts. J Biol Chem 284:14316–14325PubMedCrossRefGoogle Scholar
  9. Jaya N, Garcia V, Vierling E (2009) Substrate binding site flexibility of the small heat shock protein molecular chaperones. Proc Natl Acad Sci U S A 106:15604–15609PubMedCrossRefGoogle Scholar
  10. Koshlukova SE, Lloyd TL, Araujo MW, Edgerton M (1999) Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. J Biol Chem 274:18872–18879PubMedCrossRefGoogle Scholar
  11. Koshlukova SE, Araujo MW, Baev D, Edgerton M (2000) Released ATP is an extracellular cytotoxic mediator in salivary histatin 5-induced killing of Candida albicans. Infect Immun 68:6848–6856PubMedCrossRefGoogle Scholar
  12. Kragol G, Lovas S, Varadi G, Condie BA, Hoffmann R, Otvos L (2001) The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry 40:3016–3026PubMedCrossRefGoogle Scholar
  13. La Valle R, Bromuro C, Ranucci L, Muller HM, Crisanti A, Cassone A (1995) Molecular cloning and expression of a 70-kilodalton heat shock protein of Candida albicans. Infect Immun 63:4039–4045PubMedGoogle Scholar
  14. LaFayette SL, Collins C, Zaas AK, Schell WA, Betancourt-Quiroz M, Gunatilaka AA, Perfect JR, Cowen LE (2010) PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90. PLoS Pathog 6:e1001069PubMedCrossRefGoogle Scholar
  15. Li XS, Reddy MS, Baev D, Edgerton M (2003) Candida albicans Ssa 1/2p is the cell envelope binding protein for human salivary histatin 5. J Biol Chem 278:28553–28561PubMedCrossRefGoogle Scholar
  16. Li XS, Sun JN, Okamoto-Shibayama K, Edgerton M (2006) Candida albicans cell wall ssa proteins bind and facilitate import of salivary histatin 5 required for toxicity. J Biol Chem 281:22453–22463PubMedCrossRefGoogle Scholar
  17. Lopez-Ribot JL, Chaffin WL (1996) Members of the Hsp70 family of proteins in the cell wall of Saccharomyces cerevisiae. J Bacteriol 178:4724–4726PubMedGoogle Scholar
  18. Lopez-Ribot JL, Alloush HM, Masten BJ, Chaffin WL (1996) Evidence for presence in the cell wall of Candida albicans of a protein related to the hsp70 family. Infect Immun 64:3333–3340PubMedGoogle Scholar
  19. Mattaj IW, Englmeier L (1998) Nucleocytoplasmic transport: the soluble phase. Annu Rev Biochem 67:265–306PubMedCrossRefGoogle Scholar
  20. Mayer FL, Wilson D, Jacobsen ID, Miramon P, Slesiona S, Bohovych IM et al (2012) Small but crucial: the novel small heat shock protein Hsp21 mediates stress adaptation and virulence in Candida albicans. PLoS One 7:e38584PubMedCrossRefGoogle Scholar
  21. Melchior F, Gerace L (1995) Mechanisms of nuclear protein import. Curr Opin Cell Biol 7:310–318PubMedCrossRefGoogle Scholar
  22. Okuno Y, Imamoto N, Yoneda Y (1993) 70-kDa heat-shock cognate protein colocalizes with karyophilic proteins into the nucleus during their transport in vitro. Exp Cell Res 206:134–142PubMedCrossRefGoogle Scholar
  23. Otvos L Jr, Insug O, Rogers ME, Consolvo PJ, Condie BA, Lovas S et al (2000) Interaction between heat shock proteins and antimicrobial peptides. Biochemistry 39:14150–14159Google Scholar
  24. Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294PubMedCrossRefGoogle Scholar
  25. Peisker K, Chiabudini M, Rospert S (2010) The ribosome-bound Hsp70 homolog Ssb of Saccharomyces cerevisiae. Biochim Biophys Acta 1803:662–672PubMedCrossRefGoogle Scholar
  26. Quan X, Rassadi R, Rabie B, Matusiewicz N, Stochaj U (2004) Regulated nuclear accumulation of the yeast hsp70 Ssa 4p in ethanol-stressed cells is mediated by the N-terminal domain, requires the nuclear carrier Nmd5p and protein kinase C. FASEB J 18:899–901PubMedGoogle Scholar
  27. Robbins N, Leach MD, Cowen LE (2012) Lysine deacetylases Hda1 and Rpd3 regulate Hsp90 function thereby governing fungal drug resistance. Cell Rep 2:878–888PubMedCrossRefGoogle Scholar
  28. Rutherford SL, Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396:336–342PubMedCrossRefGoogle Scholar
  29. Sales K, Brandt W, Rumbak E, Lindsey G (2000) The LEA-like protein HSP 12 in Saccharomyces cerevisiae has a plasma membrane location and protects membranes against desiccation and ethanol-induced stress. Biochim Biophys Acta 1463:267–278PubMedCrossRefGoogle Scholar
  30. Senn H, Shapiro RS, Cowen LE (2012) Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans. Mol Biol Cell 23:268–283PubMedCrossRefGoogle Scholar
  31. 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 19:621–629PubMedCrossRefGoogle Scholar
  32. Shi Y, Thomas JO (1992) The transport of proteins into the nucleus requires the 70-kilodalton heat shock protein or its cytosolic cognate. Mol Cell Biol 12:2186–2192PubMedGoogle Scholar
  33. Shulga N, Roberts P, Gu Z, Spitz L, Tabb MM, Nomura M et al (1996) In vivo nuclear transport kinetics in Saccharomyces cerevisiae: a role for heat shock protein 70 during targeting and translocation. J Cell Biol 135:329–339PubMedCrossRefGoogle Scholar
  34. Shulga N, James P, Craig EA, Goldfarb DS (1999) A nuclear export signal prevents Saccharomyces cerevisiae Hsp70 Ssb1p from stimulating nuclear localization signal-directed nuclear transport. J Biol Chem 274:16501–16507PubMedCrossRefGoogle Scholar
  35. 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:e1000532PubMedCrossRefGoogle Scholar
  36. Sun JN, Li W, Jang WS, Nayyar N, Sutton MD, Edgerton M (2008) Uptake of the antifungal cationic peptide Histatin 5 by Candida albicans Ssa 2p requires binding to non-conventional sites within the ATPase domain. Mol Microbiol 70:1246–1260PubMedCrossRefGoogle Scholar
  37. Sun JN, Solis NV, Phan QT, Bajwa JS, Kashleva H, Thompson A et al (2010) Host cell invasion and virulence mediated by Candida albicans Ssa 1. PLoS Pathog 6:e1001181PubMedCrossRefGoogle Scholar
  38. Vylkova S, Li XS, Berner JC, Edgerton M (2006) Distinct antifungal mechanisms: beta-defensins require Candida albicans Ssa 1 protein, while Trk1p mediates activity of cysteine-free cationic peptides. Antimicrob Agents Chemother 50:324–331PubMedCrossRefGoogle Scholar
  39. Welker S, Rudolph B, Frenzel E, Hagn F, Liebisch G, Schmitz G et al (2010) Hsp12 is an intrinsically unstructured stress protein that folds upon membrane association and modulates membrane function. Mol Cell 39:507–520PubMedCrossRefGoogle Scholar
  40. Young JC, Moarefi I, Hartl FU (2001) Hsp90: a specialized but essential protein-folding tool. J Cell Biol 154:267–273PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Oral Biology, School of Dental MedicineState University of New York at BuffaloBuffaloUSA

Personalised recommendations