Skip to main content
SpringerLink
Log in

The Unmysterious Roles of HSP90: Ovarian Pathology and Autoantibodies

  • Chapter
  • First Online:
The Role of Heat Shock Proteins in Reproductive System Development and Function

Part of the book series: Advances in Anatomy, Embryology and Cell Biology ((ADVSANAT,volume 222))

Abstract

The heat shock proteins (HSPs) are a group of evolutionarily conserved proteins with important physiological functions, whose synthesis is enhanced by elevated temperature or other stresses. HSPs show high sequence homology between different species, from bacteria to humans. Despite the significant degree of evolutionary conservation, HSPs are highly immunogenic. Of the several HSPs, HSP90 is an abundant, constitutively expressed chaperone constituting around 1–2% of total cellular protein under non-stress conditions. This protein from even the most distantly related eukaryotes has 50% amino acid identity, and all have more than 40% identity with the Escherichia coli protein. They are immunodominant antigens for many common microbes, and thus their epitopes are recognized by the immune system. As HSPs are overexpressed at sites of acute and chronic inflammation, individuals are likely to be sensitized during the course of a microbial infection encountered during life. This chapter considers the evidence of a role for HSP90 in autoimmune ovarian failure, where autoantibodies to it have been observed in patients, and has been correlated to infertility.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahonen P, Miettinen A, Perheentupa J (1987) Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. J Clin Endocrinol Metab 64:494–500

    Article  CAS  PubMed  Google Scholar 

  • Anasti JN (1998) Premature ovarian failure: an update. Fertil Steril 70:1–15

    Article  CAS  PubMed  Google Scholar 

  • Barbarino PM, Forges T, Faure GC, Bene MC (2005) Gonadal antibodies interfering with female reproduction. Best Pract Res Clin Endocrinol Metab 19(1):135–148

    Article  Google Scholar 

  • Bardwell JCA, Craig EA (1987) Eukaryotic Mr 83,000 heat shock protein has a homologue in Escherichia coli. Proc Natl Acad Sci USA 84:5177–5181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bensaude O, Morange M (1983) Spontaneous high Expression of heat-shock proteins in mouse embryonal carcinoma cells and ectoderm from day 8 mouse embryo. EMBO J 2:173–177

    CAS  PubMed  PubMed Central  Google Scholar 

  • Betterle C, Pra D, Mantero F, Zanchetta R (2002) Autoimmune adrenal insufficiency and autoimmune polyendocrinopathy syndromes: auto antibodies, auto antigens and their applicability in diagnosis and disease prediction. Endocr Rev 23:327–364

    Article  CAS  PubMed  Google Scholar 

  • Biswas S, Sharma YD (1994) Enhanced expression of Plasmodium falciparum heat shock protein PFHSP70-1 at higher temperatures and parasite survival. FEMS Microbiol Lett 124:425–430

    Article  CAS  PubMed  Google Scholar 

  • Calvert ME, Digilio LC, Herr JC, Coonrod SA (2003) Oolemmal proteomics identification of highly abundant heat shock proteins and molecular chaperones in the mature mouse egg and their localization on the plasma membrane. Reprod Biol Endocrinol 1:27

    Article  PubMed  PubMed Central  Google Scholar 

  • Choudhury A, Khole VV (2013) HSP90 antibodies: a detrimental factor responsible for ovarian dysfunction. Am J Reprod Immunol 70(5):372–385

    CAS  PubMed  Google Scholar 

  • Coulam CB, Adamson SC, Annegers JF (1986) Incidence of premature ovarian failure. Obstet Gynecol 67:604–606

    CAS  PubMed  Google Scholar 

  • Cusick ME, Klitgord N, Vidal M, Hill DE (2005) Interactome: gateway into systems biology. Hum Mol Genet 14(Spec No. 2): R171–81

    Google Scholar 

  • Czar MJ, Welsh MJ, Pratt WB (1996) Immunofluorescence localization of the 90-kDa heat-shock protein to cytoskeleton. Eur J Cell Biol 70(4):322–330

    CAS  PubMed  Google Scholar 

  • Damewood MD, Zacur HA, Hoffman GJ, Rock JA (1986) Circulating antiovarian antibodies in premature ovarian failure. Obstet Gynecol 68:850–854

    CAS  PubMed  Google Scholar 

  • de Moraes-Ruehsen H, Jones GS (1967) Premature ovarian failure. Fertil Steril 18:440–461

    Article  PubMed  Google Scholar 

  • Eustace BK, Jay DG (2004) Extracellular roles for the molecular chaperone, HSP90. Cell Cycle 3(9):1098–1100

    Article  CAS  PubMed  Google Scholar 

  • Falsone SF, Gesslbauer B, Tirk F, Piccinini AM, Kungl AJ (2005) A proteomic snapshot of the human heat shock protein 90 interactome. FEBS Lett 579(28):6350–6354

    Article  CAS  PubMed  Google Scholar 

  • Faulds G, Conroy S, Madaio M, Isenberg D, Latchman D (1995) Increased levels of antibodies to heat shock proteins with increasing age in MRL/MP-LPR mice. Br J Rheumatol 34:610–615

    Article  CAS  PubMed  Google Scholar 

  • Fenichel P, Sosset C, Barbarino-Monnier P, Bene MC, Hieronimus S, Harter M (1997) Prevalence, specificity and significance of ovarian antibodies during spontaneous premature ovarian failure. Hum Reprod 12(12):2623–2628

    Article  CAS  PubMed  Google Scholar 

  • Forges T, Monnier-Barbarino P, Faure GC, Bene MC (2004) Autoimmunity and antigenic targets in ovarian pathology. Hum Reprod Update 10(2):163–175

    Article  CAS  PubMed  Google Scholar 

  • Gallucci S, Matzinger P (2001) Danger signals: SOS to the immune system. Curr Opin Immunol 13:114–119

    Article  CAS  PubMed  Google Scholar 

  • Gruppi CM, Zakeri ZF, Wolgemuth DJ (1991) Stage and lineage-regulated expression of two HSP90 transcripts during mouse germ cell differentiation and embryogenesis. Mol Reprod Dev 28:209–217

    Article  CAS  PubMed  Google Scholar 

  • Gupta RS (1995) Phylogenetic analysis of the 90 kD heat shock family of protein sequences and an examination of the relationship among animals, plants, and fungi species. Mol Biol Evol 12:1063–1073

    CAS  PubMed  Google Scholar 

  • Hayem G, De Bandt M, Palazzo E, Roux S, Combe B, Eliaou JF et al (1999) Anti-heat shock protein 70 kDa and 90-kd antibodies in serum of patients with rheumatoid arthritis. Ann Rheum Dis 58:292–296

    Article  Google Scholar 

  • Hilscher B, Hilscher W, Bulthoff-Ohnolz B, Kramer U, Birke A, Pelzer H, Gauss G (1974) Kinetics of gametogenesis. I. Comparative histological and autoradiographic studies of oocytes and transitional prospermatogonia during oogenesis and prespermatogenesis. Cell Tissue Res 154:443–470

    Article  CAS  PubMed  Google Scholar 

  • Hoek A, Schoemaker J, Drexhage HA (1997) Premature ovarian failure and ovarian autoimmunity. Endocr Rev 18:107–134

    CAS  PubMed  Google Scholar 

  • Kellermayer MS, Csermely P (1995) ATP induces dissociation of the 90 kDa heat shock protein (HSP90) from F-actin: interference with the binding of heavy meromyosin. Biochem Biophys Res Commun 211(1):166–174

    Article  CAS  PubMed  Google Scholar 

  • Khole V, Mande P, Choudhary A, Pires E (2012) Validation of novel candidate biomarkers for diagnosis of ovarian autoimmunity. Advances in developing affordable in vitro molecular diagnostics. Yashraj research foundation and Mahatma Gandhi Mission University, pp 139–151

    Google Scholar 

  • Koyasu S, Nishida E, Kadowaki T, Matsuzaki F, Iida K, Harada F, Kasuga M, Sakai H, Yahara I (1986) Two mammalian heat shock proteins, HSP90 and HSP100, are actin-binding proteins. Proc Natl Acad Sci USA 83(21):8054–8058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Latchman DS, Isenberg DA (1994) The role of HSP90 in SLE. Autoimmunity 19(3):211–218

    Article  CAS  PubMed  Google Scholar 

  • Lele Z, Hartson SD, Martin CC, Whitesell L, Matts RL, Krone PH (1999) Disruption of zebrafish somite development by pharmacologic inhibition of Hsp90. Dev Biol 210:56–70

    Article  CAS  PubMed  Google Scholar 

  • Lernmark A (2001) Series introduction: autoimmune diseases: are markers ready for prediction? J Clin Investig 108(8):1091–1096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindquist S, Craig EA (1988) The heat shock proteins. Annu Rev Genet 22:631–677

    Article  CAS  PubMed  Google Scholar 

  • Loktionova SA, Ilyinskaya OP, Gabai VL, Kabakov AE (1996) Distinct effects of heat shock and ATP depletion on distribution and isoform patterns of human Hsp27 in endothelial cells. FEBS Lett 392(2):100–104

    Article  CAS  PubMed  Google Scholar 

  • Loones MT, Rallu M, Mezger V, Morange M (1997) HSP gene expression and HSF2 in mouse development. Cell Mol Life Sci 53:179–190

    Article  CAS  PubMed  Google Scholar 

  • Lotz GP, Brychzy A, Heinz S, Obermann WM (2008) A novel HSP90 chaperone complex regu lates intracellular vesicle transport. J Cell Sci 121:717–723

    Article  CAS  PubMed  Google Scholar 

  • Luborsky JL (2002) Ovarian autoimmune disease and ovarian autoantibodies. J Womens Health Gend Based Med 11:585–599

    Article  PubMed  Google Scholar 

  • Mande PV, Parikh FR, Hinduja I, Zaveri K, Vaidya R, Gajbhiye R, Khole VV (2011) Identification and validation of candidate biomarkers involved in human ovarian autoimmunity. Reprod BioMed Online 23(4):471–483

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • Morimoto RI (1993) Cells in stress: transcriptional activation of heat shock genes. Science 259(5100):1409–1410

    Article  CAS  PubMed  Google Scholar 

  • Neuer A, Mele C, Liu HC, Rosenwaks Z, Witkin SS (1998) Monoclonal antibodies to mammalian heat shock proteins impair mouse embryo development in vitro. Hum Reprod 13(4):987–990

    Article  CAS  PubMed  Google Scholar 

  • Neumann S, Ziv E, Lantner F, Schechter I (1993) Regulation of HSP70 gene expression during the life cycle of the parasitic helminth Schistosoma mansoni. FEBS J 212(2):589–596

    Article  CAS  Google Scholar 

  • Novosad JA, Sophia NK, Zhi-Bin T, Nelson LM (2003) Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: a controlled evaluation. BMC Womens Health 3:2

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohsako S, Bunick D, Hayashi Y (1995) Immunocytochemical observation of the 90 KD heat shock protein (HSP90): high expression in primordial and pre-meiotic germ cells of male and female gonads. J Histochem Cytochem 43:67–76

    Article  CAS  PubMed  Google Scholar 

  • Pires ES (2010) Multiplicity of molecular and cellular targets in human ovarian autoimmunity: an update. J Assist Reprod Genet 27:519–524

    Article  PubMed  PubMed Central  Google Scholar 

  • Pires ES, Khole VV (2009a) A ‘block’ in the road to fertility: autoantibodies to an immunodominant heat shock protein 90-beta in human ovarian autoimmunity. Fertil Steril 92:1395–1409

    Article  CAS  PubMed  Google Scholar 

  • Pires ES, Khole VV (2009b) Anti-ovarian antibodies: specificity, prevalence, multiple antigenicity and significance in human ovarian autoimmunity. Current Paradigm of Reproductive Immunology Research signpost, Trivandrum, India, pp 159–190. ISBN: 978–81–308-0373-9

    Google Scholar 

  • Pires ES, Parte PP, Meherji PK, Khan SA, Khole VV (2006) Naturally occurring anti-albumin antibodies are responsible for false positivity in diagnosis of autoimmune premature ovarian failure. J Histochem Cytochem 54(4):397–405

    Article  CAS  PubMed  Google Scholar 

  • Pires ES, Meherji PK, Vaidya RR, Parikh FR, Ghosalkar MN, Khole VV (2007) Specific and sensitive immunoassay detects multiple anti-ovarian antibodies in women with infertility. J Histochem Cytochem 55(12):1181–1190

    Article  CAS  PubMed  Google Scholar 

  • Pires ES, Choudhury AK, Idicula-Thomas S, Khole VV (2011a) Anti-HSP90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380-389) of HSP90 beta protein. Reprod Biol Endocrinol 9:16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pires ES, Parikh FR, Mande PV, Uttamchandani SA, Savkar S, Khole VV (2011b) Can anti-ovarian antibody testing be useful in an IVF-ET clinic? J Assist Reprod Genet 28(1):55–64

    Article  PubMed  Google Scholar 

  • Pires ES, Hlavin C, Macnamara E, Ishola-Gbenla A, Doerwaldt C, Chamberlain C, Klotz K, Herr A, Khole A, Chertihin O, Curnow E, Feldman SH, Mandal A, Shetty J, Flickinger C, Herr JC (2013) SAS1B protein [ovastacin] shows temporal and spatial restriction to oocytes in several eutherian orders and initiates translation at the primary to secondary follicle transition. Dev Dyn 242:1405–1426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Redmond T, Sanchez ER, Bresnick EH, Schlesinger MJ, Toft DO, Pratt WB, Welsh MJ (1989) Immunofluorescence colocalization of the 90-kDa heat-shock protein and microtubules in interphase and mitotic mammalian cells. Eur J Cell Biol 50(1):66–75

    CAS  PubMed  Google Scholar 

  • Ruiz-Arguelles A, Alarcon-Segovia D (2001) Penetration of autoantibodies into living cells, 2000. Isr Med Assoc J 3(2):121–126

    CAS  PubMed  Google Scholar 

  • Schlatter H, Langer T, Rosmus S, Onneken ML, Fasold H (2002) A novel function for the HSP90 kDa heat-shock protein (HSP90): facilitating nuclear export of 60 S ribosomal subunits. Biochem J 362:675–684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sidera K, Gaitanou M, Stellas D, Matsas R, Patsavoudi E (2008) A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2. J Biol Chem 283(4):2031–2041

    Article  CAS  PubMed  Google Scholar 

  • Sreedhar AM, Kalmar E, Csermely P, Shen YF (2004) Hsp90 isoforms: functions, expression and clinical importance. FEBS Lett 562(1–3):11–15

    Article  PubMed  Google Scholar 

  • Sundblad V, Bussmann L, Chiauzzi VA, Pancholi V, Charreau EH (2006) α-enolase: a novel auto antigen in patients with premature ovarian failure. Clin Endocrinol 65:745–751

    Article  CAS  Google Scholar 

  • Te J, Jia L, Rogers J, Miller A, Hartson SD (2007) Novel subunits of the mammalian HSP90 signal transduction chaperone. J Proteome Res 6:1963–1973

    Article  CAS  PubMed  Google Scholar 

  • Trieb K, Gerth R, Holzer G, Grohs JG, Berger P, Kotz R (2000) Antibodies to heat shock protein 90 in osteosarcoma patients correlate with response to neoadjuvant chemotherapy. Br J Cancer 82:85–87

    Article  CAS  PubMed  Google Scholar 

  • Tsaytler PA, Krijgsveld J, Goerdayal SS, Rüdiger S, Egmond MR (2009) Novel Hsp90 partners discovered using complementary proteomic approaches. Cell Stress Chaperones 14(6):629–638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Eden W (1999) Immunity to heat shock proteins and arthritic disorders. Infect Dis Obstet Gynecol 7:49–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Eden W, van der Zee R, van Kooten P, Berlo SE, Cobelens PM, Kavelaars A, Heijnen CJ, Prakken B, Roord S, Albani S (2002) Balancing the immune system: Th1 and Th2. Ann Rheum Dis 61:ii25–ii28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vidal CI, Mintz PJ, Lu K, Ellis LM, Manenti L, Giavazzi R et al (2004) An HSP90-mimic peptide revealed by fingerprinting the pool of antibodies from ovarian cancer patients. Oncogene 23:8859–8867

    Article  CAS  PubMed  Google Scholar 

  • Voss AK, Thomas T, Gruss P (2000) Mice lacking HSP90b fail to develop a placental labyrinth. Development 127:1–11

    CAS  PubMed  Google Scholar 

  • Witkin SS, Sultan KM, Neal GS, Jeremias J, Grifo JA, Rosenwaks Z (1994) Unsuspected Chlamydia trachomatis infections in the female genital tract and in vitro fertilization outcome. Am J Obstet Gynecol 171:1208–1214

    Article  CAS  PubMed  Google Scholar 

  • Zhao R, Kakihara Y, Gribun A, Huen J, Yang G, Khanna M, Costanzo M, Brost RL, Boone C, Hughes TR, Yip CM, Houry WA (2008) Molecular chaperone HSP90 stabilizes Pih1/Nop17 to maintain R2TP complex activity that regulates snoRNA accumulation. J Cell Biol 180:563–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author would like to place on record the timely help received by the journal Fertility & Sterility for permitting reproduction of 2 figures from his previously published work [Fig. 4. Panel B2 and B5 and Fig. 7. Panel B1 of Pires ES and Khole VV. 2009: A ‘block’ in the road to fertility: autoantibodies to an immunodominant heat shock protein 90-beta in human ovarian autoimmunity. Fertility & Sterility 92:1395–1409]. He also thanks the journal of Reproductive Biology and Endocrinology for allowing him to reproduce two figures from his earlier work [Fig. 1A and Fig. 5A of Pires ES, Choudhury AK, Idicula-Thomas S, Khole VV. Anti-HSP90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380–389) of HSP90 beta protein. Reprod Biol Endocrinol. 2011; 9: 16]. The author would also like to place on record his gratitude to his Ph.D. mentor, the late Dr. Vrinda V Khole from the National Institute for Research in Reproductive Health (ICMR), Mumbai, India for giving him the opportunity to explore and conduct research in this field.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, School of Medicine, University of Virginia, 800732, Jordan Hall, Charlottesville, VA, 22908, USA

    Eusebio S. Pires Ph.D.

Authors
  1. Eusebio S. Pires Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eusebio S. Pires Ph.D. .

Editor information

Editors and Affiliations

  1. Dept. of Veterinary Biomed. Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Daniel J. MacPhee

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Pires, E.S. (2017). The Unmysterious Roles of HSP90: Ovarian Pathology and Autoantibodies. In: MacPhee, D. (eds) The Role of Heat Shock Proteins in Reproductive System Development and Function. Advances in Anatomy, Embryology and Cell Biology, vol 222. Springer, Cham. https://doi.org/10.1007/978-3-319-51409-3_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-51409-3_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-51408-6

  • Online ISBN: 978-3-319-51409-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation