Heat Shock Protein 90: Truly Moonlighting!

  • Eusebio S. PiresEmail author
Part of the Heat Shock Proteins book series (HESP, volume 13)


Hsp90 is an essential and abundantly expressed molecular chaperone in any living cell. The multiplicity of Hsp90 cellular functions is driven by its interaction with a broad range of partner proteins and thereby establishing itself as a moonlighting molecule. There are newer insights emerging to ascertain the cellular and physiological roles of Hsp90, such as (and not limited to) chromatin remodeling, gene regulation and developmental pathways. Hsp90 has been recognized as an important therapeutic target and has been linked to an increasing number of diseases, including cancer. Development of Hsp90 therapeutic reagents would be valuable research tools towards the maintenance of the proteome in health and disease. This review revisits the expression, structure-function, and clinical significance of the Hsp90 and its forms and reinforces its impact as a disease target.


Hsp90 Hsp90 diversity HSPC Moonlighting roles Therapeutic candidate 



Anti-ovarian antibodies


Eggs, germinal vesicle breakdown oocyte


Heat shock proteins




In vitro fertilization- embryo transfer


Liquid chromatography/mass spectrometry


Matrix-assisted laser desorption/ionization time-of-flight/time-of-flight


Premature ovarian failure


Primary ovarian insufficiency



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 who mentored him during the course of his graduate degree. The author thanks the journal Fertility & Sterility for permitting reproduction of one figure from his previously published work [Fig. 12.4. Panel B2 and B5 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]. Thank you to the journal of Reproductive Biology and Endocrinology for allowing him to reproduce one figure from his earlier work [Fig. 12.1a of Pires ES, Choudhury AK, Idicula-Thomas S, and 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].


  1. Bardwell, J. C. A., & Craig, E. A. (1987). Eukaryotic Mr 83,000 heat shock protein has a homologue in Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America, 84, 5177–5181.CrossRefGoogle Scholar
  2. Bensaude, O., & Morange, M. (1983). Spontaneous high expression of heat-shock proteins in mouse embryonal carcinoma cells and ectoderm from day 8 mouse embryo. The EMBO Journal, 2, 173–177.PubMedPubMedCentralGoogle Scholar
  3. Cardillo, M. R., & Ippoliti, F. (2006). IL-6, IL-10 and HSP-90 expression in tissue microarrays from human prostate cancer assessed by computer-assisted image analysis. Anticancer Research, 26, 3409–3416.PubMedGoogle Scholar
  4. Chadli, A., Graham, J. D., Abel, M. G., et al. (2006). GCUNC45 is a novel regulator for the progesterone receptor/Hsp90 chaperoning pathway. Molecular and Cellular Biology, 26(5), 1722–1730.CrossRefGoogle Scholar
  5. Chadli, A., Felts, S. J., & Toft, D. O. (2008). GCUNC45 is the first Hsp90 co-chaperone to show α/β isoform specificity. Journal of Biological Chemistry, 283(15), 9509–9512.CrossRefGoogle Scholar
  6. Choudhury, A., & Khole, V. V. (2013). Hsp90 antibodies: a detrimental factor responsible for ovarian dysfunction. American Journal of Reproductive Immunology, 70(5), 372–385.PubMedGoogle Scholar
  7. Cornford, P. A., et al. (2000). Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Research, 60, 7099–7105.PubMedGoogle Scholar
  8. Csermely, P., Schnaider, T., Soti, C., Prohaszka, Z., & Nardai, G. (1998). The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacology & Therapeutics, 79, 129–168.CrossRefGoogle Scholar
  9. Elpek, G. O., Karaveli, S., Simsek, T., Keles, N., & Aksoy, N. H. (2003). Expression of heat-shock proteins Hsp27, Hsp70 and Hsp90 in malignant epithelial tumour of the ovaries. APMIS, 111, 523–530.CrossRefGoogle Scholar
  10. Falsone, F. S., Bernd, G., Florian, T., Anna-Maria, P., Andreas, J., & Kung, l. (2005). A proteomic snapshot of the human heat shock protein 90 interactome. FEBS Letters, 579, 6350–6354.CrossRefGoogle Scholar
  11. Fecek, R. J., Simeng, W., & Walter, J. S. (2015). Immunotherapeutic targeting of Hsp90 client proteins in BRAF-inhibitor resistant melanoma. Journal for ImmunoTherapy of Cancer, 3(Suppl2), 432.CrossRefGoogle Scholar
  12. Gallucci, S., & Matzinger, P. (2001). Danger signals: SOS to the immune system. Current Opinion in Immunology, 13, 114–119.CrossRefGoogle Scholar
  13. Grad, I., Cederroth, C. R., Walicki, J., et al. (2010). The molecular chaperone Hsp90α is required for meiotic progression of spermatocytes beyond pachytene in the mouse. PLoS One, 5(12), e15770.CrossRefGoogle Scholar
  14. Gruppi, C. M., Zakeri, Z. F., & Wolgemuth, D. J. (1991). Stage and lineage-regulated expression of two hsp90 transcripts during mouse germ cell differentiation and embryogenesis. Molecular Reproduction and Development, 28(3), 209–217.CrossRefGoogle Scholar
  15. Gupta, R. S. (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. Molecular Biology and Evolution, 12, 1063–1073.PubMedGoogle Scholar
  16. 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 and Tissue Research, 154, 443–470.CrossRefGoogle Scholar
  17. Kajiwara, C., Kondo, S., Uda, S., et al. (2012). Spermatogenesis arrest caused by conditional deletion of Hsp90α in adult mice. Biology Open, 1(10), 977–982.CrossRefGoogle Scholar
  18. Kampinga, H. H., Hageman, J., Vos, M. J., Kubota, H., Tanguay, R. M., Bruford, E. A., et al. (2009). Guidelines for the nomenclature of the human heat shock proteins. Cell Stress & Chaperones, 14(1), 105–111.CrossRefGoogle Scholar
  19. Karras, G. I., Song, Y., Sahni, N., Máté, F., Jenny, X., Marc, V., Alan, D., Luke, W., & Lindquist, S. (2017). Hsp90 shapes the consequences of human genetic variation. Cell, 168(5), 856–866.CrossRefGoogle Scholar
  20. Lele, Z., Hartson, S. D., Martin, C. C., Whitesell, L., Matts, R. L., & Krone, P. H. (1999). Developmental Biology, 210, 56–70.CrossRefGoogle Scholar
  21. Li, J., Soroka, J., & Buchner, J. (2012). The Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 1823(3), 624–635.CrossRefGoogle Scholar
  22. Li, K., Xue, Y., Chen, A., Jiang, Y., Xie, H., Shi, Q., et al. (2014). Heat shock protein 90 has roles in intracellular calcium homeostasis, protein tyrosine phosphorylation regulation, and progesterone-responsive sperm function in human sperm. PLoS One, 9(12), e115841.CrossRefGoogle Scholar
  23. Loones, M. T., Rallu, M., Mezger, V., & Morange, M. (1997). HSP gene expression and HSF2 in mouse development. Cellular and Molecular Life Sciences, 53, 179–190.CrossRefGoogle Scholar
  24. Mbofung, R. M., McKenzie, J. A., Malu, S., et al. (2017). Hsp90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nature Communications, 8, 451.CrossRefGoogle Scholar
  25. Millson, S. H., Truman, A. W., Racz, A., et al. (2007). Expressed as the sole Hsp90 of yeast, the α and β isoforms of human Hsp90 differ with regard to their capacities for activation of certain client proteins, whereas only Hsp90β generates sensitivity to the Hsp90 inhibitor radicicol. The FEBS Journal, 274(7), 4453–4463.CrossRefGoogle Scholar
  26. Miyake, H., Muramaki, M., Kurahashi, T., Takenaka, A., & Fujisawa, M. (2010). Expression of potential molecular markers in prostate cancer: Correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. Urologic Oncology, 28, 145–151.CrossRefGoogle Scholar
  27. Morimoto, R. I. (1993). Cells in stress: Transcriptional activation of heat shock genes. Science, 259(5100), 1409–1410.CrossRefGoogle Scholar
  28. Pacey, S., et al. (2012). A phase II trial of 17-allylamino, 17-demethoxygeldanamycin [17-AAG, tanespimycin] in patients with metastatic melanoma. Investigational New Drugs, 30, 341–349.CrossRefGoogle Scholar
  29. Pick, E., et al. (2007). High Hsp90 expression is associated with decreased survival in breast cancer. Cancer Research, 67, 2932–2937.CrossRefGoogle Scholar
  30. Pires, E. S. (2010). Multiplicity of molecular and cellular targets in human ovarian autoimmunity an update. Journal of Assisted Reproduction and Genetics, 27, 519–524.CrossRefGoogle Scholar
  31. Pires, E. S. (2017). The Unmysterious roles of Hsp90: Ovarian pathology and autoantibodies. In D. MacPhee (Ed.), The Role of Heat Shock Proteins in Reproductive System Development and Function, Advances in Anatomy, Embryology and Cell Biology (Vol. 222, pp. 29–44). Springer.CrossRefGoogle Scholar
  32. Pires, E. S., & Khole, V. V. (2009a). A ‘block’ in the road to fertility: Autoantibodies to an immunodominant heat shock protein 90-beta in human ovarian autoimmunity. Fertility and Sterility, 92, 1395–1409.CrossRefGoogle Scholar
  33. Pires, E. S., & Khole, V. V. (2009b). Anti- ovarian antibodies: Specificity, prevalence, multipleantigenicity and significance in human ovarian autoimmunity. In Current Paradigm of Reprod Immunol (pp. 159–190). Trivandrum: Research signpost Trivandrum. ISBN: 978-81-308-0373-9.Google Scholar
  34. Pires, E. S., Parte, P. P., Meherji, P. K., Khan, S. A., & Khole, V. V. (2006). Naturally occurring anti-albumin antibodies are responsible for false positivity in diagnosis of autoimmune premature ovarian failure. The Journal of Histochemistry and Cytochemistry, 54(4), 397–405.CrossRefGoogle Scholar
  35. Pires, E. S., Meherji, P. K., Vaidya, R. R., Parikh, F. R., Ghosalkar, M. N., & Khole, V. V. (2007). Specific and sensitive immunoassays detect multiple anti-ovarian antibodies in women with infertility. The Journal of Histochemistry and Cytochemistry, 55(12), 1181–1190.CrossRefGoogle Scholar
  36. Pires, E. S., Choudhury, A. K., Idicula-Thomas, S., & Khole, V. V. (2011a). Anti-Hsp90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380–389) of Hsp90 beta protein. Reproductive Biology and Endocrinology, 9, 16.CrossRefGoogle Scholar
  37. Pires, E. S., Parikh, F. R., Mande, P. V., Uttamchandani, S. A., Savkar, S., & Khole, V. V. (2011b). Can anti-ovarian antibody testing be useful in an IVF-ET clinic? Journal of Assisted Reproduction and Genetics, 28(1), 55–64.CrossRefGoogle Scholar
  38. Pires, E. S., Hlavin, C., Macnamara, E., Ishola-Gbenla, K., Doerwaldt, C., Chamberlain, C., Klotz, K., Herr, A. K., Khole, A., Chertihin, O., Curnow, E., Feldman, S. H., Mandal, A., Shetty, J., Flickinger, C., & Herr, J. C. (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. Developmental Dynamics, 242, 1405–1426.CrossRefGoogle Scholar
  39. Pires, E. S., D’Souza, R., Needham, M., Herr, A., Jazaeri, A., Li, H., Stoler, M., Anderson-Knapp, K., Thomas, T., Mandal, A., Gougeon, A., Flickinger, C., Bruns, D., Pollok, B., & Herr, J. C. (2015). Membrane associated cancer-oocyte neoantigen SAS1B/ovastacin is a candidate immunotherapeutic target for uterine tumors. Oncotarget, 6(30), 30194–30211.CrossRefGoogle Scholar
  40. Purandhar, K., Jena, P. K., Prajapati, B., Rajput, P., & Seshadri, S. (2014). Understanding the role of heat shock protein Isoforms in male fertility, Aging and Apoptosis. The World Journal of Men’s Health, 32(3), 123–132.CrossRefGoogle Scholar
  41. Röhl, A., Rohrberg, J., & Buchner, J. (2013). The chaperone Hsp90: Changing partners for demanding clients. Trends in Biochemical Sciences, 38(5), 253–262.CrossRefGoogle Scholar
  42. Schopf, H. F., Maximilian, M. B., & Johannes, B. (2017). The Hsp90 chaperone machinery. Nature Reviews Molecular Cell Biology, 18, 345–360.CrossRefGoogle Scholar
  43. Solit, D. B., et al. (2008). Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clinical Cancer Research, 14, 8302–8307.CrossRefGoogle Scholar
  44. Sreedhar, S. A., Kalmar, E., Csermely, P., & Shen, Y. F. (2004). Hsp90 isoforms: functions, expression and clinical importance. FEBS Letters, 562, 11–15.CrossRefGoogle Scholar
  45. Website: Scholar
  46. Website: Scholar
  47. Voss, A. K., Thomas, T., & Gruss, P. (2000). Development, 127, 1–11.PubMedGoogle Scholar
  48. Witkin, S. S., Sultan, K. M., Neal, G. S., et al. (1994). Unsuspected Chlamydia trachomatis infections in the female genital tract and in vitro fertilization outcome. American Journal of Obstetrics and Gynecology, 171, 1208–1214.CrossRefGoogle Scholar
  49. Zuehlke, A., & Johnson, J. L. (2010). Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers, 93(3), 211–217.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Obstetrics & Gynecology at the School of MedicineUniversity of VirginiaVirginiaUSA

Personalised recommendations