Emerging Role of HSP70 in Human Diseases

  • Anjali Garg
  • Bandana Kumari
  • Manish KumarEmail author
Part of the Heat Shock Proteins book series (HESP, volume 14)


HSP70 are prominent stress proteins, which also act like molecular chaperones. The synthesis of HSP70 increases when the cell is exposed to any form of stress physical, biological or chemical. Under stress conditions, HSP70 recognize and bind to the unstable protein substrates and protect them from denaturation and aggregation. Besides, HSP70 are also essential during normal growth where they assist in folding of nascent proteins, degradation of misfolded and truncated proteins and, in subcellular localizations of proteins and vesicles. Since HSP70 are involved in a plethora of cellular activities, their role been implicated with several pathological diseases primarily related to apoptosis, carcinogenesis, amyloidogenesis. Here, we summarize the current knowledge on the HSP70 and their relevance in diseases such as cancer, diabetes, seizures and many more. Further, the relevance of HSP70 to serve as biomarkers and/or therapeutics in human diseases is also discussed.


Chaperone Heat shock proteins Human disease Protein aggregation Protein refolding Stress 



Alcoholic fatty liver diseases


Apoptosis-inducing factor


Adenosine triphosphate


Death inducing signaling complex


Heat shock protein


Inducible nitric oxide synthase


Matrix metalloproteinase


Nonalcoholic fatty liver diseases


Nucleotide binding domain


Nucleotide exchange factor


Substrate binding domain


Toll-like receptor



The work was supported by grants from Indian Council of Medical Research, India to AG (ICMR JRF: 3/1/3/JRF-2016/LS/HRD-3 (32262) and BK (ICMR SRF: BIC/11(33)/2014). Authors also acknowledge efforts of Dr. Neelja Singhal for critical reading of manuscript.


  1. Boston, R. S., Viitanen, P. V., & Vierling, E. (1996). Molecular chaperones and protein folding in plants. Plant Molecular Biology, 32, 191–222.CrossRefPubMedGoogle Scholar
  2. Chebotareva, N. V., Neprintseva, N. V., Bobkova, I. N., & Kozlovskaia, L. V. (2014). Investigation of 70-kDa heat shock protein in the serum and urine of patients with chronic glomerulonephritis. Terapevticheskiĭ Arkhiv, 86, 18–23.PubMedGoogle Scholar
  3. Colvin, T. A., Gabai, V. L., Gong, J., Calderwood, S. K., Li, H., Gummuluru, S., Matchuk, O. N., Smirnova, S. G., Orlova, N. V., Zamulaeva, I. A., et al. (2014). Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Research, 74, 4731–4740.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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
  5. De Jong, W. W., Caspers, G. J., & Leunissen, J. A. (1998). Genealogy of the alpha-crystallin–small heat-shock protein superfamily. International Journal of Biological Macromolecules, 22, 151–162.CrossRefPubMedGoogle Scholar
  6. De Maio, A. (1999). Heat shock proteins: Facts, thoughts, and dreams. Shock, 11, 1–12.CrossRefPubMedGoogle Scholar
  7. Di Naso, F. C., Porto, R. R., Fillmann, H. S., Maggioni, L., Padoin, A. V., Ramos, R. J., Mottin, C. C., Bittencourt, A., Marroni, N. A., de Bittencourt, P. I., & Jr. (2015). Obesity depresses the anti-inflammatory HSP70 pathway, contributing to NAFLD progression. Obesity (Silver Spring), 23, 120–129.CrossRefGoogle Scholar
  8. Dulin, E., Garcia-Barreno, P., & Guisasola, M. C. (2010). Extracellular heat shock protein 70 (HSPA1A) and classical vascular risk factors in a general population. Cell Stress & Chaperones, 15, 929–937.CrossRefGoogle Scholar
  9. Dvoriantchikova, G., Santos, A. R., Saeed, A. M., Dvoriantchikova, X., & Ivanov, D. (2014). Putative role of protein kinase C in neurotoxic inflammation mediated by extracellular heat shock protein 70 after ischemia-reperfusion. Journal of Neuroinflammation, 11, 81.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Fink, A. L. (1999). Chaperone-mediated protein folding. Physiological Reviews, 79, 425–449.CrossRefPubMedGoogle Scholar
  11. Flaherty, K. M., DeLuca-Flaherty, C., & McKay, D. B. (1990). Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature, 346, 623–628.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gragerov, A., Zeng, L., Zhao, X., Burkholder, W., & Gottesman, M. E. (1994). Specificity of DnaK-peptide binding. Journal of Molecular Biology, 235, 848–854.CrossRefPubMedGoogle Scholar
  13. Gurbuxani, S., Schmitt, E., Cande, C., Parcellier, A., Hammann, A., Daugas, E., Kouranti, I., Spahr, C., Pance, A., Kroemer, G., et al. (2003). Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene, 22, 6669–6678.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hartl, F. U. (1996). Molecular chaperones in cellular protein folding. Nature, 381, 571–579.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hartl, F. U., & Hayer-Hartl, M. (2002). Molecular chaperones in the cytosol: From nascent chain to folded protein. Science, 295, 1852–1858.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kalmar, B., & Greensmith, L. (2009). Induction of heat shock proteins for protection against oxidative stress. Advanced Drug Delivery Reviews, 61, 310–318.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kampinga, H. H., Hageman, J., Vos, M. J., Kubota, H., Tanguay, R. M., Bruford, E. A., Cheetham, M. E., Chen, B., & Hightower, L. E. (2009). Guidelines for the nomenclature of the human heat shock proteins. Cell Stress & Chaperones, 14, 105–111.CrossRefGoogle Scholar
  18. Kavanagh, K., Flynn, D. M., Jenkins, K. A., Zhang, L., & Wagner, J. D. (2011). Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys. American Journal of Physiology. Endocrinology and Metabolism, 300, E894–E901.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Krepuska, M., Szeberin, Z., Sótonyi, P., Sarkadi, H., Fehérvári, M., Apor, A., Rimely, E., Prohászka, Z., & Acsády, G. (2011). Serum level of soluble HSP70 is associated with vascular calcification. Cell Stress & Chaperones, 16, 257–265.CrossRefGoogle Scholar
  20. Lanneau, D., Brunet, M., Frisan, E., Solary, E., Fontenay, M., & Garrido, C. (2008). Heat shock proteins: Essential proteins for apoptosis regulation. Journal of Cellular and Molecular Medicine, 12, 743–761.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lee, K. J., Kim, Y. M., Kim, D. Y., Jeoung, D., Han, K., Lee, S. T., Lee, Y. S., Park, K. H., Park, J. H., Kim, D. J., et al. (2006). Release of heat shock protein 70 (Hsp70) and the effects of extracellular Hsp70 on matric metalloproteinase-9 expression in human monocytic U937 cells. Experimental & Molecular Medicine, 38, 364–374.CrossRefGoogle Scholar
  22. Leri, O., Teichner, A., Sinopoli, M. T., Abbolito, M. R., Pustorino, R., Nicosia, R., & Paparo Barbaro, S. (1996). Heat-shock-proteins-antibodies in patients with Helicobacter pylori associated chronic gastritis. Rivista Europea per le Scienze Mediche e Farmacologiche, 18, 45–47.PubMedGoogle Scholar
  23. Miot, M., Reidy, M., Doyle, S. M., Hoskins, J. R., Johnston, D. M., Genest, O., Vitery, M. C., Masison, D. C., & Wickner, S. (2011). Species-specific collaboration of heat shock proteins (Hsp) 70 and 100 in thermotolerance and protein disaggregation. Proceedings of the National Academy of Sciences of the United States of America, 108, 6915–6920.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Nakhjavani, M., Morteza, A., Khajeali, L., Esteghamati, A., Khalilzadeh, O., Asgarani, F., & Outeiro, T. F. (2010). Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress & Chaperones, 15, 959–964.CrossRefGoogle Scholar
  25. Pierzchalski, P., Jastrzebska, M., Link-Lenczowski, P., Leja-Szpak, A., Bonior, J., Jaworek, J., Okon, K., & Wojcik, P. (2014). The dynamics of heat shock system activation in Monomac-6 cells upon Helicobacter pylori infection. Journal of Physiology and Pharmacology, 65, 791–800.PubMedPubMedCentralGoogle Scholar
  26. Qiu, X. B., Shao, Y. M., Miao, S., & Wang, L. (2006). The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cellular and Molecular Life Sciences, 63, 2560–2570.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Qu, B., Jia, Y., Liu, Y., Wang, H., Ren, G., & Wang, H. (2015a). The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: A literature review. Cell Stress & Chaperones, 20, 885–892.CrossRefGoogle Scholar
  28. Qu, B. G., Wang, H., Jia, Y. G., Su, J. L., Wang, Z. D., Wang, Y. F., Han, X. H., Liu, Y. X., Pan, J. D., & Ren, G. Y. (2015b). Changes in tumor necrosis factor-alpha, heat shock protein 70, malondialdehyde, and superoxide dismutase in patients with different severities of alcoholic fatty liver disease: A prospective observational study. Medicine (Baltimore), 94, e643.CrossRefGoogle Scholar
  29. Radons, J. (2016). The human HSP70 family of chaperones: Where do we stand? Cell Stress & Chaperones, 21, 379–404.CrossRefGoogle Scholar
  30. Ritossa, F. (1962). A new puffing pattern induced by temperature and DNP in Drosophila. Experientia, 18, 571–573.CrossRefGoogle Scholar
  31. Singh, K., Agrawal, N. K., Gupta, S. K., Mohan, G., Chaturvedi, S., & Singh, K. (2015). Decreased expression of heat shock proteins may lead to compromised wound healing in type 2 diabetes mellitus patients. Journal of Diabetes and its Complications, 29, 578–588.CrossRefPubMedGoogle Scholar
  32. Tissieres, A., Mitchell, H. K., & Tracy, U. M. (1974). Protein synthesis in salivary glands of Drosophila melanogaster: Relation to chromosome puffs. Journal of Molecular Biology, 84, 389–398.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Tóth, M. E., Gombos, I., & Sántha, M. (2015). Heat shock proteins and their role in human disease. Acta Biologica Szegediensis, 59, 21–141.Google Scholar
  34. Verghese, J., Abrams, J., Wang, Y., & Morano, K. A. (2012). Biology of the heat shock response and protein chaperones: Budding yeast (Saccharomyces cerevisiae) as a model system. Microbiology and Molecular Biology Reviews, 76, 115–158.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Vierling, E. (1997). The small heat shock proteins in plants are members of an ancient family of heat induced proteins. Acta Physiologiae Plantarum, 19, 539–547.CrossRefGoogle Scholar
  36. Whitley, D., Goldberg, S. P., & Jordan, W. D. (1999). Heat shock proteins: A review of the molecular chaperones. Journal of Vascular Surgery, 29, 748–751.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Xu, Z. S., Li, Z. Y., Chen, Y., Chen, M., Li, L. C., & Ma, Y. Z. (2012). Heat shock protein 90 in plants: Molecular mechanisms and roles in stress responses. International Journal of Molecular Sciences, 13, 15706–15723.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Yaglom, J. A., Gabai, V. L., & Sherman, M. Y. (2007). High levels of heat shock protein Hsp72 in cancer cells suppress default senescence pathways. Cancer Research, 67, 2373–2381.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Yang, X., He, H., Yang, W., Song, T., Guo, C., Zheng, X., & Liu, Q. (2010). Effects of HSP70 antisense oligonucleotide on the proliferation and apoptosis of human hepatocellular carcinoma cells. Journal of Huazhong University of Science and Technology. Medical Sciences, 30, 337–343.CrossRefGoogle Scholar
  40. Yeo, M., Park, H. K., Kim, D. K., Cho, S. W., Kim, Y. S., Cho, S. Y., Paik, Y. K., & Hahm, K. B. (2004). Restoration of heat shock protein 70 suppresses gastric mucosal inducible nitric oxide synthase expression induced by Helicobacter pylori. Proteomics, 4, 3335–3342.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Zhao, J. H., Meng, X. L., Zhang, J., Li, Y. L., Li, Y. J., & Fan, Z. M. (2014). Oxygen glucose deprivation post-conditioning protects cortical neurons against oxygen-glucose deprivation injury: Role of HSP70 and inhibition of apoptosis. Journal of Huazhong University of Science and Technology. Medical Sciences, 34, 18–22.CrossRefGoogle Scholar
  42. Zhu, X., Zhao, X., Burkholder, W. F., Gragerov, A., Ogata, C. M., Gottesman, M. E., & Hendrickson, W. A. (1996). Structural analysis of substrate binding by the molecular chaperone DnaK. Science, 272, 1606–1614.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiophysicsUniversity of Delhi South CampusNew DelhiIndia

Personalised recommendations