Skip to main content

Advertisement

SpringerLink
Log in

Role of Heat Shock Proteins in Diseases and Their Therapeutic Potential

  • Review Article
  • Published:
Indian Journal of Microbiology Aims and scope Submit manuscript

Abstract

Heat shock proteins are ubiquitously expressed intracellular proteins and act as molecular chaperones in processes like protein folding and protein trafficking between different intracellular compartments. They are induced during stress conditions like oxidative stress, nutritional deficiencies and radiation. They are released into extracellular compartment during necrosis. However, recent research findings highlights that, they are not solely present in cytoplasm, but also released into extracellular compartment during normal conditions and even in the absence of necrosis. When present in extracellular compartment, they have been shown to perform various functions like antigen presentation, intercellular signaling and induction of pro-inflammatory cytokines. Heat shock proteins represents as dominant microbial antigens during infection. The phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins has led to proposition that, microbial heat shock proteins can induce self reactivity to host heat shock proteins and result in autoimmune diseases. The self-reactivity of heat shock proteins protects host against disease by controlling induction and release of pro-inflammatory cytokines. However, antibodies to self heat shock proteins haven been implicated in pathogenesis of autoimmune diseases like arthritis and atherosclerosis. Some heat shock proteins are potent inducers of innate and adaptive immunity. They activate dendritic cells and natural killer cells through toll-like receptors, CD14 and CD91. They play an important role in MHC-antigen processing and presentation. These immune effector functions of heat shock proteins are being exploited them as therapeutic agents as well as therapeutic targets for various infectious diseases and cancers.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ritossa FA (1962) A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia 18:571–573

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Welch WJ (1993) How cells respond to stress. Sci Am 268:56–64

    Article  PubMed  CAS  Google Scholar 

  4. Kaufamann SHE (1991) Heat shock proteins and pathogenesis of bacterial infections. Springer Semin Immunopathol 13:25–36

    Article  Google Scholar 

  5. Morimoto RI, Tissires A, Georgopoulos C (1990) The stress response, function of the proteins, and perspectives. In: Morimoto RI, Tissires A, Georgopoulos C (eds) Stress proteins in biology and medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 1–36

    Google Scholar 

  6. Craig EA, Gross CA (1991) Is hsp70 the cellular thermometer? Trends Biochem Sci 16:135

    Article  PubMed  CAS  Google Scholar 

  7. Voellmy R (1994) Transduction of the stress signal and mechanisms of transcriptional regulation of heat shock/stress protein gene expression in higher eukaryotes. Crit Rev Eukaryot Gene Expr 4:357–401

    PubMed  CAS  Google Scholar 

  8. Knauf U (1996) Repression of human heat shock factor 1 activity at control temperature by phosphorylation. Genes Dev 10:2782–2793

    Article  PubMed  CAS  Google Scholar 

  9. Kim J (1997) Analysis of the phosphorylation of human heat shock transcription factor-1 by MAP kinase family members. J Cell Biochem 67:43–54

    Article  PubMed  CAS  Google Scholar 

  10. Fink AL (1999) Chaperone-mediated protein folding. Physiol Rev 79:425–449

    PubMed  CAS  Google Scholar 

  11. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858

    Article  PubMed  CAS  Google Scholar 

  12. Llorca O, Martin-Benito J, Ritco-Vonsovici M, Grantham J, Hynes GM, Willison KR (2000) Eukaryotic chaperonin CCT stabilizes actin and tubulin folding intermediates in open quasi-native conformations. EMBO J 19:5971–5979

    Article  PubMed  CAS  Google Scholar 

  13. Hartl FU, Hlodan R, T Langer (1994) Molecular chaperones in protein folding: the art of avoiding sticky situations. Trends Biochem Sci 19:21–25

    Article  Google Scholar 

  14. DeNagel DC, Pierce SK (1992) A case of chaperones in antigen processing. Immunol Today 13:86–89

    Article  PubMed  CAS  Google Scholar 

  15. Flynn GC, Chappell GT, Rothman JE (1989) Peptide binding and release by proteins implicated as catalysts of protein assembly. Science 245:385–390

    Article  PubMed  CAS  Google Scholar 

  16. Melnick J, Argon Y (1995) Molecular chaperones and the biosynthesis of antigen receptors. Immunol Today 16:243–250

    Article  PubMed  CAS  Google Scholar 

  17. Melnick J, Dul JL, Argon Y (1994) Sequential interaction of chaperonin Bip and GRP94 with immunoglobulin chains in the endoplasmic reticulum. Nature 370:373–375

    Article  PubMed  CAS  Google Scholar 

  18. Galdiero M, de l’Ero GC, Marcatili A (1997) Cytokine and adhesion molecule expression in human monocytes and endothelial cells stimulated with bacterial heat shock proteins. Infect Immun 65:699–707

    PubMed  CAS  Google Scholar 

  19. Retzlaff C (1994) Bacterial heat shock proteins directly induce cytokine mRNA and interleukin-1 secretion in macrophage cultures. Infect Immun 62:5689–5693

    PubMed  CAS  Google Scholar 

  20. Peetermans WE (1994) Mycobacterial heat-shock protein-65 induces proinflammatory cytokines but does not activate human mononuclear phagocytes. Scand J Immunol 39:613–617

    Article  PubMed  CAS  Google Scholar 

  21. Bulut Y, Michelsen KS, Hayrapetian L, Naiki Y, Spallek R, Singh M (2005) Mycobacterium tuberculosis heat shock proteins use diverse toll-like receptor pathways to activate pro-inflammatory signals. J Biol Chem 280(22):20961–20967

    Article  PubMed  CAS  Google Scholar 

  22. Kol A (1999) Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Investig 103:571–577

    Article  PubMed  CAS  Google Scholar 

  23. Chen W (1999) Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J Immunol 162:3212–3219

    PubMed  CAS  Google Scholar 

  24. Asea A, Rehli M, Kabingu E (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  PubMed  CAS  Google Scholar 

  25. Tsan M-F, Gao B (2004) Endogenous ligands of toll-like receptors. J Leukoc Biol 76(3):514–519

    Article  PubMed  CAS  Google Scholar 

  26. Williams DB, Watts TH (1995) Molecular chaperones in antigen processing. Curr Opin Immunol 7:77–84

    Article  PubMed  CAS  Google Scholar 

  27. Vanbuskirk A, Crump BL, Margoliash E, Pierce SK (1989) A peptide binding protein having a role in antigen presentation is a member of the hsp70 heat shock family. J Exp Med 170:1799–1809

    Article  PubMed  CAS  Google Scholar 

  28. Jacquier-Sarlin MR, Fuller K, Dinh-Xuan AT, Richard MJ, Polla BS (1994) Protective effects of hsp70 in inflammation. Experientia 50:1031–1038

    Article  PubMed  CAS  Google Scholar 

  29. Jackson M, Cohen-Doyle M, Peterson P, Williams D (1994) Regulation of MHC class I transport by the molecular chaperone, calnexin (p88/IP90). Science 263:348–387

    Article  Google Scholar 

  30. Rajagopalan S, Brenner M (1994) Calnexin retains unassembled major histocompatibility complex class I free heavy chains in the endoplasmic reticulum. J Exp Med 180:407–412

    Article  PubMed  CAS  Google Scholar 

  31. Anderson KS, Cresswell P (1994) A role for calnexin (IP90) in the assembly of class II MHC molecules. EMBO J 13:675–682

    PubMed  CAS  Google Scholar 

  32. Bonnerot C, Marks M, Cosson P, Robertson E, Bikof E, Germain R, Bonifacino J (1994) Association with Bip and aggregation of class II MHC molecules synthesized in the absence of invariant chain. EMBO J 13:934–944

    PubMed  CAS  Google Scholar 

  33. Singh-Jasuja H (2000) Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor mediated endocytosis. J Exp Med 191:1965–1974

    Article  PubMed  CAS  Google Scholar 

  34. Srivastava P (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2:185–194

    Article  PubMed  CAS  Google Scholar 

  35. Gullo CA, Teoh G (2004) Heat shock proteins: to present or not, that is the question. Immunol Lett 94:1–10

    Article  PubMed  CAS  Google Scholar 

  36. Fields PI, Swanson RV, Haidaris CG, Heffron F (1986) Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Proc Natl Acad Sci USA 83:5189

    Article  PubMed  CAS  Google Scholar 

  37. Shinnick TM (1991) Heat shock proteins as antigens of bacterial and parasitic pathogens. Curr Top Microbiol Immunol 167:145–160

    PubMed  CAS  Google Scholar 

  38. Shinnick TM, Vodkin MH, Williams JC (1988) The Mycobacterium tuberculosis 65-kilodalton antigen is a heat shock protein which corresponds to common antigen and to the Escherichia coli GroEL protein. Infect Immun 56:446–451

    PubMed  CAS  Google Scholar 

  39. Kaufmann SHE, Schoel B, Wand-Wurttenberger A, Steinhoff U, Munk ME, Koga T (1990) T cells, stress proteins and pathogenesis of mycobacterial infections. Curr Top Microbiol Immunol 155:125–141

    PubMed  CAS  Google Scholar 

  40. Noll A, Autenrieth IB (1996) Immunity against Yersinia enterocolitica by vaccination with Yersinia hsp60 immunostimulating complexes or Yersinia hsp60 plus interleukin-12. Infect Immun 64:2955–2961

    PubMed  CAS  Google Scholar 

  41. Young DB, Lathringa RB, Hendrix RW, Sweetser D, Young RA (1988) Stress proteins are immune targets in leprosy and tuberculosis. Proc Natl Acad Sci USA 85:4267–4270

    Article  PubMed  CAS  Google Scholar 

  42. Hiromatsu K, Yoshikai Y, Matsuzaki G, Ohga S, Muramori K, Matsumoto K (1992) A protective role of γS T cells in primary infection with Listeria monocytogenes in mice. J Exp Med 175:49–56

    Article  PubMed  CAS  Google Scholar 

  43. Buchmeier NA, Heffron F (1990) Induction of Salmonella stress proteins upon infection of macrophages. Science 248:730–732

    Article  PubMed  CAS  Google Scholar 

  44. Johnson K, Charles I, Dougan G, Pickard D, O’Gaora P, Costa G (1991) The role of a stress-response protein in Salmonella typhimurium virulence. Mol Microbiol 5:401–407

    Article  PubMed  CAS  Google Scholar 

  45. Morrison RP (1991) Chlamydial hsp 60 and the immunopathogenesis of chlamydial disease. Semin Immunol 3:25

    PubMed  CAS  Google Scholar 

  46. Del Giudice G, Gervaix A, Costantino P, Wyler CA, Tougne C, De Graeff-Meeder ER (1993) Priming to heat shock proteins in infants vaccinated against pertussis. J Immunol 150:2025–2032

    PubMed  CAS  Google Scholar 

  47. Ferrero RL, Thilberge JM, Kansau I, Wuscher N, Huerre M, Labigne A (1995) The GroES homolog of Helicobacter pylori confers protective immunity against mucosal infection in mice. Proc Natl Acad Sci USA 92:6499–6503

    Article  PubMed  CAS  Google Scholar 

  48. Gomez FJ, Allendoerfer R, Deepe GS Jr (1995) Vaccination with recombinant heat shock protein 60 from Histoplasma capsulatum protects mice against pulmonary histoplasmosis. Infect Immun 63:2587–2595

    PubMed  CAS  Google Scholar 

  49. Hansen K, Bangsborg JM, Fjordvang H, Pedersen NS, Hindersson P (1988) Immunochemical characterization of and isolation of the gene for Borrelia burgdorferi immunodominant 60-kilodalton antigen common to a wide range of bacteria. Infect Immun 56:2047–2053

    PubMed  CAS  Google Scholar 

  50. Rothstein NM, Higashi G, Yates J, Rajan TV (1989) Onchocerca volvulus heat shock protein 70 is a major immunogen in amicrofilaremic individuals from filariasis-endemic area. Mol Biochem Parasitol 33:229–236

    Article  PubMed  CAS  Google Scholar 

  51. Lamb JR (1989) Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol 1:191–196

    Article  PubMed  CAS  Google Scholar 

  52. Yang XD, Gasser J, Feige U (1992) Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat shock proteins specificity and mechanism. Clin Exp Immunol 87:99–104

    Article  PubMed  CAS  Google Scholar 

  53. Anderton SM, Van der Zee R, Prakken B, Nordzij A, Van Eden W (1995) Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J Exp Med 181:943–952

    Article  PubMed  CAS  Google Scholar 

  54. Van den Broek MF, Hagervorst EJM, Van Bruggen MCJ, Van Eden W, Van der Zee R, Van den Berg WB (1989) Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein. J Exp Med 170:449–466

    Article  PubMed  Google Scholar 

  55. Boog CJ, De Graeff-Meeder ER, Lucassen MA, Van der Zee R, Voorhorst-Ogink MM, Van Kooten PJ (1992) Two monoclonal antibodies generated against human hsp60 show reactivity with synovial membranes of patients with juvenile chronic arthritis. J Exp Med 175:1805–1810

    Article  PubMed  CAS  Google Scholar 

  56. De Graeff-Meeder ER, Voorhorst M, Van Eden W, Schuurman HJ, Huber J, Barkley D (1990) Antibodies to the mycobacterial 65-KD heat-shock protein are reactive with synovial tissue of adjuvant arthritic rats and patients with rheumatoid arthritis and osteoarthritis. Am J Pathol 137:1013–1017

    PubMed  Google Scholar 

  57. McLean IL, Archer MID, Pegley CFS, Kidd BL, Thompson PW (1990) Specific antibody response to the mycobacterial 65 kDa stress protein in ankylosing spondylitis and rheumatoid arthritis. Br J Rheumatol 29:426–429

    Article  PubMed  CAS  Google Scholar 

  58. Wick G (1995) Role of heat shock protein 65/60 in the pathogenesis of atherosclerosis. Int Arch Allergy Immunol 107:130–131

    Article  PubMed  CAS  Google Scholar 

  59. Frostegard J (1999) Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 145:33–43

    Article  PubMed  CAS  Google Scholar 

  60. Kleindienst R (1993) Immunology of atherosclerosis: demonstration of heat shock protein 60 expression and T lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. Am J Pathol 142:1927–1937

    PubMed  CAS  Google Scholar 

  61. Binder RJ, Han DK, Srivastava PK (2000) CD91: a receptor for heat shock protein gp96. Nat Immunol 1:151–155

    Article  PubMed  CAS  Google Scholar 

  62. Udono H, Levey DL, Srivastava PK (1994) Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+ T cells in vivo. Proc Natl Acad Sci USA 91:3077–3081

    Article  PubMed  CAS  Google Scholar 

  63. Becker T, Hartl FU, Wieland F (2002) CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J Cell Biol 158:1277–1285

    Article  PubMed  CAS  Google Scholar 

  64. Vabulas RM, Ahmad-Nejad P, da Costa C (2001) Endocytosed Hsp60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem 276:31332–31339

    Article  PubMed  CAS  Google Scholar 

  65. Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA (2000) Cutting edge: heat shock protein (Hsp) 60 activates the innate immune response: CD14 is an essential receptor for Hsp60 activation of mononuclear cells. J Immunol 164:13–17

    PubMed  CAS  Google Scholar 

  66. Berwin B, Hart JP, Rice S (2003) Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J 22:6127–6136

    Article  PubMed  CAS  Google Scholar 

  67. Silva CL, Lowrie DB (1994) A single mycobacterial protein (hsp65) expressed by a transgenic antigen-presenting cell vaccinates mice against tuberculosis. Immunology 82:244–248

    PubMed  CAS  Google Scholar 

  68. Kang HK (2004) Toxoplasma gondii-derived heat shock protein 70 stimulates the maturation of human monocyte-derived dendritic cells. Biochem Biophys Res Commun 322:899–904

    Article  PubMed  CAS  Google Scholar 

  69. Udono H, Srivastava PK (1993) Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 178:1391–1396

    Article  PubMed  CAS  Google Scholar 

  70. Udono H, Srivastava PK (1994) Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. J Immunol 152:5398–5403

    PubMed  CAS  Google Scholar 

  71. Heikema A, Agsteribbe E, Wilschut J, Huckriede A (1997) Generation of heat shock protein-based vaccines by intracellular loading of gp96 with antigenic peptides. Immunol Lett 57:69–74

    Article  PubMed  CAS  Google Scholar 

  72. Segal BH, Wang X-Y, Dennis CG, Youn R, Repasky EA, Manjili MH (2006) Heat shock proteins as vaccine adjuvants in infections and cancer. Drug Discov Today 11:534–540

    Article  PubMed  CAS  Google Scholar 

  73. Neckers L, Neckers K. (2005) Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics—an update. Expert Opin Emerg Drugs 10(1):137–149

    Article  PubMed  CAS  Google Scholar 

  74. Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y (2005) Crystal structures of human HSP90 alpha-complexed with dihydroxyphenylpyrazoles. Bioorg Med Chem Lett 5:1475–1478

    Article  Google Scholar 

Download references

Acknowledgments

This authors are grateful to National Dairy Research Institute, Karnal for providing support and fellowship.

Author information

Authors and Affiliations

  1. Biochemistry Department, National Dairy Research Institute, Karnal, Haryana, India

    Gautam Kaul & Hitesh Thippeswamy

Authors
  1. Gautam Kaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hitesh Thippeswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gautam Kaul.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaul, G., Thippeswamy, H. Role of Heat Shock Proteins in Diseases and Their Therapeutic Potential. Indian J Microbiol 51, 124–131 (2011). https://doi.org/10.1007/s12088-011-0147-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12088-011-0147-9

Keywords

Search

Navigation