Biology of Extracellular HSP60

  • Brice Nativel
  • Cynthia Planesse
  • Philippe Gasque
  • Christine Robert Da Silva
  • Olivier Meihac
  • Wildriss ViranaïckenEmail author
Part of the Heat Shock Proteins book series (HESP, volume 16)


The exposure of cells or organisms to high temperature leads to the release of alert molecules such as Heat Shock Protein: the HSP. This protein family has been initially described in Drosophila. The cellular response to a heat shock involving HSP is conserved across species, from bacteria to humans and including plants. Other stresses, such as ischemia, heavy metal poisoning, nutrient deprivation, irradiations, infections, oxidative stress and inflammation, can also induce the HSP expression. HSP form a large family of proteins which are classified according to their molecular weight: HSP100, HSP90, HSP70, HSP60, HSP40, HSP from 20 to 30 kDa and HSP10. HSP60 has different functions depending on its localization. Intracellular HSP60 can be found in the cytosol, mitochondria and the chloroplast. Therein, it has a chaperone activity by assisting the proteins folding. On the cell surface or in the extracellular medium, HSP60 acts as a danger signaling molecule. Thus, stressed or damaged cells can stimulate the immune system. Indeed, this extracellular HSP60 are involved in several inflammatory pathologies.


Apoptosis Chaperokine Extracellular HSP60 Immune activation Inflammation 



Antigen presenting cells


“chaperon” containing the T-complex of polypeptide 1


Chaperonin 60 kDa


Damage associated molecular pattern


Dendritic cells


Heat shock protein




Gamma delta T lymphocytes


Mitochondrial form


Pathogen associated molecular pattern


Rubisco binding protein


Soluble HSP60


Helper T lymphocytes


Regulatory T lymphocytes


TCP-1 Complex ring



To servier for providing design medical art for figure. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported Licence.


  1. Aalberse JA, Kapitein B, de Roock S, Klein MR, de Jager W, van der Zee R, Hoekstra MO, van Wijk F, Prakken BJ (2011) Cord blood CD4+ T cells respond to self heat shock protein 60 (HSP60). PLoS One 6:e24119PubMedPubMedCentralGoogle Scholar
  2. Apuya NR, Yadegari R, Fischer RL, Harada JJ, Zimmerman JL, Goldberg RB (2001) The Arabidopsis embryo mutant schlepperless has a defect in the chaperonin-60alpha gene. Plant Physiol 126:717–730PubMedPubMedCentralCrossRefGoogle Scholar
  3. Arya RK, Singh A, Yadav NK, Cheruvu SH, Hossain Z, Meena S, Maheshwari S, Singh AK, Shahab U, Sharma C et al (2015) Anti-breast tumor activity of Eclipta extract in-vitro and in-vivo: novel evidence of endoplasmic reticulum specific localization of Hsp60 during apoptosis. Sci Rep 5:18457PubMedPubMedCentralCrossRefGoogle Scholar
  4. Atre N, Thomas L, Mistry R, Pathak K, Chiplunkar S (2006) Role of nitric oxide in heat shock protein induced apoptosis of gammadeltaT cells. Int J Cancer 119:1368–1376PubMedCrossRefGoogle Scholar
  5. Bajramović JJ, Bsibsi M, Geutskens SB, Hassankhan R, Verhulst KC, Stege GJ, de Groot CJ, van Noort JM (2000) Differential expression of stress proteins in human adult astrocytes in response to cytokines. J Neuroimmunol 106:14–22PubMedCrossRefGoogle Scholar
  6. Balczun C, Bunse A, Schwarz C, Piotrowski M, Kück U (2006) Chloroplast heat shock protein Cpn60 from Chlamydomonas reinhardtii exhibits a novel function as a group II intron-specific RNA-binding protein. FEBS Lett 580:4527–4532PubMedCrossRefGoogle Scholar
  7. Bassan M, Zamostiano R, Giladi E, Davidson A, Wollman Y, Pitman J, Hauser J, Brenneman DE, Gozes I (1998) The identification of secreted heat shock 60 -like protein from rat glial cells and a human neuroblastoma cell line. Neurosci Lett 250:37–40PubMedCrossRefGoogle Scholar
  8. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539–1546CrossRefGoogle Scholar
  9. Benjamin CL, Ullrich SE, Kripke ML, Ananthaswamy HN (2008) p53 tumor suppressor gene: a critical molecular target for UV induction and prevention of skin cancer. Photochem Photobiol 84:55–62PubMedGoogle Scholar
  10. Binder RJ, Vatner R, Srivastava P (2004) The heat-shock protein receptors: some answers and more questions. Tissue Antigens 64:442–451PubMedCrossRefGoogle Scholar
  11. Birk OS, Douek DC, Elias D, Takacs K, Dewchand H, Gur SL, Walker MD, van der Zee R, Cohen IR, Altmann DM (1996) A role of Hsp60 in autoimmune diabetes: analysis in a transgenic model. Proc Natl Acad Sci 93:1032–1037PubMedCrossRefGoogle Scholar
  12. Bockova J, Elias D, Cohen IR (1997) Treatment of NOD diabetes with a novel peptide of the hsp60 molecule induces Th2-type antibodies. J Autoimmun 10:323–329PubMedCrossRefGoogle Scholar
  13. Campanella C, Bucchieri F, Merendino AM, Fucarino A, Burgio G, Corona DFV, Barbieri G, David S, Farina F, Zummo G et al (2012) The Odyssey of Hsp60 from tumor cells to other destinations includes plasma membrane-associated stages and Golgi and exosomal protein-trafficking modalities. PLoS One:7, e42008PubMedPubMedCentralCrossRefGoogle Scholar
  14. Cappello F, David S, Rappa F, Bucchieri F, Marasà L, Bartolotta TE, Farina F, Zummo G (2005) The expression of HSP60 and HSP10 in large bowel carcinomas with lymph node metastase. BMC Cancer 5:139PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cappello F, Conway de Macario E, Marasà L, Zummo G, Macario AJL (2008) Hsp60 expression, new locations, functions and perspectives for cancer diagnosis and therapy. Cancer Biol Ther 7:801–809PubMedCrossRefGoogle Scholar
  16. Cappello F, Caramori G, Campanella C, Vicari C, Gnemmi I, Zanini A, Spanevello A, Capelli A, La Rocca G, Anzalone R et al (2011) Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis. PLoS One 6:e28200PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chaiwatanasirikul K-A, Sala A (2011) The tumour-suppressive function of CLU is explained by its localisation and interaction with HSP60. Cell Death Dis 2:e219PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chandra D, Choy G, Tang DG (2007) Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3. J Biol Chem 282:31289–31301PubMedGoogle Scholar
  19. Chang YH, Pearson CM, Abe C (1980) Adjuvant polyarthritis. IV. Induction by a synthetic adjuvant: immunologic, histopathologic, and other studies. Arthritis Rheum 23:62–71PubMedCrossRefGoogle Scholar
  20. Chen W, Wang J, Shao C, Liu S, Yu Y, Wang Q, Cao X (2006) Efficient induction of antitumor T cell immunity by exosomes derived from heat-shocked lymphoma cells. Eur J Immunol 36:1598–1607PubMedCrossRefGoogle Scholar
  21. Cheng MY, Hartl F-U, Martin J, Pollock RA, Kalousek F, Neuper W, Hallberg EM, Hallberg RL, Horwich AL (1989) Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. Nature 337:620–625PubMedCrossRefGoogle Scholar
  22. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840PubMedCrossRefGoogle Scholar
  23. Christensen JH, Nielsen MN, Hansen J, Füchtbauer A, Füchtbauer E-M, West M, Corydon TJ, Gregersen N, Bross P (2010) Inactivation of the hereditary spastic paraplegia-associated Hspd1 gene encoding the Hsp60 chaperone results in early embryonic lethality in mice. Cell Stress Chaperones 15:851–863PubMedPubMedCentralCrossRefGoogle Scholar
  24. Cohen-Sfady M, Pevsner-Fischer M, Margalit R, Cohen IR (2009) Heat shock protein 60, via MyD88 innate signaling, protects B cells from apoptosis, spontaneous and induced. J Immunol Baltim Md 1950 183:890–896Google Scholar
  25. Cong Y, Baker ML, Jakana J, Woolford D, Miller EJ, Reissmann S, Kumar RN, Redding-Johanson AM, Batth TS, Mukhopadhyay A et al (2010) 4.0-A resolution cryo-EM structure of the mammalian chaperonin TRiC/CCT reveals its unique subunit arrangement. Proc Natl Acad Sci U S A 107:4967–4972PubMedPubMedCentralCrossRefGoogle Scholar
  26. Cromartie WJ, Craddock JG, Schwab JH, Anderle SK, Yang CH (1977) Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med 146:1585–1602PubMedCrossRefGoogle Scholar
  27. Czarnecka AM, Campanella C, Zummo G, Cappello F (2006) Heat shock protein 10 and signal transduction: a “capsula eburnea” of carcinogenesis? Cell Stress Chaperones 11:287–294PubMedPubMedCentralCrossRefGoogle Scholar
  28. Dasu MR, Devaraj S, Park S, Jialal I (2010) Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 33:861–868PubMedPubMedCentralCrossRefGoogle Scholar
  29. de Kleer I, Vercoulen Y, Klein M, Meerding J, Albani S, van der Zee R, Sawitzki B, Hamann A, Kuis W, Prakken B (2010) CD30 discriminates heat shock protein 60-induced FOXP3+ CD4+ T cells with a regulatory phenotype. J Immunol Baltim Md 1950 185:2071–2079Google Scholar
  30. Deocaris CC, Kaul SC, Wadhwa R (2006) On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones 11:116–128PubMedPubMedCentralCrossRefGoogle Scholar
  31. Devaraj S, Dasu MR, Park SH, Jialal I (2009) Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes. Diabetologia 52:1665–1668PubMedPubMedCentralCrossRefGoogle Scholar
  32. Di Felice V, David S, Cappello F, Farina F, Zummo G (2005) Is chlamydial heat shock protein 60 a risk factor for oncogenesis? Cell Mol Life Sci CMLS 62:4–9PubMedCrossRefGoogle Scholar
  33. Dominguez MDC, Lorenzo N, Barbera A, Darrasse-Jeze G, Hernández MV, Torres A, Hernández I, Gil R, Klatzmann D, Padrón G (2011) An altered peptide ligand corresponding to a novel epitope from heat-shock protein 60 induces regulatory T cells and suppresses pathogenic response in an animal model of adjuvant-induced arthritis. Autoimmunity 44:471–482CrossRefGoogle Scholar
  34. Dunn AY, Melville MW, Frydman J (2001) Review: cellular substrates of the eukaryotic chaperonin TRiC/CCT. J Struct Biol 135:176–184PubMedCrossRefGoogle Scholar
  35. Elias D, Meilin A, Ablamunits V, Birk OS, Carmi P, Könen-Waisman S, Cohen IR (1997) Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various β-cell antigens. Diabetes 46:758–765PubMedCrossRefGoogle Scholar
  36. Ellis RJ, van der Vies SM (1991) Molecular chaperones. Annu Rev Biochem 60:321–347PubMedCrossRefGoogle Scholar
  37. Fenton WA, Kashi Y, Furtak K, Horwich AL (1994) Residues in chaperonin GroEL required for polypeptide binding and release. Nature 371:614–619PubMedCrossRefGoogle Scholar
  38. Flohé SB, Brüggemann J, Lendemans S, Nikulina M, Meierhoff G, Flohé S, Kolb H (2003) Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J Immunol Baltim Md 1950 170:2340–2348Google Scholar
  39. Frydman J, Nimmesgern E, Erdjument-Bromage H, Wall JS, Tempst P, Hartl FU (1992) Function in protein folding of TRiC, a cytosolic ring complex containing TCP-1 and structurally related subunits. EMBO J 11:4767–4778PubMedPubMedCentralCrossRefGoogle Scholar
  40. 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 65:699–707PubMedPubMedCentralGoogle Scholar
  41. Gao B, Tsan M-F (2003a) Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor α from murine macrophages. J Biol Chem 278:22523–22529PubMedCrossRefGoogle Scholar
  42. Gao B, Tsan M-F (2003b) Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor α release by murine macrophages. J Biol Chem 278:174–179PubMedCrossRefGoogle Scholar
  43. Ghosh JC, Dohi T, Kang BH, Altieri DC (2008) Hsp60 regulation of tumor cell apoptosis. J Biol Chem 283:5188–5194PubMedPubMedCentralCrossRefGoogle Scholar
  44. Ghosh JC, Siegelin MD, Dohi T, Altieri DC (2010) Heat shock protein 60 regulation of the mitochondrial permeability transition pore in tumor cells. Cancer Res 70:8988–8993PubMedPubMedCentralCrossRefGoogle Scholar
  45. Goh YC, Yap CT, Huang BH, Cronshaw AD, Leung BP, Lai PBS, Hart SP, Dransfield I, Ross JA (2011) Heat-shock protein 60 translocates to the surface of apoptotic cells and differentiated megakaryocytes and stimulates phagocytosis. Cell Mol Life Sci CMLS 68:1581–1592PubMedCrossRefGoogle Scholar
  46. Goloubinoff P, Gatenby AA, Lorimer GH (1989) GroE heat-shock proteins promote assembly of foreign prokaryotic ribulose bisphosphate carboxylase oligomers in Escherichia coli. Nature 337:44–47PubMedCrossRefGoogle Scholar
  47. Goloubinoff P, Diamant S, Weiss C, Azem A (1997) GroES binding regulates GroEL chaperonin activity under heat shock. FEBS Lett 407:215–219PubMedCrossRefGoogle Scholar
  48. Green DR (2006) At the gates of death. Cancer Cell 9:328–330PubMedCrossRefGoogle Scholar
  49. Grundtman C, Wick G (2011) The autoimmune concept of atherosclerosis. Curr Opin Lipidol 22:327–334PubMedPubMedCentralCrossRefGoogle Scholar
  50. Gülden E, Mollérus S, Brüggemann J, Burkart V, Habich C (2008) Heat shock protein 60 induces inflammatory mediators in mouse adipocytes. FEBS Lett 582:2731–2736PubMedCrossRefGoogle Scholar
  51. Gülden E, Märker T, Kriebel J, Kolb-Bachofen V, Burkart V, Habich C (2009) Heat shock protein 60: evidence for receptor-mediated induction of proinflammatory mediators during adipocyte differentiation. FEBS Lett 583:2877–2881PubMedCrossRefGoogle Scholar
  52. Gupta S, Knowlton AA (2002) Cytosolic heat shock protein 60, hypoxia, and apoptosis. Circulation 106:2727–2733PubMedCrossRefGoogle Scholar
  53. Gupta S, Knowlton AA (2007) HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Physiol Heart Circ Physiol 292:H3052–H3056CrossRefGoogle Scholar
  54. Gupta RS, Ramachandra NB, Bowes T, Singh B (2008) Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10. Novartis Found Symp 291:59–68 discussion 69–73, 137–140PubMedCrossRefGoogle Scholar
  55. Habich C, Burkart V (2007) Heat shock protein 60: regulatory role on innate immune cells. Cell Mol Life Sci CMLS 64:742–751PubMedCrossRefGoogle Scholar
  56. Habich C, Baumgart K, Kolb H, Burkart V (2002) The receptor for heat shock protein 60 on macrophages is saturable, specific, and distinct from receptors for other heat shock proteins. J Immunol Baltim Md 1950 168:569–576Google Scholar
  57. Habich C, Kempe K, van der Zee R, Rümenapf R, Akiyama H, Kolb H, Burkart V (2005) Heat shock protein 60: specific binding of lipopolysaccharide. J Immunol Baltim Md 1950 174:1298–1305Google Scholar
  58. Hansen JJ, Bross P, Westergaard M, Nielsen MN, Eiberg H, Børglum AD, Mogensen J, Kristiansen K, Bolund L, Gregersen N (2003) Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10 are localised head to head on chromosome 2 separated by a bidirectional promoter. Hum Genet 112:71–77PubMedCrossRefGoogle Scholar
  59. Hayoun D, Kapp T, Edri-Brami M, Ventura T, Cohen M, Avidan A, Lichtenstein RG (2012) HSP60 is transported through the secretory pathway of 3-MCA-induced fibrosarcoma tumour cells and undergoes N-glycosylation. FEBS J 279:2083–2095PubMedCrossRefGoogle Scholar
  60. Hogervorst EJM, Boog CJP, Wagenaar JPA, Wauben MHM, van der Zee R, van Eden W (1991) T cell reactivity to an epitope of the mycobacterial 65-kDa heat-shock protein (hsp 65) corresponds with arthritis susceptibility in rats and is regulated by hsp 65-specific cellular responses. Eur J Immunol 21:1289–1296PubMedCrossRefGoogle Scholar
  61. Hunt JF, Weaver AJ, Landry SJ, Gierasch L, Deisenhofer J (1996) The crystal structure of the GroES co-chaperonin at 2.8 A resolution. Nature 379:37–45PubMedCrossRefGoogle Scholar
  62. Jindal S, Dudani AK, Singh B, Harley CB, Gupta RS (1989) Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Mol Cell Biol 9:2279–2283PubMedPubMedCentralCrossRefGoogle Scholar
  63. Juwono J, Martinus RD (2016) Does Hsp60 provide a link between mitochondrial stress and inflammation in diabetes mellitus? J Diabetes Res 2016:e8017571CrossRefGoogle Scholar
  64. Kaufman BA, Kolesar JE, Perlman PS, Butow RA (2003) A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J Cell Biol 163:457–461PubMedPubMedCentralCrossRefGoogle Scholar
  65. Kim HS, Kim EM, Lee J, Yang WH, Park TY, Kim YM, Cho JW (2006) Heat shock protein 60 modified with O-linked N-acetylglucosamine is involved in pancreatic β-cell death under hyperglycemic conditions. FEBS Lett 580:2311–2316PubMedCrossRefGoogle Scholar
  66. Kim S-C, Stice JP, Chen L, Jung JS, Gupta S, Wang Y, Baumgarten G, Trial J, Knowlton AA (2009) Extracellular heat shock protein 60, cardiac myocytes, and apoptosis. Circ Res 105:1186–1195PubMedPubMedCentralCrossRefGoogle Scholar
  67. Kol A, Bourcier T, Lichtman AH, Libby P (1999) Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest 103:571–577PubMedPubMedCentralCrossRefGoogle Scholar
  68. Kotlo K, Xing Y, Lather S, Grillon JM, Johnson K, Skidgel RA, Solaro RJ, Danziger RS (2014) PR65A phosphorylation regulates PP2A complex signaling. PLoS One 9:e85000PubMedPubMedCentralCrossRefGoogle Scholar
  69. Leach MD, Stead DA, Argo E, Brown AJP (2011) Identification of sumoylation targets, combined with inactivation of SMT3, reveals the impact of sumoylation upon growth, morphology, and stress resistance in the pathogen Candida albicans. Mol Biol Cell 22:687–702PubMedPubMedCentralCrossRefGoogle Scholar
  70. Leavenworth JW, Tang X, Kim H-J, Wang X, Cantor H (2013) Amelioration of arthritis through mobilization of peptide-specific CD8+ regulatory T cells. J Clin Invest 123:1382–1389PubMedPubMedCentralCrossRefGoogle Scholar
  71. Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, Wulczyn G, Nitsch R, Weber JR (2008) A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci 28:2320–2331PubMedCrossRefGoogle Scholar
  72. Lewthwaite J, Owen N, Coates A, Henderson B, Steptoe A (2002) Circulating human heat shock protein 60 in the plasma of British civil servants: relationship to physiological and psychosocial stress. Circulation 106:196–201PubMedCrossRefGoogle Scholar
  73. Lin KM, Lin B, Lian IY, Mestril R, Scheffler IE, Dillmann WH (2001) Combined and individual mitochondrial HSP60 and HSP10 expression in cardiac myocytes protects mitochondrial function and prevents apoptotic cell deaths induced by simulated ischemia-reoxygenation. Circulation 103:1787–1792PubMedCrossRefGoogle Scholar
  74. Lin Z, Madan D, Rye HS (2008) GroEL stimulates protein folding through forced unfolding. Nat Struct Mol Biol 15:303–311PubMedPubMedCentralCrossRefGoogle Scholar
  75. Llorca O, Carrascosa JL, Valpuesta JM (1996) Biochemical characterization of symmetric GroEL-GroES complexes. Evidence for a role in protein folding. J Biol Chem 271:68–76PubMedCrossRefGoogle Scholar
  76. Llorca O, Martín-Benito J, Ritco-Vonsovici M, Grantham J, Hynes GM, Willison KR, Carrascosa JL, Valpuesta JM (2000) Eukaryotic chaperonin CCT stabilizes actin and tubulin folding intermediates in open quasi-native conformations. EMBO J 19:5971–5979PubMedPubMedCentralCrossRefGoogle Scholar
  77. Lund PA, Large AT, Kapatai G (2003) The chaperonins: perspectives from the Archaea. Biochem Soc Trans 31:681–685PubMedCrossRefGoogle Scholar
  78. Magnoni R, Palmfeldt J, Christensen JH, Sand M, Maltecca F, Corydon TJ, West M, Casari G, Bross P (2013) Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice. Neurobiol Dis 54:12–23PubMedCrossRefGoogle Scholar
  79. Märker T, Kriebel J, Wohlrab U, Habich C (2010) Heat shock protein 60 and adipocytes: characterization of a ligand-receptor interaction. Biochem Biophys Res Commun 391:1634–1640PubMedCrossRefGoogle Scholar
  80. Märker T, Sell H, Zillessen P, Glöde A, Kriebel J, Ouwens DM, Pattyn P, Ruige J, Famulla S, Roden M et al (2012) Heat shock protein 60 as a mediator of adipose tissue inflammation and insulin resistance. Diabetes 61:615–625PubMedPubMedCentralCrossRefGoogle Scholar
  81. Märker T, Kriebel J, Wohlrab U, Burkart V, Habich C (2014) Adipocytes from New Zealand obese mice exhibit aberrant proinflammatory reactivity to the stress signal heat shock protein 60. J Diabetes Res 2014:187153PubMedPubMedCentralCrossRefGoogle Scholar
  82. Mendoza JA, Rogers E, Lorimer GH, Horowitz PM (1991) Chaperonins facilitate the in vitro folding of monomeric mitochondrial rhodanese. J Biol Chem 266:13044–13049PubMedGoogle Scholar
  83. Merendino AM, Bucchieri F, Campanella C, Marcianò V, Ribbene A, David S, Zummo G, Burgio G, Corona DFV, Conway de Macario E et al (2010) Hsp60 is actively secreted by human tumor cells. PLoS One 5:e9247PubMedPubMedCentralCrossRefGoogle Scholar
  84. Murai N, Makino Y, Yoshida M (1996) GroEL locked in a closed conformation by an interdomain cross-link can bind ATP and polypeptide but cannot process further reaction steps. J Biol Chem 271:28229–28234PubMedCrossRefGoogle Scholar
  85. Nativel B, Marimoutou M, Thon-Hon VG, Gunasekaran MK, Andries J, Stanislas G, Planesse C, Da Silva CR, Césari M, Iwema T et al (2013) Soluble HMGB1 is a novel adipokine stimulating IL-6 secretion through RAGE receptor in SW872 preadipocyte cell line: contribution to chronic inflammation in fat tissue. PLoS One 8:e76039PubMedPubMedCentralCrossRefGoogle Scholar
  86. Nielsen KL, Cowan NJ (1998) A single ring is sufficient for productive chaperonin-mediated folding in vivo. Mol Cell 2:93–99PubMedCrossRefGoogle Scholar
  87. Nielsen KL, McLennan N, Masters M, Cowan NJ (1999) A single-ring mitochondrial chaperonin (Hsp60-Hsp10) can substitute for GroEL-GroES in vivo. J Bacteriol 181:5871–5875PubMedPubMedCentralGoogle Scholar
  88. Ohashi K, Burkart V, Flohé S, Kolb H (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol Baltim Md 1950 164:558–561Google Scholar
  89. Ohue R, Hashimoto K, Nakamoto M, Furukawa Y, Masuda T, Kitabatake N, Tani F (2011) Bacterial heat shock protein 60, GroEL, can induce the conversion of naïve T cells into a CD4 CD25(+) Foxp3-expressing phenotype. J Innate Immun 3:605–613PubMedCrossRefGoogle Scholar
  90. Osterloh A, Meier-Stiegen F, Veit A, Fleischer B, von Bonin A, Breloer M (2004) Lipopolysaccharide-free heat shock protein 60 activates T cells. J Biol Chem 279:47906–47911PubMedCrossRefGoogle Scholar
  91. Osterloh A, Veit A, Gessner A, Fleischer B, Breloer M (2008) Hsp60-mediated T cell stimulation is independent of TLR4 and IL-12. Int Immunol 20:433–443PubMedCrossRefGoogle Scholar
  92. Pace A, Barone G, Lauria A, Martorana A, Piccionello AP, Pierro P, Terenzi A, Almerico AM, Buscemi S, Campanella C et al (2013) Hsp60, a novel target for antitumor therapy: structure-function features and prospective drugs design. Curr Pharm Des 19:2757–2764PubMedCrossRefGoogle Scholar
  93. Pearson CM (1956) Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med Soc Exp Biol Med N Y N 91:95–101CrossRefGoogle Scholar
  94. Pei W, Tanaka K, Huang SC, Xu L, Liu B, Sinclair J, Idol J, Varshney GK, Huang H, Lin S et al (2016) Extracellular HSP60 triggers tissue regeneration and wound healing by regulating inflammation and cell proliferation. Npj Regen Med 1:16013PubMedPubMedCentralCrossRefGoogle Scholar
  95. Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, Luo H, Zhang Y, He W, Yang K et al (2011) The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics MCP 10:M111.012658PubMedCrossRefGoogle Scholar
  96. Pfister G, Stroh CM, Perschinka H, Kind M, Knoflach M, Hinterdorfer P, Wick G (2005) Detection of HSP60 on the membrane surface of stressed human endothelial cells by atomic force and confocal microscopy. J Cell Sci 118:1587–1594PubMedCrossRefGoogle Scholar
  97. Planesse C, Nativel B, Iwema T, Gasque P, Robert-Da Silva C, Viranaïcken W (2015) Recombinant human HSP60 produced in ClearColi™ BL21(DE3) does not activate the NFκB pathway. Cytokine 73:190–195PubMedCrossRefGoogle Scholar
  98. Pockley AG, Multhoff G (2008) Cell stress proteins in extracellular fluids: friend or foe? Novartis Found Symp 291:86–95 discussion 96–100, 137–140PubMedCrossRefGoogle Scholar
  99. Pockley AG, Bulmer J, Hanks BM, Wright BH (1999) Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones 4:29–35PubMedCrossRefGoogle Scholar
  100. Pockley AG, Muthana M, Calderwood SK (2008) The dual immunoregulatory roles of stress proteins. Trends Biochem Sci 33:71–79PubMedCrossRefGoogle Scholar
  101. Priya S, Sharma SK, Sood V, Mattoo RUH, Finka A, Azem A, De Los Rios P, Goloubinoff P (2013) GroEL and CCT are catalytic unfoldases mediating out-of-cage polypeptide refolding without ATP. Proc Natl Acad Sci U S A 110:7199–7204PubMedPubMedCentralCrossRefGoogle Scholar
  102. Ranford JC, Coates ARM, Henderson B (2000) Chaperonins are cell-signalling proteins: the unfolding biology of molecular chaperones. Expert Rev Mol Med 2:1–17PubMedCrossRefGoogle Scholar
  103. Rea IM, McNerlan S, Pockley AG (2001) Serum heat shock protein and anti-heat shock protein antibody levels in aging. Exp Gerontol 36:341–352PubMedCrossRefGoogle Scholar
  104. Retzlaff C, Yamamoto Y, Okubo S, Hoffman PS, Friedman H, Klein TW (1996) Legionella pneumophila heat-shock protein-induced increase of interleukin-1 beta mRNA involves protein kinase C signalling in macrophages. Immunology 89:281PubMedPubMedCentralCrossRefGoogle Scholar
  105. Roseman AM, Chen S, White H, Braig K, Saibil HR (1996) The chaperonin ATPase cycle: mechanism of allosteric switching and movements of substrate-binding domains in GroEL. Cell 87:241–251PubMedCrossRefGoogle Scholar
  106. Rosenberger K, Dembny P, Derkow K, Engel O, Krüger C, Wolf SA, Kettenmann H, Schott E, Meisel A, Lehnardt S (2015) Intrathecal heat shock protein 60 mediates neurodegeneration and demyelination in the CNS through a TLR4- and MyD88-dependent pathway. Mol Neurodegener 10:5PubMedPubMedCentralCrossRefGoogle Scholar
  107. Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S (1999) Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. EMBO J 18:2040–2048PubMedPubMedCentralCrossRefGoogle Scholar
  108. Schett G, Metzler B, Kleindienst R, Amberger A, Recheis H, Xu Q, Wick G (1999) Myocardial injury leads to a release of heat shock protein (hsp) 60 and a suppression of the anti-hsp65 immune response. Cardiovasc Res 42:685–695PubMedCrossRefGoogle Scholar
  109. Shamaei-Tousi A, Stephens JW, Bin R, Cooper JA, Steptoe A, Coates ARM, Henderson B, Humphries SE (2006) Association between plasma levels of heat shock protein 60 and cardiovascular disease in patients with diabetes mellitus. Eur Heart J 27:1565–1570PubMedCrossRefGoogle Scholar
  110. Shamaei-Tousi A, Steptoe A, O’Donnell K, Palmen J, Stephens JW, Hurel SJ, Marmot M, Homer K, D’Aiuto F, Coates ARM et al (2007a) Plasma heat shock protein 60 and cardiovascular disease risk: the role of psychosocial, genetic, and biological factors. Cell Stress Chaperones 12:384–392PubMedPubMedCentralCrossRefGoogle Scholar
  111. Shamaei-Tousi A, D’Aiuto F, Nibali L, Steptoe A, Coates ARM, Parkar M, Donos N, Henderson B (2007b) Differential regulation of circulating levels of molecular chaperones in patients undergoing treatment for periodontal disease. PLoS One 2:e1198PubMedPubMedCentralCrossRefGoogle Scholar
  112. Sigal LH, Williams S, Soltys B, Gupta R (2001) H9724, a monoclonal antibody to Borrelia burgdorferi’s flagellin, binds to heat shock protein 60 (HSP60) within live neuroblastoma cells: a potential role for HSP60 in peptide hormone signaling and in an autoimmune pathogenesis of the neuropathy of Lyme disease. Cell Mol Neurobiol 21:477–495PubMedCrossRefGoogle Scholar
  113. Sigler PB, Xu Z, Rye HS, Burston SG, Fenton WA, Horwich AL (1998) Structure and function in GroEL-mediated protein folding. Annu Rev Biochem 67:581–608PubMedCrossRefGoogle Scholar
  114. Singh B, Patel HV, Ridley RG, Freeman KB, Gupta RS (1990) Mitochondrial import of the human chaperonin (HSP60) protein. Biochem Biophys Res Commun 169:391–396PubMedCrossRefGoogle Scholar
  115. Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, Panina Bordignon P, Meldolesi J (2009) The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem 110:284–294PubMedCrossRefGoogle Scholar
  116. Tang H, Tian E, Liu C, Wang Q, Deng H (2013) Oxidative stress induces monocyte necrosis with enrichment of cell-bound albumin and overexpression of endoplasmic reticulum and mitochondrial chaperones. PLoS One 8:e59610PubMedPubMedCentralCrossRefGoogle Scholar
  117. Terry DF, McCormick M, Andersen S, Pennington J, Schoenhofen E, Palaima E, Bausero M, Ogawa K, Perls TT, Asea A (2004) Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann N Y Acad Sci 1019:502–505PubMedPubMedCentralCrossRefGoogle Scholar
  118. Trayhurn P, Wood IS (2005) Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 33:1078–1081PubMedCrossRefGoogle Scholar
  119. Tsan M-F, Gao B (2004) Endogenous ligands of Toll-like receptors. J Leukoc Biol 76:514–519PubMedCrossRefGoogle Scholar
  120. Tsan M-F, Gao B (2009) Heat shock proteins and immune system. J Leukoc Biol 85:905–910PubMedCrossRefGoogle Scholar
  121. Vabulas RM, Ahmad-Nejad P, da Costa C, Miethke T, Kirschning CJ, Häcker H, Wagner H (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 276:31332–31339PubMedCrossRefGoogle Scholar
  122. Vachharajani V, Granger DN (2009) Adipose tissue: a motor for the inflammation associated with obesity. IUBMB Life 61:424–430PubMedPubMedCentralCrossRefGoogle Scholar
  123. van Eden W, Tholet JER, van der Zee R, Noordzij A, van Embden JDA, Hensen EJ, Cohen IR (1988) Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 331:171–173PubMedCrossRefGoogle Scholar
  124. van Roon JA, van Eden W, van Roy JL, Lafeber FJ, Bijlsma JW (1997) Stimulation of suppressive T cell responses by human but not bacterial 60-kD heat-shock protein in synovial fluid of patients with rheumatoid arthritis. J Clin Invest 100:459–463PubMedPubMedCentralCrossRefGoogle Scholar
  125. Viitanen PV, Gatenby AA, Lorimer GH (1992) Purified chaperonin 60 (groEL) interacts with the nonnative states of a multitude of Escherichia coli proteins. Protein Sci Publ Protein Soc 1:363–369CrossRefGoogle Scholar
  126. Wang Y, Chen L, Hagiwara N, Knowlton AA (2010) Regulation of heat shock protein 60 and 72 expression in the failing heart. J Mol Cell Cardiol 48:360–366PubMedCrossRefGoogle Scholar
  127. Wick G, Kleindienst R, Dietrich H, Xu Q (1992) Is atherosclerosis an autoimmune disease? Trends Food Sci Technol 3:114–119CrossRefGoogle Scholar
  128. Wu C (1995) Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol 11:441–469PubMedCrossRefGoogle Scholar
  129. Xie J, Zhu H, Guo L, Ruan Y, Wang L, Sun L, Zhou L, Wu W, Yun X, Shen A et al (2010) Lectin-like oxidized low-density lipoprotein receptor-1 delivers heat shock protein 60-fused antigen into the MHC class I presentation pathway. J Immunol Baltim Md 1950 185:2306–2313Google Scholar
  130. Xu Q (2002) Role of heat shock proteins in atherosclerosis. Arterioscler Thromb Vasc Biol 22:1547–1559PubMedCrossRefGoogle Scholar
  131. Xu Q, Schett G, Perschinka H, Mayr M, Egger G, Oberhollenzer F, Willeit J, Kiechl S, Wick G (2000) Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation 102:14–20PubMedCrossRefGoogle Scholar
  132. Yaffe MB, Farr GW, Miklos D, Horwich AL, Sternlicht ML, Sternlicht H (1992) TCP1 complex is a molecular chaperone in tubulin biogenesis. Nature 358:245–248PubMedCrossRefGoogle Scholar
  133. Yam AY, Xia Y, Lin H-TJ, Burlingame A, Gerstein M, Frydman J (2008) Defining the TRiC/CCT interactome links chaperonin function to stabilization of newly made proteins with complex topologies. Nat Struct Mol Biol 15:1255–1262PubMedPubMedCentralCrossRefGoogle Scholar
  134. Zhang X, He M, Cheng L, Chen Y, Zhou L, Zeng H, Pockley AG, Hu FB, Wu T (2008) Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese. Circulation 118:2687–2693PubMedPubMedCentralCrossRefGoogle Scholar
  135. Zhang D, Sun L, Zhu H, Wang L, Wu W, Xie J, Gu J (2012) Microglial LOX-1 reacts with extracellular HSP60 to bridge neuroinflammation and neurotoxicity. Neurochem Int 61:1021–1035PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Brice Nativel
    • 1
  • Cynthia Planesse
    • 1
  • Philippe Gasque
    • 2
    • 3
  • Christine Robert Da Silva
    • 1
  • Olivier Meihac
    • 1
  • Wildriss Viranaïcken
    • 2
    Email author
  1. 1.Université de La Réunion, INSERM, UMR 1188 Diabète athérothombose Thérapies Réunion Océan Indien (DéTROI)Saint-Denis de La RéunionFrance
  2. 2.Université de La Réunion, CNRS UMR9192, INSERM U1187, IRD UMR249, Unité Mixte Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Plateforme Technologique CYROISainte-ClotildeFrance
  3. 3.Laboratoire de biologieSecteur Laboratoire d’immunologie clinique et expérimentale de la zone de l’océan indien (LICE-OI) CHU La Réunion site Félix GuyonSaint-DenisFrance

Personalised recommendations