HSP70 in Damaged Cells

  • Igor MalyshevEmail author
Part of the SpringerBriefs in Biochemistry and Molecular Biology book series (BRIEFSBIOCHEM, volume 6)


In a damaged cell HSP70 maintains protein homeostasis. To achieve this, HSP70, together with co-chaperones, prevents protein aggregation, aids in the dissociation of formed protein aggregates, and targets particular “irreparable” proteins for degradation. In addition, because of HIF-1 activation, the restoration of protein homeostasis forms a specific cell defense against hypoxic injury, against free-radical injury owing to an increase in antioxidant activity, and against calcium injury owing to a reduction in the calcium level in the cell. HSP70 can deposit mutant proteins. However, such mutant proteins can be released when denatured proteins appear in the cell. HSP70 blocks apoptosis by inhibiting the release of proapoptotic factors from mitochondria, inhibiting AIF, caspase-9 and JNK activities, as well as by increasing the Bcl-2 level and decreasing the Bax level. HSP70 protects cells from the accidental triggering of apoptosis by restricting DNA-ase folding until the inhibitor binds to this proapoptotic protein. All of the above processes lead to the general conclusion: HSP70 is a component of an intracellular system aimed at maintaining protein homeostasis and protecting damaged cells.


HSP70 Protein homeostasis Cell damage Cell defence Apoptosis 


  1. Andrabi SA, Kim NS, Yu SW et al (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA 103(48):18308–18313PubMedCrossRefGoogle Scholar
  2. Beere HM, Wolf BB, Cain K et al (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2(8):469–475PubMedCrossRefGoogle Scholar
  3. Bernard C (1878) Lectures on the phenomena common to animals and plants. In: Hoff HE, Guillemin R, Guillemin L, Charles C Thomas (1974) (trans: Springfield IL)Google Scholar
  4. Chan PH (2004) Mitochondria and neuronal death/survival signaling pathways in cerebral ischemia. Neurochem Res 29(11):1943–1949PubMedCrossRefGoogle Scholar
  5. Creagh EM, Carmody RJ, Cotter TG (2000) Heat shock protein 70 inhibits caspase-dependent and -independent apoptosis in Jurkat T cells. Exp Cell Res 257:58–66PubMedCrossRefGoogle Scholar
  6. Doyle SM, Shorter J, Zolkiewski M, Hoskins JR et al (2007a) Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity. Nat Struct Mol Biol 14(2):114–122PubMedCrossRefGoogle Scholar
  7. Doyle SM, Hoskins JR, Wickner S (2007b) Collaboration between the ClpB AAA+ remodeling protein and the DnaK chaperone system. Proc Natl Acad Sci USA 104(27):11138–11144PubMedCrossRefGoogle Scholar
  8. Engels (1987) Anti-Dühring. Marx Engels Collected Works (MECW), LondonGoogle Scholar
  9. Franzmann TM, Wühr M, Richter K, Walter S, Buchner J (2005) The activation mechanism of Hsp26 does not require dissociation of the oligomer. J Mol Biol 350(5):1083–1093PubMedCrossRefGoogle Scholar
  10. Garrido C, Kroemer G (2004) Life’s smile, death’s grin: Vital functions of apoptosis-executing proteins. Curr Opin Cell Biol 16:639–646PubMedCrossRefGoogle Scholar
  11. Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C (2001) A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol 21(5):1874–1887PubMedCrossRefGoogle Scholar
  12. Giffard RG, Yenari MA (2004) Many mechanisms for hsp70 protection from cerebral ischemia. J Neurosurg Anesthesiol 16(1):53–61PubMedCrossRefGoogle Scholar
  13. Gogvadze V, Orrenius S (2006) Mitochondrial regulation of apoptotic cell death. Chem Biol Interact 163(1–2):4–14PubMedCrossRefGoogle Scholar
  14. Guo F, Sigua C, Bali P et al (2005) Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105:1246–1255PubMedCrossRefGoogle Scholar
  15. Gurbuxani S, Schmitt E, Cande C et al (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22:6669–6678PubMedCrossRefGoogle Scholar
  16. Haslbeck M, Walke S, Stromer T et al (1999) Hsp26: a temperature-regulated chaperone. EMBO J 18(23):6744–6751PubMedCrossRefGoogle Scholar
  17. Haslbeck M, Franzmann T, Weinfurtner D, Buchner J (2005) Some like it hot: the structure and function of small heat-shock proteins. Nat Struct Mol Biol 12(10):842–846PubMedCrossRefGoogle Scholar
  18. Haslberger T, Weibezahn J, Zahn R et al (2007) M domains couple the ClpB threading motor with the DnaK chaperone activity. Mol Cell 25(2):247–260PubMedCrossRefGoogle Scholar
  19. Haslbeck M (2002) sHsps and their role in the chaperone network. Cell Mol Life Sci 59(10):1649–1657PubMedCrossRefGoogle Scholar
  20. Hinnerwisch J, Fenton WA, Furtak KJ, Farr GW, Horwich AL (2005) Loops in the central channel of ClpA chaperone mediate protein binding, unfolding, and translocation. Cell 121(7):1029–1041PubMedCrossRefGoogle Scholar
  21. Jäättelä M, Wissing D, Kokholm K, Kallunki T, Egeblad M (1998) Hsp70 exertsitsanti-apoptotic function downstream of caspase-3-like proteases. EMBO J 17:6124–6134PubMedCrossRefGoogle Scholar
  22. Jiang B, Xiao W, Shi Y, Liu M, Xiao X (2005) Heat shock pretreatment inhibited the release of Smac/DIABLO from mitochondria and apoptosis induced by hydrogen peroxide in cardiomyocytes and C2C12 myogenic cells. Cell Stress Chaperones 10(3):252–262PubMedCrossRefGoogle Scholar
  23. Kalinowska M, Garncarz W, Pietrowska M, Garrard WT, Widlak P (2005) Regulation of the human apoptotic DNase/RNase Endonuclease G: Involvement of Hsp70 and ATP. Apoptosis 10:821–830PubMedCrossRefGoogle Scholar
  24. Kauppinen TM, Swanson RA (2007) The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience 145(4):1267–1272PubMedCrossRefGoogle Scholar
  25. Kelly S, Zhang ZJ, Zhao H et al (2002) Gene transfer of HSP72 protects cornu ammonis 1 region of the hippocampus neurons from global ischemia: influence of Bcl-2. Ann Neurol 52(2):160–167PubMedCrossRefGoogle Scholar
  26. Kitagawa M, Matsumura Y, Tsuchido T (2000) Small heat shock proteins, IbpA and IbpB, are involved in resistances to heat and superoxide stresses in Escherichia coli. FEMS Microbiol Lett 184(2):165–171PubMedCrossRefGoogle Scholar
  27. Kitamura C, Ogawa Y, Nishihara T, Morotomi T, Terashita M (2003) Transient co-localization of c-Jun N-terminal kinase and c-Jun with heat shock protein 70 in pulp cells during apoptosis. J Dent Res 82(2):91–95PubMedCrossRefGoogle Scholar
  28. Lee GJ, Vierling E (2000) A small heat shock protein cooperates with heat shock protein 70 systems to reactivate a heat-denatured protein. Plant Physiol 122(1):189–198PubMedCrossRefGoogle Scholar
  29. Lee SH, Kwon HM, Kim YJ, Lee KM, Kim M, Yoon BW (2004) Effects of hsp70.1 gene knockout on the mitochondrial apoptotic pathway after focal cerebral ischemia. Stroke 35(9):2195–2199 Google Scholar
  30. Lee JS, Lee JJ, Seo JS (2005) HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis. J Biol Chem 280(8):6634–6641PubMedCrossRefGoogle Scholar
  31. Leist M, Jäättelä M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2(8):589–598PubMedCrossRefGoogle Scholar
  32. Liberek K, Lewandowska A, Zietkiewicz S (2008) Chaperones in control of protein disaggregation. EMBO J 27(2):328–335PubMedCrossRefGoogle Scholar
  33. Lum R, Tkach JM, Vierling E, Glover JR (2004) Evidence for an unfolding/threading mechanism for protein disaggregation by Saccharomyces cerevisiae Hsp104. J Biol Chem 279(28):29139–29146PubMedCrossRefGoogle Scholar
  34. Luo W, Zhong J, Chang R, Hu H, Pandey A, Semenza GL (2010) Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha. J Biol Chem 285(6):3651–3653PubMedCrossRefGoogle Scholar
  35. Martin SJ, Newmeyer DD, Mathias S et al (1995) Cell-free reconstitution of Fas-, UV radiation- and ceramide-induced apoptosis. EMBO J 14(21):5191–5200PubMedGoogle Scholar
  36. Matsumori Y, Hong SM, Aoyama K et al (2005) Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab 25:899–910PubMedCrossRefGoogle Scholar
  37. Matsumori Y, Northington FJ, Hong SM et al (2006) Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70. Stroke 37(2):507–512PubMedCrossRefGoogle Scholar
  38. Matsumoto S, Friberg H, Ferrand-Drake M, Wieloch T (1999) Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 19(7):736–741PubMedCrossRefGoogle Scholar
  39. Matuszewska M, Kuczyńska-Wiśnik D, Laskowska E, Liberek K (2005) The small heat shock protein IbpA of Escherichia coli cooperates with IbpB in stabilization of thermally aggregated proteins in a disaggregation competent state. J Biol Chem 280(13):12292–12298PubMedCrossRefGoogle Scholar
  40. Meacham GC, Patterson C, Zhang W, Younger JM, Cyr DM (2001) The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 3(1):100–105PubMedCrossRefGoogle Scholar
  41. Merry DE, Korsmeyer SJ (1997) Bcl-2 gene family in the nervous system. Annu Rev Neurosci 20:245–267PubMedCrossRefGoogle Scholar
  42. Mogk A, Deuerling E, Vorderwülbecke S, Vierling E, Bukau B (2003) Small heat shock proteins, ClpB and the DnaK system form a functional triade in reversing protein aggregation. Mol Microbiol 50(2):585–595PubMedCrossRefGoogle Scholar
  43. Nakamoto H, Suzuki N, Roy SK (2000) Constitutive expression of a small heat-shock protein confers cellular thermotolerance and thermal protection to the photosynthetic apparatus in cyanobacteria. FEBS Lett 483(2–3):169–174PubMedCrossRefGoogle Scholar
  44. Neupert W, Brunner M (2002) The protein import motor of mitochondria. Nat Rev Mol Cell Biol 3(8):555–565PubMedCrossRefGoogle Scholar
  45. Nylandsted J, Rohde M, Brand K, Bastholm L, Elling F, Jäättelä M (2000) Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci USA 97(14):7871–7876PubMedCrossRefGoogle Scholar
  46. Ouyang YB, Xu LJ, Sun YJ, Giffard RG (2006) Overexpression of inducible heat shock protein 70 and its mutants in astrocytes is associated with maintenance of mitochondrial physiology during glucose deprivation stress. Cell Stress Chaperones 11(2):180–186PubMedCrossRefGoogle Scholar
  47. Papadopoulos MC, Sun XY, Cao J, Mivechi NF, Giffard RG (1996) Over-expression of HSP-70 protects astrocytes from combined oxygen-glucose deprivation. NeuroReport 7(2):429–432PubMedCrossRefGoogle Scholar
  48. Park HS, Lee JS, Huh SH, Seo JS, Choi EJ (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J 20(3):446–456PubMedCrossRefGoogle Scholar
  49. Ravagnan L, Gurbuxani S, Susin SA et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3(9):839–843PubMedCrossRefGoogle Scholar
  50. Romero C, Benedí J, Villar A, Martín-Aragón S (2010) Involvement of Hsp70, a stress protein, in the resistance of long-term culture of PC12 cells against sodium nitroprusside (SNP)-induced cell death. Arch Toxicol 84:699–708PubMedCrossRefGoogle Scholar
  51. Rosette C, Karin M (1995) Cytoskeletal control of gene expression: depolymerization of microtubules activates NF-kappa B. Cytoskeletal control of gene expression: depolymerization of microtubules activates NF-kappa B. J Cell Biol 128(6):1111–1119PubMedCrossRefGoogle Scholar
  52. Rogue PJ, Ritz MF, Malviya AN (1993) Impaired gene transcription and nuclear protein kinase C activation in the brain and liver of aged rats. FEBS Lett 334(3):351–354PubMedCrossRefGoogle Scholar
  53. Ruchalski K, Mao H, Li Z et al (2006) Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. J Biol Chem 281:7873–7880PubMedCrossRefGoogle Scholar
  54. Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2(8):476–483PubMedCrossRefGoogle Scholar
  55. Sakahira H, Nagata S (2002) Co-translational folding of caspase-activated DNase with Hsp70, Hsp40, and inhibitor of caspase-activated DNase. J Biol Chem 277(5):3364–3370PubMedCrossRefGoogle Scholar
  56. Schaupp A, Marcinowski M, Grimminger V, Bösl B, Walter S (2007) Processing of proteins by the molecular chaperone Hsp104. J Mol Biol 370(4):674–686PubMedCrossRefGoogle Scholar
  57. Schlieker C, Weibezahn J, Patzelt H et al (2004) Substrate recognition by the AAA + chaperone ClpB. Nat Struct Mol Biol 11(7):607–615PubMedCrossRefGoogle Scholar
  58. Sharma M, Ganguly NK, Chaturvedi G et al (2003) A possible role of HSP70 in mediating cardioprotection in patients undergoing CABG. Mol Cell Biochem 247(1–2):6–31Google Scholar
  59. Shinder GA, Lacourse MC, Minotti S, Durham HD (2001) Mutant Cu/Zn-superoxide dismutase proteins have altered solubility and interact with heat shock/stress proteins in models of amyotrophic lateral sclerosis. J Biol Chem 276(16):12791–12796PubMedCrossRefGoogle Scholar
  60. Slee EA, Harte MT, Kluck RM et al (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 144(2):281–292PubMedCrossRefGoogle Scholar
  61. Steel R, Doherty JP, Buzzard K et al (2004) Hsp72 inhibits apoptosis upstream of the mitochondria and not through interactions with Apaf-1. J Biol Chem 279(49):51490–51499PubMedCrossRefGoogle Scholar
  62. Stankiewicz AR, Lachapelle G, Foo CP, Radicioni SM, Mosser DD (2005) Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 280(46):38729–38739PubMedCrossRefGoogle Scholar
  63. Suzuki K, Murtuza B, Sammut IA et al (2002) Heat shock protein 72 enhances manganese superoxide dismutase activity during myocardial ischemia-reperfusion injury, associated with mitochondrial protection and apoptosis reduction. Circulation 106(12 Suppl 1):I270–I276 PubMedGoogle Scholar
  64. Sun Y, Ouyang YB, Xu L et al (2006) The carboxyl-terminal domain of inducible Hsp70 protects from ischemic injury in vivo and in vitro. J Cereb Blood Flow Metab 26(7):937–950PubMedCrossRefGoogle Scholar
  65. Szenczi O, Kemecsei P, Miklós Z et al (2005) In vivo heat shock preconditioning mitigates calcium overload during ischaemia/reperfusion in the isolated, perfused rat heart. Pflugers Arch 449(6):518–525PubMedCrossRefGoogle Scholar
  66. Tsuchiya D, Hong S, Matsumori Y et al (2003) Overexpression of rat heat shock protein 70 is associated with reduction of early mitochondrial cytochrome C release and subsequent DNA fragmentation after permanent focal ischemia. J Cereb Blood Flow Metab 23(6):718–727PubMedCrossRefGoogle Scholar
  67. Thorburn A (2004) Death receptor-induced cell killing. Cell Signal 16(2):139–144PubMedCrossRefGoogle Scholar
  68. Urushitani M, Kurisu J, Tateno M et al (2004) CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70. J Neurochem 90(1):231–244PubMedCrossRefGoogle Scholar
  69. Weibezahn J, Tessarz P, Schlieker C et al (2004) Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB. Cell 119(5):653–655PubMedCrossRefGoogle Scholar
  70. Xu L, Giffard RG (1997) HSP70 protects murine astrocytes from glucose deprivation injury. Neurosci Lett 224(1):9–12PubMedCrossRefGoogle Scholar
  71. Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407(6805):802–809PubMedCrossRefGoogle Scholar
  72. Zietkiewicz S, Lewandowska A, Stocki P, Liberek K (2006) Hsp70 chaperone machine remodels protein aggregates at the initial step of Hsp70-Hsp100-dependent disaggregation. J Biol Chem 281(11):7022–7099PubMedCrossRefGoogle Scholar

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© The Author(s) 2013

Authors and Affiliations

  1. 1.Department of PathophysiologyMoscow State University of Medicine and DentistryMoscowRussia

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