The Functions of HSP70 in Normal Cells

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


In normal cells, the HSP70 ATPase cycle performs several fundamental functions: (1) together with co-chaperones, HSP70 forms a protein folding mechanism and provides protein transportation into organelles; (2) assisted by HSP40, HSP70 recognizes irreversibly damaged proteins and, assisted by CHIP, Bag-1 and HSJ1 ubiquitinates these proteins, thereby targeting them for degradation via proteasomes; and (3) together with the co-chaperones HSP90, HSP40, Hip, Hop and Bag-1, HSP70 recognizes normal proteins containing the marker sequence KFPRQ and sends these proteins for degradation in lysosomes. Thus, the HSP70 ATPase cycle forms a protein quality control system or the FOlding Refolding Degradation machinery (FORD) and, depending on the state of the protein, sends the protein either for re-folding or for degradation. Because of the FORD machinery, a cell maintains protein homeostasis. The HSP70 ATPase cycle also controls the activity of key signalling proteins by maintaining these proteins in an inactive or active state by regulating their levels and by intracellular transport.


HSP70 Protein folding HSP90 CHIP Proteasomal degradation Lysosomal degradation 


  1. Alberti S, Esser C, Höhfeld J (2003) BAG-1–a nucleotide exchange factor of Hsc70 with multiple cellular functions. Cell Stress Chaperon 8(3):225–231CrossRefGoogle Scholar
  2. Alberti S, Böhse K, Arndt V et al (2004) The cochaperone HspBP1 inhibits the CHIP ubiquitin ligase and stimulates the maturation of the cystic fibrosis transmembrane conductance regulator. Mol Biol Cell 15(9):4003–4010PubMedCrossRefGoogle Scholar
  3. Ancevska-Taneva N, Onoprishvili I, Andria ML et al (2006) A member of the heat shock protein 40 family, hlj1, binds to the carboxyl tail of the human mu opioid receptor. Brain Res 1081(1):28–33PubMedCrossRefGoogle Scholar
  4. Anelli T, Sitia R (2008) Protein quality control in the early secretory pathway. EMBO J 27(2):315–327PubMedCrossRefGoogle Scholar
  5. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223–230PubMedCrossRefGoogle Scholar
  6. Arndt V, Daniel C, Nastainczyk W et al (2005) BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP. Mol Biol Cell 16(12):5891–5900PubMedCrossRefGoogle Scholar
  7. Ballinger CA, Connell P, Wu Y et al (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19(6):4535–4545PubMedGoogle Scholar
  8. Bercovich B, Stancovski I, Mayer A et al (1997) Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70. J Biol Chem 272(14):9002–9010PubMedCrossRefGoogle Scholar
  9. Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125(3):443–451PubMedCrossRefGoogle Scholar
  10. Chapple JP, Cheetham ME (2003) The chaperone environment at the cytoplasmic face of the endoplasmic reticulum can modulate rhodopsin processing and inclusion formation. J Biol Chem 278(21):19087–19094PubMedCrossRefGoogle Scholar
  11. Chiang HL, Terlecky SR, Plant CP, Dice JF (1989) A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science 246(4928):382–385PubMedCrossRefGoogle Scholar
  12. Conn PM, Ulloa-Aguirre A, Ito J, Janovick JA (2007) G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev 59(3):225–250PubMedCrossRefGoogle Scholar
  13. Connell P, Ballinger CA, Jiang J et al (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3(1):93–96PubMedCrossRefGoogle Scholar
  14. Cyr DM, Höhfeld J, Patterson C (2002) Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. Trends Biochem Sci 27(7):368–375PubMedCrossRefGoogle Scholar
  15. Demand J, Lüders J, Höhfeld J (1998) The carboxy-terminal domain of Hsc70 provides binding sites for a distinct set of chaperone cofactors. Mol Cell Biol 18(4):2023–2028PubMedGoogle Scholar
  16. Demand J, Alberti S, Patterson C, Höhfeld J (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 11(20):1569–1577PubMedCrossRefGoogle Scholar
  17. Dobson CM (2003) Protein folding and misfolding. Nature 426(6968):884–890PubMedCrossRefGoogle Scholar
  18. Elliott E, Tsvetkov P, Ginzburg I (2007) BAG-1 associates with Hsc70. Tau complex and regulates the proteasomal degradation of Tau protein. J Biol Chem 282(51):37276–37284PubMedCrossRefGoogle Scholar
  19. Esser C, Alberti S, Höhfeld J (2004) Cooperation of molecular chaperones with the ubiquitin/proteasome system. Biochim Biophys Acta 1695(1–3):171–188PubMedCrossRefGoogle Scholar
  20. Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82(2):373–428PubMedGoogle Scholar
  21. Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94(1):73–82PubMedCrossRefGoogle Scholar
  22. Hartl FU, Hayer-Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol. doi: 10.1038/nsmb.1591 PubMedGoogle Scholar
  23. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479PubMedCrossRefGoogle Scholar
  24. Höhfeld J, Jentsch S (1997) GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16(20):6209–6216PubMedCrossRefGoogle Scholar
  25. Jäättelä M (1999) Escaping cell death: survival proteins in cancer. Exp Cell Res 248(1):30–43PubMedCrossRefGoogle Scholar
  26. Jiang J, Ballinger CA, Wu Y et al (2001) CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J Biol Chem 276(46):42938–42944PubMedCrossRefGoogle Scholar
  27. Kregel KC (2002) Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol 92(5):2177–2186PubMedGoogle Scholar
  28. Lanctôt PM, Leclerc PC, Escher E et al (2006) Role of N-glycan-dependent quality control in the cell-surface expression of the AT1 receptor. Biochem Biophys Res Commun 340(2):395–402PubMedCrossRefGoogle Scholar
  29. Lee DH, Sherman MY, Goldberg AL (1996) Involvement of the molecular chaperone Ydj1 in the ubiquitin-dependent degradation of short-lived and abnormal proteins in Saccharomyces cerevisiae. Mol Cell Biol 16(9):4773–4781PubMedGoogle Scholar
  30. Lüders J, Demand J, Höhfeld J (2006) The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem 275(7):4613–4617CrossRefGoogle Scholar
  31. Luo W, Zhong J, Chang R et al (2010) Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha. J Biol Chem 285(6):3651–3663PubMedCrossRefGoogle Scholar
  32. Majeski AE, Dice JF (2004) Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol 36(12):2435–2444PubMedCrossRefGoogle Scholar
  33. Meacham GC, Patterson C, Zhang W et al (2001) The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 3(1):100–105PubMedCrossRefGoogle Scholar
  34. Molinari M, Galli C, Piccaluga V et al (2002) Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER. J Cell Biol 158(2):247–257PubMedCrossRefGoogle Scholar
  35. Neuhaus EM, Mashukova A, Zhang W et al (2006) A specific heat shock protein enhances the expression of mammalian olfactory receptor proteins. Chem Senses 31(5):445–452PubMedCrossRefGoogle Scholar
  36. Nishikawa S, Brodsky JL, Nakatsukasa K (2005) Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). J Biochem 137(5):551–555PubMedCrossRefGoogle Scholar
  37. Petrucelli L, Dickson D, Kehoe K et al (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13(7):703–714PubMedCrossRefGoogle Scholar
  38. Pratt WB (1997) The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol 37:297–326PubMedCrossRefGoogle Scholar
  39. Pratt WB, Toft DO (2003) Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) 228(2):111–133Google Scholar
  40. Salvador N, Aguado C, Horst M, Knecht E (2000) Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. J Biol Chem 275(35):27447–27456PubMedGoogle Scholar
  41. Sepp-Lorenzino L, Ma Z, Lebwohl DE et al (1995) Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases. J Biol Chem 270(28):16580–16587PubMedCrossRefGoogle Scholar
  42. Westhoff B, Chapple JP, van der Spuy J et al (2005) HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome. Curr Biol 15(11):1058–1064PubMedCrossRefGoogle Scholar
  43. Whitesell L, Mimnaugh EG, De Costa B et al (1994) Inhibition of heat shock protein HSP90-pp 60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 91(18):8324–8328PubMedCrossRefGoogle Scholar
  44. Zhang Y, Nijbroek G, Sullivan ML et al (2001) Hsp70 molecular chaperone facilitates endoplasmic reticulum-associated protein degradation of cystic fibrosis transmembrane conductance regulator in yeast. Mol Biol Cell 12(5):1303–1314PubMedGoogle Scholar

Copyright information

© The Author(s) 2013

Authors and Affiliations

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

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