CHIP: A Co-chaperone for Degradation by the Proteasome

  • Adrienne L. Edkins
Part of the Subcellular Biochemistry book series (SCBI, volume 78)


Protein homeostasis relies on a balance between protein folding and protein degradation. Molecular chaperones like Hsp70 and Hsp90 fulfil well-defined roles in protein folding and conformational stability via ATP dependent reaction cycles. These folding cycles are controlled by associations with a cohort of non-client protein co-chaperones, such as Hop, p23 and Aha1. Pro-folding co-chaperones facilitate the transit of the client protein through the chaperone mediated folding process. However, chaperones are also involved in ubiquitin-mediated proteasomal degradation of client proteins. Similar to folding complexes, the ability of chaperones to mediate protein degradation is regulated by co-chaperones, such as the C terminal Hsp70 binding protein (CHIP). CHIP binds to Hsp70 and Hsp90 chaperones through its tetratricopeptide repeat (TPR) domain and functions as an E3 ubiquitin ligase using a modified RING finger domain (U-box). This unique combination of domains effectively allows CHIP to network chaperone complexes to the ubiquitin-proteasome system. This chapter reviews the current understanding of CHIP as a co-chaperone that switches Hsp70/Hsp90 chaperone complexes from protein folding to protein degradation.


CHIP STUB1 Ubiquitin Proteasome 



Financial support for research activities in the laboratory of the author from the South African National Research Foundation (NRF), Medical Research Council (MRC) South Africa, Rhodes University and Cancer Association of South Africa (CANSA) is gratefully acknowledged. The views reflected in this document are those of the author and should in no way be attributed to the NRF, MRC, Rhodes University or CANSA.


  1. Adachi H, Waza M, Tokui K et al (2007) CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model. J Neurosci 27:5115–5126PubMedGoogle Scholar
  2. Agashe VR, Hartl FU (2000) Roles of molecular chaperones in cytoplasmic protein folding. Semin Cell Dev Biol 11:15–25PubMedGoogle Scholar
  3. Ahmed SF, Deb S, Paul I et al (2012) The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation. J Biol Chem 287:15996–16006PubMedCentralPubMedGoogle Scholar
  4. Alberti S, Demand J, Esser C et al (2002) Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J Biol Chem 277:45920–45927PubMedGoogle Scholar
  5. Alberti S, Esser C, Hohfeld J (2003) BAG-1–a nucleotide exchange factor of Hsc70 with multiple cellular functions. Cell Stress Chaperones 8:225–231PubMedCentralPubMedGoogle Scholar
  6. Alberti S, Bohse 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 15:4003–4010PubMedCentralPubMedGoogle Scholar
  7. Ali MM, Roe SM, Vaughan CK et al (2006) Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature 440:1013–1017PubMedGoogle Scholar
  8. Allan RK, Ratajczak T (2011) Versatile TPR domains accommodate different modes of target protein recognition and function. Cell Stress Chaperones 16:353–367PubMedCentralPubMedGoogle Scholar
  9. Amm I, Sommer T, Wolf DH (2014) Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system. Biochim Biophys Acta 1843:182–196PubMedGoogle Scholar
  10. Babbitt SE, Kiss A, Deffenbaugh AE et al (2005) ATP hydrolysis-dependent disassembly of the 26S proteasome is part of the catalytic cycle. Cell 121:553–565PubMedGoogle Scholar
  11. 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 19:4535–4545PubMedCentralPubMedGoogle Scholar
  12. Bedford L, Paine S, Sheppard PW et al (2010) Assembly, structure, and function of the 26S proteasome. Trends Cell Biol 20:391–401PubMedCentralPubMedGoogle Scholar
  13. 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 272:9002–9010PubMedGoogle Scholar
  14. Blatch GL, Lassle M (1999) The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21:932–939PubMedGoogle Scholar
  15. Brinker A, Scheufler C, Von Der Mulbe F et al (2002) Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70 x Hop x Hsp90 complexes. J Biol Chem 277:19265–19275PubMedGoogle Scholar
  16. Brychzy A, Rein T, Winklhofer KF et al (2003) Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system. EMBO J 22:3613–3623PubMedCentralPubMedGoogle Scholar
  17. Caplan AJ (2003) What is a co-chaperone? Cell Stress Chaperones 8:105–107PubMedCentralPubMedGoogle Scholar
  18. Chang L, Thompson AD, Ung P et al (2010) Mutagenesis reveals the complex relationships between ATPase rate and the chaperone activities of Escherichia coli heat shock protein 70 (Hsp70/DnaK). J Biol Chem 285:21282–21291PubMedCentralPubMedGoogle Scholar
  19. Chapple JP, van der Spuy J, Poopalasundaram S et al (2004) Neuronal DnaJ proteins HSJ1a and HSJ1b: a role in linking the Hsp70 chaperone machine to the ubiquitin-proteasome system? Biochem Soc Trans 32:640–642PubMedGoogle Scholar
  20. Cheetham ME, Jackson AP, Anderton BH (1994) Regulation of 70-kDa heat-shock-protein ATPase activity and substrate binding by human DnaJ-like proteins, HSJ1a and HSJ1b. Eur J Biochem 226:99–107PubMedGoogle Scholar
  21. Chen ZJ, Sun LJ (2009) Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell 33:275–286PubMedGoogle Scholar
  22. Chen L, Kong X, Fu J et al (2009) CHIP facilitates ubiquitination of inducible nitric oxide synthase and promotes its proteasomal degradation. Cell Immunol 258:38–43PubMedGoogle Scholar
  23. Chen Z, Barbi J, Bu S et al (2013) The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39:272–285PubMedGoogle Scholar
  24. Choi YN, Lee SK, Seo TW et al (2014) C-terminus of Hsc70-interacting protein regulates profilin1 and breast cancer cell migration. Biochem Biophys Res Commun 446:1060–1066PubMedGoogle Scholar
  25. Ciechanover A (1998) The ubiquitin-proteasome pathway: on protein death and cell life. EMBO J 17:7151–7160PubMedCentralPubMedGoogle Scholar
  26. 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 3:93–96PubMedGoogle Scholar
  27. Cook C, Gendron TF, Scheffel K et al (2012) Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation. Hum Mol Genet 21:2936–2945PubMedCentralPubMedGoogle Scholar
  28. Cortajarena AL, Regan L (2006) Ligand binding by TPR domains. Protein Sci 15:1193–1198PubMedCentralPubMedGoogle Scholar
  29. Cyr DM, Hohfeld J, Patterson C (2002) Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. Trends Biochem Sci 27:368–375PubMedGoogle Scholar
  30. da Fonseca PC, Morris EP (2008) Structure of the human 26S proteasome: subunit radial displacements open the gate into the proteolytic core. J Biol Chem 283:23305–23314PubMedCentralPubMedGoogle Scholar
  31. Dai Q, Zhang C, Wu Y et al (2003) CHIP activates HSF1 and confers protection against apoptosis and cellular stress. EMBO J 22:5446–5458PubMedCentralPubMedGoogle Scholar
  32. Demand J, Alberti S, Patterson C et al (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 11:1569–1577PubMedGoogle Scholar
  33. Dickey CA, Kamal A, Lundgren K et al (2007) The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest 117:648–658PubMedCentralPubMedGoogle Scholar
  34. Dickey CA, Koren J, Zhang YJ et al (2008) Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci U S A 105:3622–3627PubMedCentralPubMedGoogle Scholar
  35. Ding X, Goldberg MS (2009) Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP. PLoS One 4:e5949PubMedCentralPubMedGoogle Scholar
  36. Ehrlich ES, Wang T, Luo K et al (2009) Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase. Proc Natl Acad Sci U S A 106:20330–20335PubMedCentralPubMedGoogle Scholar
  37. Eisele F, Wolf DH (2008) Degradation of misfolded protein in the cytoplasm is mediated by the ubiquitin ligase Ubr1. FEBS Lett 582:4143–4146PubMedGoogle Scholar
  38. 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 282:37276–37284PubMedGoogle Scholar
  39. Ellis RJ (1997) Molecular chaperones: avoiding the crowd. Curr Biol 7:R531–533PubMedGoogle Scholar
  40. Esser C, Alberti S, Hohfeld J (2004) Cooperation of molecular chaperones with the ubiquitin/proteasome system. Biochim Biophys Acta 1695:171–188PubMedGoogle Scholar
  41. Esser C, Scheffner M, Hohfeld J (2005) The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem 280:27443–27448PubMedGoogle Scholar
  42. Fan M, Park A, Nephew KP (2005) CHIP (carboxyl terminus of Hsc70-interacting protein) promotes basal and geldanamycin-induced degradation of estrogen receptor-alpha. Mol Endocrinol 19:2901–2914PubMedGoogle Scholar
  43. Fedorov AN, Baldwin TO (1997) Cotranslational protein folding. J Biol Chem 272:32715–32718PubMedGoogle Scholar
  44. Frydman J, Hohfeld J (1997) Chaperones get in touch: the Hip-Hop connection. Trends Biochem Sci 22:87–92PubMedGoogle Scholar
  45. Galigniana MD, Harrell JM, Housley PR et al (2004) Retrograde transport of the glucocorticoid receptor in neurites requires dynamic assembly of complexes with the protein chaperone hsp90 and is linked to the CHIP component of the machinery for proteasomal degradation. Brain Res Mol Brain Res 123:27–36PubMedGoogle Scholar
  46. Gao Y, Han C, Huang H et al (2010) Heat shock protein 70 together with its co-chaperone CHIP inhibits TNF-alpha induced apoptosis by promoting proteasomal degradation of apoptosis signal-regulating kinase1. Apoptosis 15:822–833PubMedGoogle Scholar
  47. Gao XC, Zhou CJ, Zhou ZR et al (2011) Co-chaperone HSJ1a dually regulates the proteasomal degradation of ataxin-3. PLoS One 6:e19763PubMedCentralPubMedGoogle Scholar
  48. Gao B, Wang Y, Xu W et al (2013) Inhibition of histone deacetylase activity suppresses IFN-gamma induction of tripartite motif 22 via CHIP-mediated proteasomal degradation of IRF-1. J Immunol 191:464–471PubMedGoogle Scholar
  49. Gaude H, Aznar N, Delay A et al (2012) Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. Oncogene 31:1582–1591PubMedGoogle Scholar
  50. Goldberg AL, Akopian TN, Kisselev AF et al (1997) New insights into the mechanisms and importance of the proteasome in intracellular protein degradation. Biol Chem 378:131–140PubMedGoogle Scholar
  51. Graf C, Stankiewicz M, Nikolay R et al (2010) Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes. Biochemistry 49:2121–2129PubMedGoogle Scholar
  52. Hartl FU (1996) Molecular chaperones in cellular protein folding. Nature 381:571–579PubMedGoogle Scholar
  53. Hatakeyama S, Yada M, Matsumoto M et al (2001) U box proteins as a new family of ubiquitin-protein ligases. J Biol Chem 276:33111–33120PubMedGoogle Scholar
  54. Hatakeyama S, Matsumoto M, Kamura T et al (2004a) U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy. J Neurochem 91:299–307Google Scholar
  55. Hatakeyama S, Matsumoto M, Yada M et al (2004b) Interaction of U-box-type ubiquitin-protein ligases (E3s) with molecular chaperones. Genes Cells 9:533–548Google Scholar
  56. Heinemeyer W, Ramos PC, Dohmen RJ (2004) The ultimate nanoscale mincer: assembly, structure and active sites of the 20S proteasome core. Cell Mol Life Sci 61:1562–1578PubMedGoogle Scholar
  57. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479PubMedGoogle Scholar
  58. Hiromura M, Yano M, Mori H et al (1998) Intrinsic ADP-ATP exchange activity is a novel function of the molecular chaperone, Hsp70. J Biol Chem 273:5435–5438PubMedGoogle Scholar
  59. Hofmann RM, Pickart CM (1999) Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96:645–653PubMedGoogle Scholar
  60. Hohfeld J (1998) Regulation of the heat shock conjugate Hsc70 in the mammalian cell: the characterization of the anti-apoptotic protein BAG-1 provides novel insights. Biol Chem 379:269–274PubMedGoogle Scholar
  61. Hohfeld J, Cyr DM, Patterson C (2001) From the cradle to the grave: molecular chaperones that may choose between folding and degradation. EMBO Rep 2:885–890PubMedCentralPubMedGoogle Scholar
  62. Hwang JR, Zhang C, Patterson C (2005) C-terminus of heat shock protein 70-interacting protein facilitates degradation of apoptosis signal-regulating kinase 1 and inhibits apoptosis signal-regulating kinase 1-dependent apoptosis. Cell Stress Chaperones 10:147–156PubMedCentralPubMedGoogle Scholar
  63. Imai J, Yashiroda H, Maruya M et al (2003) Proteasomes and molecular chaperones: cellular machinery responsible for folding and destruction of unfolded proteins. Cell Cycle 2:585–590PubMedGoogle Scholar
  64. Jacobson AD, Zhang NY, Xu P et al (2009) The lysine 48 and lysine 63 ubiquitin conjugates are processed differently by the 26 s proteasome. J Biol Chem 284:35485–35494PubMedCentralPubMedGoogle Scholar
  65. Jang KW, Lee JE, Kim SY et al (2011a) The C-terminus of Hsp70-interacting protein promotes Met receptor degradation. J Thorac Oncol 6:679–687Google Scholar
  66. Jang KW, Lee KH, Kim SH et al (2011b) Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-kappaB inactivation to regulate breast cancer cell invasion. J Cell Biochem 112:3612–3620Google Scholar
  67. 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 276:42938–42944PubMedGoogle Scholar
  68. Johnson ES, Bartel B, Seufert W et al (1992) Ubiquitin as a degradation signal. EMBO J 11:497–505PubMedCentralPubMedGoogle Scholar
  69. Johnson ES, Ma PC, Ota IM et al (1995) A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem 270:17442–17456PubMedGoogle Scholar
  70. Kabani M, McLellan C, Raynes DA et al (2002) HspBP1, a homologue of the yeast Fes1 and Sls1 proteins, is an Hsc70 nucleotide exchange factor. FEBS Lett 531:339–342PubMedGoogle Scholar
  71. Kajiro M, Hirota R, Nakajima Y et al (2009) The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways. Nat Cell Biol 11:312–319PubMedGoogle Scholar
  72. Kalia LV, Kalia SK, Chau H et al (2011) Ubiquitinylation of alpha-synuclein by carboxyl terminus Hsp70-interacting protein (CHIP) is regulated by Bcl-2-associated athanogene 5 (BAG5). PLoS One 6:e14695PubMedCentralPubMedGoogle Scholar
  73. Kastle M, Grune T (2012) Interactions of the proteasomal system with chaperones: protein triage and protein quality control. Prog Mol Biol Transl Sci 109:113–160PubMedGoogle Scholar
  74. Kettern N, Dreiseidler M, Tawo R et al (2010) Chaperone-assisted degradation: multiple paths to destruction. Biol Chem 391:481–489PubMedGoogle Scholar
  75. Knapp RT, Wong MJ, Kollmannsberger LK et al (2014) Hsp70 cochaperones HspBP1 and BAG-1M differentially regulate steroid hormone receptor function. PLoS One 9:e85415PubMedCentralPubMedGoogle Scholar
  76. Ko HS, Bailey R, Smith WW et al (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc Natl Acad Sci U S A 106:2897–2902PubMedCentralPubMedGoogle Scholar
  77. Ko HR, Kim CK, Lee SB et al (2014) P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP. Cell Death Dis 5:e1131PubMedCentralPubMedGoogle Scholar
  78. Koegl M, Hoppe T, Schlenker S et al (1999) A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96:635–644PubMedGoogle Scholar
  79. Kosik KS, Shimura H (2005) Phosphorylated tau and the neurodegenerative foldopathies. Biochim Biophys Acta 1739:298–310PubMedGoogle Scholar
  80. Kriegenburg F, Ellgaard L, Hartmann-Petersen R (2012) Molecular chaperones in targeting misfolded proteins for ubiquitin-dependent degradation. FEBS J 279:532–542PubMedGoogle Scholar
  81. Kundrat L, Regan L (2010a) Balance between folding and degradation for Hsp90-dependent client proteins: a key role for CHIP. Biochemistry 49:7428–7438Google Scholar
  82. Kundrat L, Regan L (2010b) Identification of residues on Hsp70 and Hsp90 ubiquitinated by the cochaperone CHIP. J Mol Biol 395:587–594Google Scholar
  83. Landry SJ, Gierasch LM (1994) Polypeptide interactions with molecular chaperones and their relationship to in vivo protein folding. Annu Rev Biophys Biomol Struct 23:645–669PubMedGoogle Scholar
  84. Lecker SH, Goldberg AL, Mitch WE (2006) Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807–1819PubMedGoogle Scholar
  85. Lee I, Schindelin H (2008) Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes. Cell 134:268–278PubMedGoogle Scholar
  86. Li F, Xie P, Fan Y et al (2009) C terminus of Hsc70-interacting protein promotes smooth muscle cell proliferation and survival through ubiquitin-mediated degradation of FoxO1. J Biol Chem 284:20090–20098PubMedCentralPubMedGoogle Scholar
  87. Li J, Soroka J, Buchner J (2012) The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta 1823:624–635PubMedGoogle Scholar
  88. Loffek S, Woll S, Hohfeld J et al (2010) The ubiquitin ligase CHIP/STUB1 targets mutant keratins for degradation. Hum Mutat 31:466–476PubMedGoogle Scholar
  89. Lotz GP, Lin H, Harst A et al (2003) Aha1 binds to the middle domain of Hsp90, contributes to client protein activation, and stimulates the ATPase activity of the molecular chaperone. J Biol Chem 278:17228–17235PubMedGoogle Scholar
  90. Luders J, Demand J, Hohfeld J (2000) The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem 275:4613–4617PubMedGoogle Scholar
  91. 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 285:3651–3663PubMedCentralPubMedGoogle Scholar
  92. Mao Y, Deng A, Qu N et al (2006) ATPase domain of Hsp70 exhibits intrinsic ATP-ADP exchange activity. Biochemistry (Mosc) 71:1222–1229Google Scholar
  93. Marques C, Guo W, Pereira P et al (2006) The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. FASEB J 20:741–743PubMedCentralPubMedGoogle Scholar
  94. Martin L, Latypova X, Terro F (2011) Post-translational modifications of tau protein: implications for Alzheimer's disease. Neurochem Int 58:458–471PubMedGoogle Scholar
  95. Maruyama T, Kadowaki H, Okamoto N et al (2010) CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response. EMBO J 29:2501–2514PubMedCentralPubMedGoogle Scholar
  96. Matsumura Y, Sakai J, Skach WR (2013) Endoplasmic reticulum protein quality control is determined by cooperative interactions between Hsp/c70 protein and the CHIP E3 ligase. J Biol Chem 288:31069–31079PubMedCentralPubMedGoogle Scholar
  97. McDonough H, Patterson C (2003) CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 8:303–308PubMedCentralPubMedGoogle Scholar
  98. McLaughlin SH, Smith HW, Jackson SE (2002) Stimulation of the weak ATPase activity of human hsp90 by a client protein. J Mol Biol 315:787–798PubMedGoogle Scholar
  99. McLellan CA, Raynes DA, Guerriero V (2003) HspBP1, an Hsp70 cochaperone, has two structural domains and is capable of altering the conformation of the Hsp70 ATPase domain. J Biol Chem 278:19017–19022PubMedGoogle Scholar
  100. Meacham GC, Patterson C, Zhang W et al (2001) The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol 3:100–105PubMedGoogle Scholar
  101. Medeiros R, Baglietto-Vargas D, LaFerla FM (2011) The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci Ther 17:514–524PubMedCentralPubMedGoogle Scholar
  102. Meimaridou E, Gooljar SB, Chapple JP (2009) From hatching to dispatching: the multiple cellular roles of the Hsp70 molecular chaperone machinery. J Mol Endocrinol 42:1–9PubMedGoogle Scholar
  103. Morishima Y, Wang AM, Yu Z et al (2008) CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins. Hum Mol Genet 17:3942–3952PubMedCentralPubMedGoogle Scholar
  104. Muller P, Hrstka R, Coomber D et al (2008) Chaperone-dependent stabilization and degradation of p53 mutants. Oncogene 27:3371–3383PubMedGoogle Scholar
  105. Muller P, Ruckova E, Halada P et al (2013) C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene 32:3101–3110PubMedGoogle Scholar
  106. Murata S, Minami Y, Minami M et al (2001) CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep 2:1133–1138PubMedCentralPubMedGoogle Scholar
  107. Murata S, Chiba T, Tanaka K (2003) CHIP: a quality-control E3 ligase collaborating with molecular chaperones. Int J Biochem Cell Biol 35:572–578PubMedGoogle Scholar
  108. Murata S, Yashiroda H, Tanaka K (2009) Molecular mechanisms of proteasome assembly. Nat Rev Mol Cell Biol 10:104–115PubMedGoogle Scholar
  109. Nillegoda NB, Theodoraki MA, Mandal AK et al (2010) Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins. Mol Biol Cell 21:2102–2116PubMedCentralPubMedGoogle Scholar
  110. Odunuga OO, Hornby JA, Bies C et al (2003) Tetratricopeptide repeat motif-mediated Hsc70-mSTI1 interaction. Molecular characterization of the critical contacts for successful binding and specificity. J Biol Chem 278:6896–6904PubMedGoogle Scholar
  111. Ohi MD, Vander Kooi CW, Rosenberg JA et al (2003) Structural insights into the U-box, a domain associated with multi-ubiquitination. Nat Struct Biol 10:250–255PubMedGoogle Scholar
  112. Olsen SK, Lima CD (2013) Structure of a ubiquitin E1-E2 complex: insights to E1-E2 thioester transfer. Mol Cell 49:884–896PubMedCentralPubMedGoogle Scholar
  113. Ortega J, Heymann JB, Kajava AV et al (2005) The axial channel of the 20S proteasome opens upon binding of the PA200 activator. J Mol Biol 346:1221–1227PubMedGoogle Scholar
  114. Panaretou B, Prodromou C, Roe SM et al (1998) ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. EMBO J 17:4829–4836PubMedCentralPubMedGoogle Scholar
  115. Paul I, Ahmed SF, Bhowmik A et al (2013) The ubiquitin ligase CHIP regulates c-Myc stability and transcriptional activity. Oncogene 32:1284–1295PubMedGoogle Scholar
  116. Peng HM, Morishima Y, Jenkins GJ et al (2004) Ubiquitylation of neuronal Nitric-oxide synthase by CHIP, a chaperone-dependent E3 ligase. J Biol Chem 279:52970–52977PubMedGoogle Scholar
  117. Petrucelli L, Dickson D, Kehoe K et al (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13:703–714PubMedGoogle Scholar
  118. Prodromou C, Roe SM, O’Brien R et al (1997) Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90:65–75PubMedGoogle Scholar
  119. Prodromou C, Siligardi G, O’Brien R et al (1999) Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO J 18:754–762PubMedCentralPubMedGoogle Scholar
  120. Prodromou C, Panaretou B, Chohan S et al (2000) The ATPase cycle of Hsp90 drives a molecular ‘clamp’ via transient dimerization of the N-terminal domains. EMBO J 19:4383–4392PubMedCentralPubMedGoogle Scholar
  121. Qian SB, McDonough H, Boellmann F et al (2006) CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature 440:551–555PubMedCentralPubMedGoogle Scholar
  122. Raynes DA, Guerriero V Jr (1998) Inhibition of Hsp70 ATPase activity and protein renaturation by a novel Hsp70-binding protein. J Biol Chem 273:32883–32888PubMedGoogle Scholar
  123. Ronnebaum SM, Wu Y, McDonough H et al (2013) The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination. Mol Cell Biol 33:4461–4472PubMedCentralPubMedGoogle Scholar
  124. Roos-Mattjus P, Sistonen L (2004) The ubiquitin-proteasome pathway. Ann Med 36:285–295PubMedGoogle Scholar
  125. Ruckova E, Muller P, Nenutil R et al (2012) Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer. Cell Mol Biol Lett 17:446–458PubMedGoogle Scholar
  126. Saeki Y, Kudo T, Sone T et al (2009) Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome. EMBO J 28:359–371PubMedCentralPubMedGoogle Scholar
  127. Sahara N, Murayama M, Mizoroki T et al (2005) In vivo evidence of CHIP up-regulation attenuating tau aggregation. J Neurochem 94:1254–1263PubMedGoogle Scholar
  128. Salminen A, Ojala J, Kaarniranta K et al (2011) Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer’s disease. Prog Neurobiol 93:99–110PubMedGoogle Scholar
  129. Sarkar S, Brautigan DL, Parsons SJ et al (2014) Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells. Oncogene 33:26–33PubMedCentralPubMedGoogle Scholar
  130. Scheffner M, Nuber U, Huibregtse JM (1995) Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature 373:81–83PubMedGoogle Scholar
  131. Shang Y, Zhao X, Tian B et al (2014) CHIP/Stub1 interacts with eIF5A and mediates its degradation. Cell Signal 26:1098–1104PubMedGoogle Scholar
  132. Shimura H, Schwartz D, Gygi SP et al (2004) CHIP-Hsc70 complex ubiquitinates phosphorylated tau and enhances cell survival. J Biol Chem 279:4869–4876PubMedGoogle Scholar
  133. Shin Y, Klucken J, Patterson C et al (2005) The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem 280:23727–23734PubMedGoogle Scholar
  134. Siligardi G, Hu B, Panaretou B et al (2004) Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle. J Biol Chem 279:51989–51998PubMedGoogle Scholar
  135. Sisoula C, Trachana V, Patterson C et al (2011) CHIP-dependent p53 regulation occurs specifically during cellular senescence. Free Radic Biol Med 50:157–165PubMedGoogle Scholar
  136. Sledz P, Unverdorben P, Beck F et al (2013) Structure of the 26S proteasome with ATP-gammaS bound provides insights into the mechanism of nucleotide-dependent substrate translocation. Proc Natl Acad Sci U S A 110:7264–7269PubMedCentralPubMedGoogle Scholar
  137. Smith HT (1988) A “new” protein: ubiquitin. Science 242:787–788PubMedGoogle Scholar
  138. Smith MC, Scaglione KM, Assimon VA et al (2013) The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry 52:5354–5364PubMedGoogle Scholar
  139. Spratt DE, Wu K, Kovacev J et al (2012) Selective recruitment of an E2~ubiquitin complex by an E3 ubiquitin ligase. J Biol Chem 287:17374–17385PubMedCentralPubMedGoogle Scholar
  140. Stankiewicz M, Nikolay R, Rybin V et al (2010) CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70-bound subtrates. FEBS J 277:3353–3367PubMedGoogle Scholar
  141. Strickland E, Qu BH, Millen L et al (1997) The molecular chaperone Hsc70 assists the in vitro folding of the N-terminal nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator. J Biol Chem 272:25421–25424PubMedGoogle Scholar
  142. Su CH, Wang CY, Lan KH et al (2011) Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase. Cell Signal 23:1824–1830PubMedGoogle Scholar
  143. Sun L, Chen ZJ (2004) The novel functions of ubiquitination in signaling. Curr Opin Cell Biol 16:119–126PubMedGoogle Scholar
  144. Tanaka K (2009) The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci 85:12–36PubMedCentralPubMedGoogle Scholar
  145. Tastan Bishop O, Edkins AL, Blatch GL (2014) Sequence and domain conservation of the coelacanth Hsp40 and Hsp90 chaperones suggests conservation of function. J Exp Zool B Mol Dev Evol 322(6):359–378 doi:10.1002/jez.b.22541Google Scholar
  146. Tsukahara F, Maru Y (2010) Bag1 directly routes immature BCR-ABL for proteasomal degradation. Blood 116:3582–3592PubMedGoogle Scholar
  147. Tsvetkov P, Adamovich Y, Elliott E et al (2011) E3 ligase STUB1/CHIP regulates NAD(P)H:quinone oxidoreductase 1 (NQO1) accumulation in aged brain, a process impaired in certain Alzheimer disease patients. J Biol Chem 286:8839–8845PubMedCentralPubMedGoogle Scholar
  148. Unverdorben P, Beck F, Sledz P et al (2014) Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome. Proc Natl Acad Sci U S A 111:5544–5549PubMedCentralPubMedGoogle Scholar
  149. Van Der Spuy J, Kana BD, Dirr HW et al (2000) Heat shock cognate protein 70 chaperone-binding site in the co-chaperone murine stress-inducible protein 1 maps to within three consecutive tetratricopeptide repeat motifs. Biochem J 345(Pt 3):645–651PubMedCentralPubMedGoogle Scholar
  150. Wagner SA, Beli P, Weinert BT et al (2011) A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol Cell Proteomics 10:M 111 013284Google Scholar
  151. Walz J, Erdmann A, Kania M et al (1998) 26S proteasome structure revealed by three-dimensional electron microscopy. J Struct Biol 121:19–29PubMedGoogle Scholar
  152. Wang X, DeFranco DB (2005) Alternative effects of the ubiquitin-proteasome pathway on glucocorticoid receptor down-regulation and transactivation are mediated by CHIP, an E3 ligase. Mol Endocrinol 19:1474–1482PubMedGoogle Scholar
  153. Wang J, Zhao Q, Qi Q et al (2011) Gambogic acid-induced degradation of mutant p53 is mediated by proteasome and related to CHIP. J Cell Biochem 112:509–519PubMedGoogle Scholar
  154. Wang Y, Guan S, Acharya P et al (2012) Multisite phosphorylation of human liver cytochrome P450 3A4 enhances its gp78- and CHIP-mediated ubiquitination: a pivotal role of its Ser-478 residue in the gp78-catalyzed reaction. Mol Cell Proteomics 11:M 111 010132Google Scholar
  155. Wang S, Li Y, Hu YH et al (2013) STUB1 is essential for T-cell activation by ubiquitinating CARMA1. Eur J Immunol 43:1034–1041PubMedGoogle Scholar
  156. Wegele H, Muller L, Buchner J (2004) Hsp70 and Hsp90–a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1–44PubMedGoogle Scholar
  157. Welch WJ, Brown CR (1996) Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1:109–115PubMedCentralPubMedGoogle Scholar
  158. 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 15:1058–1064PubMedGoogle Scholar
  159. Whitesell L, Cook P (1996) Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells. Mol Endocrinol 10:705–712PubMedGoogle Scholar
  160. Whitesell L, Sutphin PD, Pulcini EJ et al (1998) The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent. Mol Cell Biol 18:1517–1524PubMedCentralPubMedGoogle Scholar
  161. Wiederkehr T, Bukau B, Buchberger A (2002) Protein turnover: a CHIP programmed for proteolysis. Curr Biol 12:R26–28PubMedGoogle Scholar
  162. Wilkinson KD (2000) Ubiquitination and deubiquitination: targeting of proteins for degradation by the proteasome. Semin Cell Dev Biol 11:141–148PubMedGoogle Scholar
  163. Willmer T, Contu L, Blatch GL et al (2013) Knockdown of Hop downregulates RhoC expression, and decreases pseudopodia formation and migration in cancer cell lines. Cancer Lett 328:252–260PubMedGoogle Scholar
  164. Wolf DH, Sommer T, Hilt W (2004) Death gives birth to life: the essential role of the ubiquitin-proteasome system in biology. Biochim Biophys Acta 1695:1–2PubMedGoogle Scholar
  165. Xu W, Marcu M, Yuan X et al (2002) Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci U S A 99:12847–12852PubMedCentralPubMedGoogle Scholar
  166. Xu Z, Devlin KI, Ford MG et al (2006) Structure and interactions of the helical and U-box domains of CHIP, the C terminus of HSP70 interacting protein. Biochemistry 45:4749–4759PubMedGoogle Scholar
  167. Xu Z, Kohli E, Devlin KI et al (2008) Interactions between the quality control ubiquitin ligase CHIP and ubiquitin conjugating enzymes. BMC Struct Biol 8:26PubMedCentralPubMedGoogle Scholar
  168. Yang SW, Oh KH, Park E et al (2013) USP47 and C terminus of Hsp70-interacting protein (CHIP) antagonistically regulate katanin-p60-mediated axonal growth. J Neurosci 33:12728–12738PubMedGoogle Scholar
  169. Younger JM, Ren HY, Chen L et al (2004) A foldable CFTRΔF508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase. J Cell Biol 167:1075–1085PubMedCentralPubMedGoogle Scholar
  170. Zhang C, Xu Z, He XR et al (2005a) CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice. Am J Physiol Heart Circ Physiol 288:H2836–2842Google Scholar
  171. Zhang M, Windheim M, Roe SM et al (2005b) Chaperoned ubiquitylation–crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol Cell 20:525–538Google Scholar
  172. Zhou P, Fernandes N, Dodge IL et al (2003) ErbB2 degradation mediated by the co-chaperone protein CHIP. J Biol Chem 278:13829–13837PubMedGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Biochemistry and Microbiology, Biomedical Biotechnology Research Unit (BioBRU)Rhodes UniversityGrahamstownSouth Africa

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