Skip to main content

Hsp40 Co-chaperones as Drug Targets: Towards the Development of Specific Inhibitors

  • Chapter
  • First Online:
Heat Shock Protein Inhibitors

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 19))

Abstract

The heat shock protein 40 (Hsp40/DNAJ) family of co-chaperones modulates the activity of the major molecular chaperone heat shock protein 70 (Hsp70) protein group. Hsp40 stimulates the basal ATPase activity of Hsp70 and hence regulates the affinity of Hsp70 for substrate proteins. The number of Hsp40 genes in most organisms is substantially greater than the number of Hsp70 genes. Therefore, different Hsp40 family members may regulate different activities of the same Hsp70. This fact, along with increasing knowledge of the function of Hsp40 in diseases, has led to certain Hsp40 isoforms being considered promising drug targets. Here we review the role of Hsp40 in human disease and recent developments towards the creation of Hsp40-specific inhibitors.

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

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11:579–592

    Article  CAS  Google Scholar 

  2. Sterrenberg JN, Blatch GL, Edkins AL (2011) Human DNAJ in cancer and stem cells. Cancer Lett 312:129–142

    Article  CAS  Google Scholar 

  3. Mitra A, Shevde LA, Samant RS (2009) Multi-faceted role of HSP40 in cancer. Clin Exp Metastasis 26:559–567

    Article  CAS  Google Scholar 

  4. Cyr DM, Lu X, Douglas MG (1992) Regulation of Hsp70 function by a eukaryotic DnaJ homolog. J Biol Chem 267:20927–20931

    CAS  Google Scholar 

  5. Suh WC, Burkholder WF, Lu CZ et al (1998) Interaction of the Hsp70 molecular chaperone, DnaK, with its cochaperone DnaJ. Proc Natl Acad Sci U S A 95:15223–15228

    Article  CAS  Google Scholar 

  6. Laufen T, Mayer MP, Beisel C et al (1999) Mechanism of regulation of hsp70 chaperones by DnaJ cochaperones. Proc Natl Acad Sci U S A 96:5452–5457

    Article  CAS  Google Scholar 

  7. Terada K, Mori M (2000) Human DnaJ homologs dj2 and dj3, and bag-1 are positive cochaperones of hsc70. J Biol Chem 275:24728–24734

    Article  CAS  Google Scholar 

  8. Langer T, Lu C, Echols H et al (1992) Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding. Nature 356:683–689

    Article  CAS  Google Scholar 

  9. Lu Z, Cyr DM (1998) Protein folding activity of Hsp70 is modified differentially by the hsp40 co-chaperones Sis1 and Ydj1. J Biol Chem 273:27824–27830

    Article  CAS  Google Scholar 

  10. Fan CY, Ren HY, Lee P et al (2005) The type I Hsp40 zinc finger-like region is required for Hsp70 to capture non-native polypeptides from Ydj1. J Biol Chem 280:695–702

    Article  CAS  Google Scholar 

  11. Hageman J, van Waarde MA, Zylicz A et al (2011) The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities. Biochem J 435:127–142

    Article  CAS  Google Scholar 

  12. Mansson C, Kakkar V, Monsellier E et al (2013) DNAJB6 is a peptide-binding chaperone which can suppress amyloid fibrillation of polyglutamine peptides at substoichiometric molar ratios. Cell Stress Chaperones. doi:10.1007/s12192-013-0448-5

    Google Scholar 

  13. Hageman J, Rujano MA, van Waarde MA et al (2010) A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation. Mol Cell 37:355–369

    Article  CAS  Google Scholar 

  14. Vos MJ, Hageman J, Carra S et al (2008) Structural and functional diversities between members of the human HSPB, HSPH, HSPA, and DNAJ chaperone families. Biochemistry 47:7001–7011

    Article  CAS  Google Scholar 

  15. Hageman J, Kampinga HH (2009) Computational analysis of the human HSPH/HSPA/DNAJ family and cloning of a human HSPH/HSPA/DNAJ expression library. Cell Stress Chaperones 14:1–21

    Article  CAS  Google Scholar 

  16. Bhattacharya A, Kurochkin AV, Yip GN et al (2009) Allostery in Hsp70 chaperones is transduced by subdomain rotations. J Mol Biol 388:475–490

    Article  CAS  Google Scholar 

  17. Swain JF, Schulz EG, Gierasch LM (2006) Direct comparison of a stable isolated Hsp70 substrate-binding domain in the empty and substrate-bound states. J Biol Chem 281:1605–1611

    Article  CAS  Google Scholar 

  18. Bertelsen EB, Chang L, Gestwicki JE et al (2009) Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proc Natl Acad Sci U S A 106:8471–8476

    Article  CAS  Google Scholar 

  19. Zhu X, Zhao X, Burkholder WF et al (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272:1606–1614

    Article  CAS  Google Scholar 

  20. Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684

    Article  CAS  Google Scholar 

  21. Szabo A, Langer T, Schroder H et al (1994) The ATP hydrolysis-dependent reaction cycle of the Escherichia coli Hsp70 system DnaK, DnaJ, and GrpE. Proc Natl Acad Sci U S A 91:10345–10349

    Article  CAS  Google Scholar 

  22. Summers DW, Douglas PM, Ramos CH et al (2009) Polypeptide transfer from Hsp40 to Hsp70 molecular chaperones. Trends Biochem Sci 34:230–233

    Article  CAS  Google Scholar 

  23. Kabani M, Beckerich JM, Brodsky JL (2002) Nucleotide exchange factor for the yeast Hsp70 molecular chaperone Ssa1p. Mol Cell Biol 22:4677–4689

    Article  CAS  Google Scholar 

  24. Choglay AA, Chapple JP, Blatch GL et al (2001) Identification and characterization of a human mitochondrial homologue of the bacterial co-chaperone GrpE. Gene 267:125–134

    Article  CAS  Google Scholar 

  25. Kampinga HH, Hageman J, Vos MJ et al (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14:105–111

    Article  CAS  Google Scholar 

  26. Cheetham ME, Caplan AJ (1998) Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaperones 3:28–36

    Article  CAS  Google Scholar 

  27. Mitra A, Fillmore RA, Metge BJ et al (2008) Large isoform of MRJ (DNAJB6) reduces malignant activity of breast cancer. Breast Cancer Res 10:R22

    Article  CAS  Google Scholar 

  28. Qian YQ, Patel D, Hartl FU et al (1996) Nuclear magnetic resonance solution structure of the human Hsp40 (HDJ-1) J-domain. J Mol Biol 260:224–235

    Article  CAS  Google Scholar 

  29. Pellecchia M, Szyperski T, Wall D et al (1996) NMR structure of the J-domain and the Gly/Phe-rich region of the Escherichia coli DnaJ chaperone. J Mol Biol 260:236–250

    Article  CAS  Google Scholar 

  30. Tsai J, Douglas MG (1996) A conserved HPD sequence of the J-domain is necessary for YDJ1 stimulation of Hsp70 ATPase activity at a site distinct from substrate binding. J Biol Chem 271:9347–9354

    Article  CAS  Google Scholar 

  31. Hennessy F, Boshoff A, Blatch GL (2005) Rational mutagenesis of a 40 kDa heat shock protein from Agrobacterium tumefaciens identifies amino acid residues critical to its in vivo function. Int J Biochem Cell Biol 37:177–191

    Article  CAS  Google Scholar 

  32. Yan W, Craig EA (1999) The glycine-phenylalanine-rich region determines the specificity of the yeast Hsp40 Sis1. Mol Cell Biol 19:7751–7758

    Article  CAS  Google Scholar 

  33. Banecki B, Liberek K, Wall D et al (1996) Structure-function analysis of the zinc finger region of the DnaJ molecular chaperone. J Biol Chem 271:14840–14848

    Article  CAS  Google Scholar 

  34. Szabo A, Korszun R, Hartl FU et al (1996) A zinc finger-like domain of the molecular chaperone DnaJ is involved in binding to denatured protein substrates. EMBO J 15:408–417

    CAS  Google Scholar 

  35. Farh L, Mitchell DA, Deschenes RJ (1995) Farnesylation and proteolysis are sequential, but distinct steps in the CaaX box modification pathway. Arch Biochem Biophys 318:113–121

    Article  CAS  Google Scholar 

  36. Cao M, Wei C, Zhao L et al (2014) DnaJA1/Hsp40 is co-opted by influenza A virus to enhance its viral RNA polymerase activity. J Virol 88:14078–14089

    Article  CAS  Google Scholar 

  37. Stark JL, Mehla K, Chaika N et al (2014) Structure and function of human DnaJ homologue subfamily a member 1 (DNAJA1) and its relationship to pancreatic cancer. Biochemistry 53:1360–1372

    Article  CAS  Google Scholar 

  38. Urano E, Morikawa Y, Komano J (2013) Novel role of HSP40/DNAJ in the regulation of HIV-1 replication. J Acquir Immune Defic Syndr 64:154–162

    Article  CAS  Google Scholar 

  39. Tang D, Khaleque MA, Jones EL et al (2005) Expression of heat shock proteins and heat shock protein messenger ribonucleic acid in human prostate carcinoma in vitro and in tumors in vivo. Cell Stress Chaperones 10:46–58

    Article  CAS  Google Scholar 

  40. Walker VE, Wong MJ, Atanasiu R et al (2010) Hsp40 chaperones promote degradation of the HERG potassium channel. J Biol Chem 285:3319–3329

    Article  CAS  Google Scholar 

  41. Jan CI, Yu CC, Hung MC et al (2011) Tid1, CHIP and ErbB2 interactions and their prognostic implications for breast cancer patients. J Pathol 225:424–437

    Article  CAS  Google Scholar 

  42. Cheng H, Cenciarelli C, Nelkin G et al (2005) Molecular mechanism of hTid-1, the human homolog of Drosophila tumor suppressor l(2)Tid, in the regulation of NF-kappaB activity and suppression of tumor growth. Mol Cell Biol 25:44–59

    Article  CAS  Google Scholar 

  43. Copeland E, Balgobin S, Lee CM et al (2011) hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas. Oncogene 30:2252–2263

    Article  CAS  Google Scholar 

  44. Kurzik-Dumke U, Horner M, Czaja J et al (2008) Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor. Int J Mol Med 21:19–31

    CAS  Google Scholar 

  45. Blumen SC, Astord S, Robin V et al (2012) A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation. Ann Neurol 71:509–519

    Article  CAS  Google Scholar 

  46. Borrell-Pages M, Canals JM, Cordelieres FP et al (2006) Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 116:1410–1424

    Article  CAS  Google 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, e19763

    Article  CAS  Google Scholar 

  48. Gess B, Auer-Grumbach M, Schirmacher A et al (2014) HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum. Neurology 83:1726–1732

    Article  CAS  Google Scholar 

  49. Chang TP, Yu SL, Lin SY et al (2010) Tumor suppressor HLJ1 binds and functionally alters nucleophosmin via activating enhancer binding protein 2alpha complex formation. Cancer Res 70:1656–1667

    Article  CAS  Google Scholar 

  50. Liu Y, Zhou J, Zhang C et al (2014) HLJ1 is a novel biomarker for colorectal carcinoma progression and overall patient survival. Int J Clin Exp Pathol 7:969–977

    Google Scholar 

  51. Tsai MF, Wang CC, Chang GC et al (2006) A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst 98:825–838

    Article  CAS  Google Scholar 

  52. Menezes ME, Mitra A, Shevde LA et al (2012) DNAJB6 governs a novel regulatory loop determining Wnt/beta-catenin signalling activity. Biochem J 444:573–580

    Article  CAS  Google Scholar 

  53. Mitra A, Menezes ME, Pannell LK et al (2012) DNAJB6 chaperones PP2A mediated dephosphorylation of GSK3beta to downregulate beta-catenin transcription target, osteopontin. Oncogene 31:4472–4483

    Article  CAS  Google Scholar 

  54. Harms MB, Sommerville RB, Allred P et al (2012) Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann Neurol 71:407–416

    Article  CAS  Google Scholar 

  55. Sandell SM, Mahjneh I, Palmio J et al (2013) 'Pathognomonic' muscle imaging findings in DNAJB6 mutated LGMD1D. Eur J Neurol. doi:10.1111/ene.12239

    Google Scholar 

  56. Durrenberger PF, Filiou MD, Moran LB et al (2009) DnaJB6 is present in the core of Lewy bodies and is highly up-regulated in parkinsonian astrocytes. J Neurosci Res 87:238–245

    Article  CAS  Google Scholar 

  57. Gillis J, Schipper-Krom S, Juenemann K et al (2013) The DNAJB6 and DNAJB8 protein chaperones prevent intracellular aggregation of polyglutamine peptides. J Biol Chem 288:17225–17237

    Article  CAS  Google Scholar 

  58. Couthouis J, Raphael AR, Siskind C et al (2014) Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy. Neuromuscul Disord 24:431–435

    Article  Google Scholar 

  59. Mansson C, Arosio P, Hussein R et al (2014) Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Abeta42) aggregates leads to sub-stoichiometric inhibition of amyloid formation. J Biol Chem 289:31066–31076

    Article  CAS  Google Scholar 

  60. Mansson C, Kakkar V, Monsellier E et al (2014) DNAJB6 is a peptide-binding chaperone which can suppress amyloid fibrillation of polyglutamine peptides at substoichiometric molar ratios. Cell Stress Chaperones 19:227–239

    Article  CAS  Google Scholar 

  61. Mitra A, Menezes ME, Shevde LA et al (2010) DNAJB6 induces degradation of {beta}-catenin and causes partial reversal of mesenchymal phenotype. J Biol Chem 285:24686–24694

    Google Scholar 

  62. Sarparanta J, Jonson PH, Golzio C et al (2012) Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet 44(450-455):S451–S452

    Google Scholar 

  63. Zhang TT, Jiang YY, Shang L et al (2014) Overexpression of DNAJB6 promotes colorectal cancer cell invasion through an IQGAP1/ERK-dependent signaling pathway. Mol Carcinog. doi:10.1002/mc.22194

    Google Scholar 

  64. Nishizawa S, Hirohashi Y, Torigoe T et al (2012) HSP DNAJB8 controls tumor-initiating ability in renal cancer stem-like cells. Cancer Res 72:2844–2854

    Article  CAS  Google Scholar 

  65. Morita R, Nishizawa S, Torigoe T et al (2014) Heat shock protein DNAJB8 is a novel target for immunotherapy of colon cancer-initiating cells. Cancer Sci 105:389–395

    Article  CAS  Google Scholar 

  66. Hoshino T, Nakaya T, Araki W et al (2007) Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides. Biochem J 402:581–589

    Article  CAS  Google Scholar 

  67. Bernal-Bayard J, Cardenal-Munoz E, Ramos-Morales F (2010) The Salmonella type III secretion effector, salmonella leucine-rich repeat protein (SlrP), targets the human chaperone ERdj3. J Biol Chem 285:16360–16368

    Article  CAS  Google Scholar 

  68. Massey S, Burress H, Taylor M et al (2011) Structural and functional interactions between the cholera toxin A1 subunit and ERdj3/HEDJ, a chaperone of the endoplasmic reticulum. Infect Immun 79:4739–4747

    Article  CAS  Google Scholar 

  69. Tan YL, Genereux JC, Pankow S et al (2014) ERdj3 is an endoplasmic reticulum degradation factor for mutant glucocerebrosidase variants linked to Gaucher’s disease. Chem Biol 21:967–976

    Article  CAS  Google Scholar 

  70. Wen KW, Damania B (2010) Hsp90 and Hsp40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1. Oncogene 29:3532–3544

    Article  CAS  Google Scholar 

  71. Grove DE, Fan CY, Ren HY et al (2011) The endoplasmic reticulum-associated Hsp40 DNAJB12 and Hsc70 cooperate to facilitate RMA1 E3-dependent degradation of nascent CFTRDeltaF508. Mol Biol Cell 22:301–314

    Article  CAS  Google Scholar 

  72. Yamamoto YH, Kimura T, Momohara S et al (2010) A novel ER J-protein DNAJB12 accelerates ER-associated degradation of membrane proteins including CFTR. Cell Struct Funct 35:107–116

    Article  CAS  Google Scholar 

  73. Michailidou K, Hall P, Gonzalez-Neira A et al (2013) Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 45(353-361):361e351–361e352

    Google Scholar 

  74. Pharoah PD, Tsai YY, Ramus SJ et al (2013) GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat Genet 45(362-370):370e361–370e362

    Google Scholar 

  75. Greiner J, Ringhoffer M, Taniguchi M et al (2004) mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. Int J Cancer 108:704–711

    Article  CAS  Google Scholar 

  76. Resto VA, Caballero OL, Buta MR et al (2000) A putative oncogenic role for MPP11 in head and neck squamous cell cancer. Cancer Res 60:5529–5535

    CAS  Google Scholar 

  77. Synofzik M, Haack TB, Kopajtich R et al (2014) Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet 95:689–697

    Article  CAS  Google Scholar 

  78. Benitez BA, Alvarado D, Cai Y et al (2011) Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis. PLoS One 6, e26741

    Article  CAS  Google Scholar 

  79. Cadieux-Dion M, Andermann E, Lachance-Touchette P et al (2013) Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease. Clin Genet 83:571–575

    Article  CAS  Google Scholar 

  80. Greaves J, Lemonidis K, Gorleku OA et al (2012) Palmitoylation-induced aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis. J Biol Chem 287:37330–37339

    Article  CAS  Google Scholar 

  81. Noskova L, Stranecky V, Hartmannova H et al (2011) Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet 89:241–252

    Article  CAS  Google Scholar 

  82. Velinov M, Dolzhanskaya N, Gonzalez M et al (2012) Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in a proportion of cases: study of the Parry family and 8 other families. PLoS One 7, e29729

    Article  CAS  Google Scholar 

  83. Edvardson S, Cinnamon Y, Ta-Shma A et al (2012) A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile Parkinsonism. PLoS One 7, e36458

    Article  CAS  Google Scholar 

  84. Koroglu C, Baysal L, Cetinkaya M et al (2013) DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. Parkinsonism Relat Disord 19:320–324

    Article  Google Scholar 

  85. Vauthier V, Jaillard S, Journel H et al (2012) Homozygous deletion of an 80 kb region comprising part of DNAJC6 and LEPR genes on chromosome 1P31.3 is associated with early onset obesity, mental retardation and epilepsy. Mol Genet Metab 106:345–350

    Article  CAS  Google Scholar 

  86. Yang T, Li XN, Li XG et al (2014) DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial-mesenchymal transition. Biochem Biophys Res Commun 455:298–304

    Article  CAS  Google Scholar 

  87. Liu CM, Fann CS, Chen CY et al (2011) ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22 associated with the subgroup of schizophrenia with deficits in attention and executive function. Biol Psychiatry 70:51–58

    Article  CAS  Google Scholar 

  88. Pan Z, Chen S, Pan X et al (2010) Differential gene expression identified in Uigur women cervical squamous cell carcinoma by suppression subtractive hybridization. Neoplasma 57:123–128

    Article  CAS  Google Scholar 

  89. Lyng H, Brovig RS, Svendsrud DH et al (2006) Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genomics 7:268

    Article  CAS  Google Scholar 

  90. Corazzari M, Lovat PE, Armstrong JL et al (2007) Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57. Br J Cancer 96:1062–1071

    Article  CAS  Google Scholar 

  91. Thomas CG, Spyrou G (2009) ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis. J Biol Chem 284:6282–6290

    Article  CAS  Google Scholar 

  92. Williams JM, Inoue T, Banks L et al (2013) The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation. Mol Biol Cell 24:785–795

    Article  CAS  Google Scholar 

  93. Ioakeimidis F, Ott C, Kozjak-Pavlovic V et al (2014) A splicing mutation in the novel mitochondrial protein DNAJC11 causes motor neuron pathology associated with cristae disorganization, and lymphoid abnormalities in mice. PLoS One 9, e104237

    Article  CAS  Google Scholar 

  94. Katoh M, Katoh M (2003) Identification and characterization of FLJ10737 and CAMTA1 genes on the commonly deleted region of neuroblastoma at human chromosome 1p36.31-p36.23. Int J Oncol 23:1219–1224

    CAS  Google Scholar 

  95. De Bessa SA, Salaorni S, Patrao DF et al (2006) JDP1 (DNAJC12/Hsp40) expression in breast cancer and its association with estrogen receptor status. Int J Mol Med 17:363–367

    Google Scholar 

  96. He HL, Lee YE, Chen HP et al (2015) Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer. Exp Mol Pathol 98:338–345

    Article  CAS  Google Scholar 

  97. Sundaram SK, Huq AM, Sun Z et al (2011) Exome sequencing of a pedigree with Tourette syndrome or chronic tic disorder. Ann Neurol 69:901–904

    Article  CAS  Google Scholar 

  98. Vilarino-Guell C, Rajput A, Milnerwood AJ et al (2014) DNAJC13 mutations in Parkinson disease. Hum Mol Genet 23:1794–1801

    Article  CAS  Google Scholar 

  99. Yi Z, Sperzel L, Nurnberger C et al (2011) Identification and characterization of the host protein DNAJC14 as a broadly active flavivirus replication modulator. PLoS Pathog 7, e1001255

    Article  CAS  Google Scholar 

  100. Yi Z, Yuan Z, Rice CM et al (2012) Flavivirus replication complex assembly revealed by DNAJC14 functional mapping. J Virol 86:11815–11832

    Article  CAS  Google Scholar 

  101. Lindsey JC, Lusher ME, Strathdee G et al (2006) Epigenetic inactivation of MCJ (DNAJD1) in malignant paediatric brain tumours. Int J Cancer 118:346–352

    Article  CAS  Google Scholar 

  102. Shridhar V, Bible KC, Staub J et al (2001) Loss of expression of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer. Cancer Res 61:4258–4265

    CAS  Google Scholar 

  103. Strathdee G, Vass JK, Oien KA et al (2005) Demethylation of the MCJ gene in stage III/IV epithelial ovarian cancer and response to chemotherapy. Gynecol Oncol 97:898–903

    Article  CAS  Google Scholar 

  104. Davey KM, Parboosingh JS, McLeod DR et al (2006) Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J Med Genet 43:385–393

    Article  CAS  Google Scholar 

  105. Ojala T, Polinati P, Manninen T et al (2012) New mutation of mitochondrial DNAJC19 causing dilated and noncompaction cardiomyopathy, anemia, ataxia, and male genital anomalies. Pediatr Res 72:432–437

    Article  CAS  Google Scholar 

  106. Sparkes R, Patton D, Bernier F (2007) Cardiac features of a novel autosomal recessive dilated cardiomyopathic syndrome due to defective importation of mitochondrial protein. Cardiol Young 17:215–217

    Article  Google Scholar 

  107. Sun G, Gargus JJ, Ta DT et al (2003) Identification of a novel candidate gene in the iron-sulfur pathway implicated in ataxia-susceptibility: human gene encoding HscB, a J-type co-chaperone. J Hum Genet 48:415–419

    Article  CAS  Google Scholar 

  108. Davila S, Furu L, Gharavi AG et al (2004) Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat Genet 36:575–577

    Article  CAS  Google Scholar 

  109. Janssen MJ, Salomon J, Te Morsche RH et al (2012) Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease. PLoS One 7, e50324

    Article  CAS  Google Scholar 

  110. Waanders E, Croes HJ, Maass CN et al (2008) Cysts of PRKCSH mutated polycystic liver disease patients lack hepatocystin but express Sec63p. Histochem Cell Biol 129:301–310

    Article  CAS  Google Scholar 

  111. Waanders E, te Morsche RH, de Man RA et al (2006) Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease. Hum Mutat 27:830

    Article  Google Scholar 

  112. Waanders E, Venselaar H, te Morsche RH et al (2010) Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Clin Genet 78:47–56

    Article  CAS  Google Scholar 

  113. Wei H, Xiang L, Wayne AS et al (2012) Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy. Proc Natl Acad Sci U S A 109:6898–6903

    Article  CAS  Google Scholar 

  114. Chen YP, Song W, Huang R et al (2013) GAK rs1564282 and DGKQ rs11248060 increase the risk for Parkinson’s disease in a Chinese population. J Clin Neurosci 20:880–883

    Article  CAS  Google Scholar 

  115. Li NN, Chang XL, Mao XY et al (2012) GWAS-linked GAK locus in Parkinson’s disease in Han Chinese and meta-analysis. Hum Genet 131:1089–1093

    Article  CAS  Google Scholar 

  116. Lin CH, Chen ML, Tai YC et al (2013) Reaffirmation of GAK, but not HLA-DRA, as a Parkinson’s disease susceptibility gene in a Taiwanese population. Am J Med Genet B Neuropsychiatr Genet 162B:841–846

    Article  CAS  Google Scholar 

  117. Pankratz N, Wilk JB, Latourelle JC et al (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 124:593–605

    Article  CAS  Google Scholar 

  118. Susa M, Choy E, Liu X et al (2010) Cyclin G-associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. Mol Cancer Ther 9:3342–3350

    Article  CAS  Google Scholar 

  119. Baets J, Deconinck T, Smets K et al (2010) Mutations in SACS cause atypical and late-onset forms of ARSACS. Neurology 75:1181–1188

    Article  CAS  Google Scholar 

  120. Miyatake S, Miyake N, Doi H et al (2012) A novel SACS mutation in an atypical case with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Intern Med 51:2221–2226

    Article  CAS  Google Scholar 

  121. Parfitt DA, Michael GJ, Vermeulen EG et al (2009) The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Hum Mol Genet 18:1556–1565

    Article  CAS  Google Scholar 

  122. Merla G, Ucla C, Guipponi M et al (2002) Identification of additional transcripts in the Williams-Beuren syndrome critical region. Hum Genet 110:429–438

    Article  CAS  Google Scholar 

  123. Knox C, Luke GA, Blatch GL et al (2011) Heat shock protein 40 (Hsp40) plays a key role in the virus life cycle. Virus Res 160:15–24

    Article  CAS  Google Scholar 

  124. Pesce ER, Cockburn IL, Goble JL et al (2010) Malaria heat shock proteins: drug targets that chaperone other drug targets. Infect Disord Drug Targets 10:147–157

    Article  CAS  Google Scholar 

  125. Njunge JM, Ludewig MH, Boshoff A et al (2013) Hsp70s and J proteins of Plasmodium parasites infecting rodents and primates: structure, function, clinical relevance, and drug targets. Curr Pharm Des 19:387–403

    Article  CAS  Google Scholar 

  126. Andrews JF, Sykora LJ, Letostak TB et al (2012) Cellular stress stimulates nuclear localization signal (NLS) independent nuclear transport of MRJ. Exp Cell Res 318:1086–1093

    Article  CAS  Google Scholar 

  127. Izawa I, Nishizawa M, Ohtakara K et al (2000) Identification of Mrj, a DnaJ/Hsp40 family protein, as a keratin 8/18 filament regulatory protein. J Biol Chem 275:34521–34527

    Article  CAS  Google Scholar 

  128. Dey S, Banerjee P, Saha P (2009) Cell cycle specific expression and nucleolar localization of human J-domain containing co-chaperone Mrj. Mol Cell Biochem 322:137–142

    Article  CAS  Google Scholar 

  129. Mitra A, Menezes ME, Shevde LA et al (2010) DNAJB6 induces degradation of beta-catenin and causes partial reversal of mesenchymal phenotype. J Biol Chem 285:24686–24694

    Article  CAS  Google Scholar 

  130. Chuang JZ, Zhou H, Zhu M et al (2002) Characterization of a brain-enriched chaperone, MRJ, that inhibits Huntingtin aggregation and toxicity independently. J Biol Chem 277:19831–19838

    Article  CAS  Google Scholar 

  131. Watson ED, Mattar P, Schuurmans C et al (2009) Neural stem cell self-renewal requires the Mrj co-chaperone. Dev Dyn 238:2564–2574

    Article  CAS  Google Scholar 

  132. Sato T, Hayashi YK, Oya Y et al (2013) DNAJB6 myopathy in an Asian cohort and cytoplasmic/nuclear inclusions. Neuromuscul Disord 23:269–276

    Article  Google Scholar 

  133. Lawson JC, Blatch GL, Edkins AL (2009) Cancer stem cells in breast cancer and metastasis. Breast Cancer Res Treat 118:241–254

    Article  Google Scholar 

  134. Fewell SW, Smith CM, Lyon MA et al (2004) Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem 279:51131–51140

    Article  CAS  Google Scholar 

  135. Chang L, Bertelsen EB, Wisen S et al (2008) High-throughput screen for small molecules that modulate the ATPase activity of the molecular chaperone DnaK. Anal Biochem 372:167–176

    Article  CAS  Google Scholar 

  136. Wisen S, Bertelsen EB, Thompson AD et al (2010) Binding of a small molecule at a protein-protein interface regulates the chaperone activity of hsp70-hsp40. ACS Chem Biol 5:611–622

    Article  CAS  Google Scholar 

  137. Chang L, Miyata Y, Ung PM et al (2011) Chemical screens against a reconstituted multiprotein complex: myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism. Chem Biol 18:210–221

    Article  CAS  Google Scholar 

  138. Lai YH, Yu SL, Chen HY et al (2013) The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer. Carcinogenesis 34:1069–1080

    Article  CAS  Google Scholar 

  139. Wang CC, Tsai MF, Hong TM et al (2005) The transcriptional factor YY1 upregulates the novel invasion suppressor HLJ1 expression and inhibits cancer cell invasion. Oncogene 24:4081–4093

    Article  CAS  Google Scholar 

  140. Chen HW, Lee JY, Huang JY et al (2008) Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1. Cancer Res 68:7428–7438

    Article  CAS  Google Scholar 

  141. Bischofberger P, Han W, Feifel B et al (2003) D-Peptides as inhibitors of the DnaK/DnaJ/GrpE chaperone system. J Biol Chem 278:19044–19047

    Article  CAS  Google Scholar 

  142. Siegenthaler RK, Christen P (2006) Tuning of DnaK chaperone action by nonnative protein sensor DnaJ and thermosensor GrpE. J Biol Chem 281:34448–34456

    Article  CAS  Google Scholar 

  143. Cassel JA, Ilyin S, McDonnell ME et al (2012) Novel inhibitors of heat shock protein Hsp70-mediated luciferase refolding that bind to DnaJ. Bioorg Med Chem 20:3609–3614

    Article  CAS  Google Scholar 

  144. World Health Organisation (2014) World Malaria Report 2014. World Health Organisation, Geneva

    Google Scholar 

  145. Botha M, Pesce ER, Blatch GL (2007) The Hsp40 proteins of Plasmodium falciparum and other apicomplexa: regulating chaperone power in the parasite and the host. Int J Biochem Cell Biol 39:1781–1803

    Article  CAS  Google Scholar 

  146. Acharya P, Kumar R, Tatu U (2007) Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum. Mol Biochem Parasitol 153:85–94

    Article  CAS  Google Scholar 

  147. Rug M, Maier AG (2011) The heat shock protein 40 family of the malaria parasite Plasmodium falciparum. IUBMB Life 63:1081–1086

    Article  CAS  Google Scholar 

  148. Shonhai A, Maier AG, Przyborski JM et al (2011) Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein Pept Lett 18:143–157

    Article  CAS  Google Scholar 

  149. Hiller NL, Bhattacharjee S, van Ooij C et al (2004) A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306:1934–1937

    Article  CAS  Google Scholar 

  150. Marti M, Good RT, Rug M et al (2004) Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306:1930–1933

    Article  CAS  Google Scholar 

  151. Hiss JA, Przyborski JM, Schwarte F et al (2008) The Plasmodium export element revisited. PLoS One 3, e1560

    Article  CAS  Google Scholar 

  152. Boddey JA, Carvalho TG, Hodder AN et al (2013) Role of plasmepsin V in export of diverse protein families from the Plasmodium falciparum exportome. Traffic 14:532–550

    Article  CAS  Google Scholar 

  153. Kumar A, Tanveer A, Biswas S et al (2010) Nuclear-encoded DnaJ homolog of Plasmodium falciparum interacts with replication ori of the apicoplast genome. Mol Microbiol. doi:10.1111/j.1365-2958.2010.07033.x

    Google Scholar 

  154. Botha M, Chiang AN, Needham PG et al (2011) Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock. Cell Stress Chaperones 16:389–401

    Article  CAS  Google Scholar 

  155. Watanabe J (1997) Cloning and characterization of heat shock protein DnaJ homologues from Plasmodium falciparum and comparison with ring infected erythrocyte surface antigen. Mol Biochem Parasitol 88:253–258

    Article  CAS  Google Scholar 

  156. Flom GA, Lemieszek M, Fortunato EA et al (2008) Farnesylation of Ydj1 is required for in vivo interaction with Hsp90 client proteins. Mol Biol Cell 19:5249–5258

    Article  CAS  Google Scholar 

  157. Misra G, Ramachandran R (2009) Hsp70-1 from Plasmodium falciparum: protein stability, domain analysis and chaperone activity. Biophys Chem 142:55–64

    Article  CAS  Google Scholar 

  158. Nicoll WS, Botha M, McNamara C et al (2007) Cytosolic and ER J-domains of mammalian and parasitic origin can functionally interact with DnaK. Int J Biochem Cell Biol 39:736–751

    Article  CAS  Google Scholar 

  159. Kulzer S, Rug M, Brinkmann K et al (2010) Parasite-encoded Hsp40 proteins define novel mobile structures in the cytosol of the P. falciparum-infected erythrocyte. Cell Microbiol 12:1398–1420

    Article  CAS  Google Scholar 

  160. Acharya P, Chaubey S, Grover M et al (2012) An exported heat shock protein 40 associates with pathogenesis-related knobs in Plasmodium falciparum infected erythrocytes. PLoS One 7, e44605

    Article  CAS  Google Scholar 

  161. Crabb BS, Cooke BM, Reeder JC et al (1997) Targeted gene disruption shows that knobs enable malaria-infected red cells to cytoadhere under physiological shear stress. Cell 89:287–296

    Article  CAS  Google Scholar 

  162. Miller LH, Baruch DI, Marsh K et al (2002) The pathogenic basis of malaria. Nature 415:673–679

    Article  CAS  Google Scholar 

  163. de Koning-Ward TF, Gilson PR, Boddey JA et al (2009) A newly discovered protein export machine in malaria parasites. Nature 459:945–949

    Article  CAS  Google Scholar 

  164. Bullen HE, Charnaud SC, Kalanon M et al (2012) Biosynthesis, localization, and macromolecular arrangement of the Plasmodium falciparum translocon of exported proteins (PTEX). J Biol Chem 287:7871–7884

    Article  CAS  Google Scholar 

  165. Riglar DT, Rogers KL, Hanssen E et al (2013) Spatial association with PTEX complexes defines regions for effector export into Plasmodium falciparum-infected erythrocytes. Nat Commun 4:1415

    Article  CAS  Google Scholar 

  166. Maier AG, Rug M, O'Neill MT et al (2008) Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell 134:48–61

    Article  CAS  Google Scholar 

  167. Kulzer S, Charnaud S, Dagan T et al (2012) Plasmodium falciparum-encoded exported hsp70/hsp40 chaperone/co-chaperone complexes within the host erythrocyte. Cell Microbiol 14:1784–1795

    Article  CAS  Google Scholar 

  168. Da Silva E, Foley M, Dluzewski AR et al (1994) The Plasmodium falciparum protein RESA interacts with the erythrocyte cytoskeleton and modifies erythrocyte thermal stability. Mol Biochem Parasitol 66:59–69

    Article  Google Scholar 

  169. Silva MD, Cooke BM, Guillotte M et al (2005) A role for the Plasmodium falciparum RESA protein in resistance against heat shock demonstrated using gene disruption. Mol Microbiol 56:990–1003

    Article  CAS  Google Scholar 

  170. Pei X, Guo X, Coppel R et al (2007) The ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum stabilizes spectrin tetramers and suppresses further invasion. Blood 110:1036–1042

    Article  CAS  Google Scholar 

  171. Diez-Silva M, Park Y, Huang S et al (2012) Pf155/RESA protein influences the dynamic microcirculatory behavior of ring-stage Plasmodium falciparum infected red blood cells. Sci Rep 2:614

    Article  CAS  Google Scholar 

  172. Sargeant TJ, Marti M, Caler E et al (2006) Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol 7:R12

    Article  CAS  Google Scholar 

  173. Mayer C, Slater L, Erat MC et al (2012) Structural analysis of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) intracellular domain reveals a conserved interaction epitope. J Biol Chem 287:7182–7189

    Article  CAS  Google Scholar 

  174. Parish LA, Mai DW, Jones ML et al (2013) A member of the Plasmodium falciparum PHIST family binds to the erythrocyte cytoskeleton component band 4.1. Malar J 12:160

    Article  CAS  Google Scholar 

  175. Kilili GK, LaCount DJ (2011) An erythrocyte cytoskeleton-binding motif in exported Plasmodium falciparum proteins. Eukaryot Cell 10:1439–1447

    Article  CAS  Google Scholar 

  176. Ramya TN, Surolia N, Surolia A (2006) 15-Deoxyspergualin modulates Plasmodium falciparum heat shock protein function. Biochem Biophys Res Commun 348:585–592

    Article  CAS  Google Scholar 

  177. Chiang AN, Valderramos JC, Balachandran R et al (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg Med Chem 17:1527–1533

    Article  CAS  Google Scholar 

  178. Cockburn IL, Pesce ER, Pryzborski JM et al (2011) Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1. Biol Chem 392:431–438

    Article  CAS  Google Scholar 

  179. Cesa LC, Patury S, Komiyama T et al (2013) Inhibitors of Difficult Protein-Protein Interactions Identified by High-Throughput Screening of Multiprotein Complexes. ACS Chem Biol. doi:10.1021/cb400356m

    Google Scholar 

  180. Makley LN, Gestwicki JE (2013) Expanding the number of ‘druggable’ targets: non-enzymes and protein–protein interactions. Chem Biol Drug Des 81:22–32

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Research activities in the laboratory of ALE are funded by the Cancer Association of South Africa (CANSA), Medical Research Council South Africa (MRC-SA), National Research Foundation (NRF) and Rhodes University. The views expressed are those of the authors and should not be attributed to CANSA, MRC-SA, NRF or Rhodes University. We have attempted to review the literature thoroughly, and we apologise if we have inadvertently missed any important contributions to the field.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Adrienne L. Edkins .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Pesce, ER., Blatch, G.L., Edkins, A.L. (2015). Hsp40 Co-chaperones as Drug Targets: Towards the Development of Specific Inhibitors. In: McAlpine, S., Edkins, A. (eds) Heat Shock Protein Inhibitors. Topics in Medicinal Chemistry, vol 19. Springer, Cham. https://doi.org/10.1007/7355_2015_92

Download citation

Publish with us

Policies and ethics