Cell Stress and Chaperones

, Volume 24, Issue 1, pp 125–148 | Cite as

The Hsp70/J-protein machinery of the African trypanosome, Trypanosoma brucei

  • Stephen John Bentley
  • Miebaka Jamabo
  • Aileen BoshoffEmail author
Original Paper


The etiological agent of the neglected tropical disease African trypanosomiasis, Trypanosoma brucei, possesses an expanded and diverse repertoire of heat shock proteins, which have been implicated in cytoprotection, differentiation, as well as progression and transmission of the disease. Hsp70 plays a crucial role in proteostasis, and inhibition of its interactions with co-chaperones is emerging as a potential therapeutic target for numerous diseases. In light of genome annotations and the release of the genome sequence of the human infective subspecies, an updated and current in silico overview of the Hsp70/J-protein machinery in both T. brucei brucei and T. brucei gambiense was conducted. Functional, structural, and evolutionary analyses of the T. brucei Hsp70 and J-protein families were performed. The Hsp70 and J-proteins from humans and selected kinetoplastid parasites were used to assist in identifying proteins from T. brucei, as well as the prediction of potential Hsp70–J-protein partnerships. The Hsp70 and J-proteins were mined from numerous genome-wide proteomics studies, which included different lifecycle stages and subcellular localisations. In this study, 12 putative Hsp70 proteins and 67 putative J-proteins were identified to be encoded on the genomes of both T. brucei subspecies. Interestingly there are 6 type III J-proteins that possess tetratricopeptide repeat-containing (TPR) motifs. Overall, it is envisioned that the results of this study will provide a future context for studying the biology of the African trypanosome and evaluating Hsp70 and J-protein interactions as potential drug targets.


African trypanosomiasis Trypanosoma brucei Hsp70 J-protein Hsp110 


Funding information

This work was funded by a grant from the National Research Foundation (NRF), grant number 87663. S.J.B. is the recipient of an NRF Doctoral Innovation Scholarship. M.J. is the recipient of an NRF DAAD Fellowship.

Supplementary material

12192_2018_950_MOESM1_ESM.docx (221 kb)
Fig. S1 Alignment of the Hsp70 superfamily from T. brucei in relation to human and other selected kinetoplastids. Multiple sequence alignment of the full-length amino acid sequences was performed using the in-built ClustalW program (Larkin et al. 2007) with default parameters in the MEGA7 software (Kumar et al. 2016). Degree of amino acid conservation is symbolized by the following: (*) all fully conserved residues; (:) one of the residues is fully conserved and (.) residues are weakly conserved. Accession numbers for the J-protein amino acid sequences used in this study are provided in Table 1 and Table S1. (DOCX 220 kb)
12192_2018_950_Fig4_ESM.png (274 kb)
Fig. S2

Schematic representation of the domain architecture of the HSPA/Hsp70 proteins in T. brucei. Each protein sequence for the T. brucei HSPA/Hsp70 family is represented by an open bar with the number of amino acids indicated on either side of the protein bar with the various protein domains and other associated features that were identified using Prosite (Sigrist et al. 2009) and SMART (Letunic et al. 2012). These domains and associated features include the N-terminal nucleotide binding domain (NBD; blue), substrate binding domain (SBD I; light green), C-terminal region (SBD II; yellow) and targeting signal peptides (S; pink). The molecular weight (MW), and isoelectric point (pI) for each T. brucei Hsp70 protein was calculated using the compute pI/Mw tool from ExPASy (; Gasteiger et al. 2005). Data on the phenotypic knockdown screen, using RNAi conducted by Alsford et al. (2011), for HSPA/Hsp70 protein member is provided: ALL-All lifecycle stages; BSF- Bloodstream; DIFF- Differentiation; NE- Non-essential; ND-Not determined. (PNG 273 kb)

12192_2018_950_MOESM2_ESM.tif (607 kb)
High resolution image (TIF 607 kb)
12192_2018_950_Fig5_ESM.png (199 kb)
Fig. S3

Schematic representation of the domain architecture of the HSPH/Hsp110 proteins in T. brucei. Each protein sequence for the T. brucei HSPH/Hsp110 family is represented by an open bar with the number of amino acids indicated on either side of the protein bar with the various protein domains and other associated features that were identified using Prosite (Sigrist et al. 2009) and SMART (Letunic et al. 2012). These domains and associated features include the N-terminal nucleotide binding domain (NBD; blue), substrate binding domain (SBD I; dark green), C-terminal region (SBD II; yellow) and targeting signal peptides (S; pink). The molecular weight (MW), and isoelectric point (pI) for each T. brucei Hsp110 protein was calculated using the compute pI/Mw tool from ExPASy (; Gasteiger et al. 2005). Data on the phenotypic knockdown screen, using RNAi conducted by Alsford et al. (2011), for HSPH/Hsp110 protein member is provided: ALL-All lifecycle stages; BSF- Bloodstream; DIFF- Differentiation. (PNG 199 kb)

12192_2018_950_MOESM3_ESM.tif (509 kb)
High resolution image (TIF 508 kb)
12192_2018_950_MOESM4_ESM.docx (105 kb)
Fig. S4 Alignment of the Type I, II and IV J-protein subfamilies from T. brucei in relation to human and other selected kinetoplastids. Multiple sequence alignment of the full-length amino acid sequences was performed using the in-built ClustalW program (Larkin et al. 2007) with default parameters in the MEGA7 software (Kumar et al. 2016). Degree of amino acid conservation is symbolized by the following: (*) all fully conserved residues; (:) one of the residues is fully conserved and (.) residues are weakly conserved. Accession numbers for the J-protein amino acid sequences used in this study are provided in Table 2 and Table S2. (DOCX 104 kb)
12192_2018_950_MOESM5_ESM.docx (28 kb)
Table S1 Accession numbers for HSPA/Hsp70 and HSPH/Hsp110 amino acid sequences used in this study. (DOCX 27 kb)
12192_2018_950_MOESM6_ESM.docx (24 kb)
Table S2 Accession numbers for J-protein amino acid sequences used in this study. (DOCX 23 kb)


  1. Acestor N, Panigrahi AK, Ogata Y, Anupama A, Stuart KD (2009) Protein composition of Trypanosoma brucei mitochondrial membranes. Proteomics 9:5497–5508. Google Scholar
  2. Acestor N, Zíková A, Dalley RA, Anupama A, Panigrahi AK, Stuart KD (2011) Trypanosoma brucei mitochondrial respiratome: composition and organization in procyclic form. Mol Cell Proteomics MCP 10:M110.006908. Google Scholar
  3. Agarraberes FA, Dice JF (2001) A molecular chaperon complex at the lysosomal membrane is required for protein translocation. J Cell Biol 114:2491–2499Google Scholar
  4. Ahrendt E, Braun JE (2010) Channel triage: emerging insights into the processing and quality control of hERG potassium channels by DnaJA proteins 1, 2 and 4. Channels (Austin) 4(5):335–336Google Scholar
  5. Alsford S, Turner DJ, Obado SO, Sanchez-Flores A, Glover L, Berriman M, Hertz-Fowler C, Horn D (2011) High-throughput phenotyping using parallel sequencing of RNA interference targets in the African trypanosome. Genome Res 21(6):915–924Google Scholar
  6. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25(1):25–29Google Scholar
  7. Aslett M, Aurrecoechea C, Berriman M, Brestelli J, Brunk BP, Carrington M, Depledge DP, Fischer S, Gajria B, Gao X, Gardner MJ, Gingle A, Grant G, Harb OS, Heiges M, Hertz-Fowler C, Houston R, Innamorato F, Iodice J, Kissinger JC, Kraemer E, Li W, Logan FJ, Miller JA, Mitra S, Myler PJ, Nayak V, Pennington C, Phan I, Pinney DF, Ramasamy G, Rogers MB, Roos DS, Ross C, Sivam D, Smith DF, Srinivasamoorthy G, Stoeckert CJ Jr, Subramanian S, Thibodeau R, Tivey A, Treatman C, Velarde G, Wang H (2010) TriTrypDB: a functional genomic resource for the Trypanosomatidae. Nucleic Acids Res 38(Database issue):D457–D462Google Scholar
  8. Bangs JD, Uyetake L, Brickman MJ, Balber AE, Boothroyd JC (1993) Molecular cloning and cellular localization of a BiP homologue in Trypanosoma brucei. Divergent ER retention signals in a lower eukaryote. J Cell Sci 105(4):1101–1113Google Scholar
  9. Bangs JD, Brouch EM, Ransom DM, Roggy JL (1996) A soluble secretory reporter system in Trypanosoma brucei. Studies on endoplasmic reticulum targeting. J Biol Chem 271(31):18387–18393Google Scholar
  10. Barrett MP, Croft SL (2012) Management of trypanosomiasis and leishmaniasis. Br Med Bull 104:175–196Google Scholar
  11. Boorstein WR, Ziegelhoffer T, Craig EA (1994) Molecular evolution of the HSP70 multigene family. J Mol Evol 38(1):1–17Google Scholar
  12. 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 39:1781–1803Google Scholar
  13. Brameier M, Krings A, MacCallum RM (2007) NucPred—predicting nuclear localization of proteins. Bioinformatics 23:1159–1160Google Scholar
  14. Brehmer D, Rüdiger S, Gässler CS, Klostermeier D, Packschies L, Reinstein J, Mayer MP, Bukau B (2001) Tuning of chaperone activity of Hsp70 proteins by modulation of nucleotide exchange. Nat Struct Biol 8:427–432Google Scholar
  15. Broadhead R, Dawe HR, Farr H, Griffiths S, Hart SR, Portman N, Shaw MK, Ginger ML, Gaskell SJ, McKean PG, Gull K (2006) Flagellar motility is required for the viability of the bloodstream trypanosome. Nature 440:224–227. Google Scholar
  16. Brocchieri L, de Macario EC, Macario AJL (2008) hsp70 genes in the human genome: conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol 8:19Google Scholar
  17. Brochu C, Haimeur A, Ouellette M (2004) The heat shock protein HSP70 and heat shock cognate protein HSC70 contribute to antimony tolerance in the protozoan parasite Leishmania. Cell Stress Chaperones 9(3):294–303Google Scholar
  18. Brun R, Blum J, Chappius F, Burri C (2010) Human African trypanosomiasis. Lancet 375(9709):148–159Google Scholar
  19. Brychzy A, Rein T, Winklhofer KF, Hartl FU, Young JC, Obermann WMJ (2003) Cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system. EMBO J 22(14):3613–3623Google Scholar
  20. Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92(3):351–366Google Scholar
  21. Burger A, Ludewig ML, Boshoff A (2014) Investigating the chaperone properties of a novel heat shock protein, Hsp70.c, from Trypanosoma brucei. J Parasitol Res 2014:172582Google Scholar
  22. Butter F, Bucerius F, Michel M, Cicova Z, Mann M, Janzen CJ (2013) Comparative proteomics of two life cycle stages of stable isotope-labeled Trypanosoma brucei reveals novel components of the parasite’s host adaptation machinery. Mol Cell Proteomics MCP 12:172–179. Google Scholar
  23. Cheetham ME, Caplan AJ (1998) Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaperones 3(1):28–36Google Scholar
  24. Claros MG, Vincens P (1996) Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem 241:779–786Google Scholar
  25. Codonho BS, Costa S, Peloso E de F, Joazeiro PP, Gadelha FR, Giorgio S (2016) HSP70 of Leishmania amazonensis alters resistance to different stresses and mitochondrial bioenergetics. Mem Inst Oswaldo Cruz 111(7):460–468Google Scholar
  26. Colasante C, Ellis M, Ruppert T, Voncken F (2006) Comparative proteomics of glycosomes from bloodstream form and procyclic culture formTrypanosoma brucei brucei. PROTEOMICS 6(11):3275-3293Google Scholar
  27. Craig EA, Huang P, Aron R, Andrew A (2006) The diverse roles of J-proteins, the obligate Hsp70 co-chaperone. Rev Physiol Biochem Pharmacol 156:1–21Google Scholar
  28. D'Andrea LD, Regan L (2003) TPR proteins: the versatile helix. Trends Biochem Sci 28(12):655–662Google Scholar
  29. Daugaard M, Rohde M, Jäättelä M (2007) The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett 581(19):3702–3710Google Scholar
  30. Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP (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(5):385–393Google Scholar
  31. DeGrasse JA, Chait BT, Field MC, Rout MP (2008) High-yield isolation and subcellular proteomic characterization of nuclear and subnuclear structures from trypanosomes. Methods Mol Biol Clifton NJ 463:77–92. Google Scholar
  32. Deocaris CC, Kaul SC, Wadhwa R (2006) On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones 11(2):116–128Google Scholar
  33. Deschamps P, Lara E, Marande W, López-García P, Ekelund F, Moreira D (2011) Phylogenomic analysis of kinetoplastids supports that trypanosomatids arose from within bodonids. Mol Biol Evol 28:53–58Google Scholar
  34. Dragovic Z, Broadley SA, Shomura Y, Bracher A, Hartl FU (2006) Molecular chaperones of the Hsp110 family act as nucleotide exchange factors of Hsp70s. EMBO J 25(11):2519–2528Google Scholar
  35. Drini S, Criscuolo A, Lechat P, Imamura H, Skalický T, Rachidi N, Lukeš J, Dujardin JC, Späth GF (2016) Species- and strain-specific adaptation of the HSP70 super family in pathogenic Trypanosomatids. Genome Biol Evol 8(6):1980–1995Google Scholar
  36. Droll D, Minia I, Fadda A, Singh A, Stewart M, Queiroz R, Clayton C (2013) Post-transcriptional regulation of the trypanosome heat shock response by a zinc finger protein. PLoS Pathog 9(4):e1003286Google Scholar
  37. Dvorak JA (1984) The natural heterogeneity of Trypanosoma cruzi: biological and medical implications. J Cell Biochem 24(4):357–371Google Scholar
  38. Easton DP, Kaneko Y, Subjeck JR (2000) The Hsp110 and Grp1 70 stress proteins: newly recognized relatives of the Hsp70s. Cell Stress Chaperones 5(4):276–290Google Scholar
  39. Edkins AL, Ludewig MH, Blatch GL (2004) A Trypanosoma cruzi heat shock protein 40 is able to stimulate the adenosine triphosphate hydrolysis activity of heat shock protein 70 and can substitute for a yeast heat shock protein 40. Int J Biochem Cell Biol 36(8):1585–1598Google Scholar
  40. Emmer BT, Nakayasu ES, Souther C, Choi H, Sobreira TJP, Epting CL, Nesvizhskii AI, Almeida IC, Engman DM (2011) Global analysis of protein palmitoylation in African trypanosomes. Eukaryot Cell 10(3):455-463Google Scholar
  41. Engman DM, Kirchhoff LV, Donelson JE (1989) Molecular cloning of mtp70, a mitochondrial member of the hsp70 family. Mol Cell Biol 9(11):5163–5168Google Scholar
  42. Engstler M, Pfohl T, Herminghaus S, Boshart M, Wiegertjes G, Heddergott N, Overath P (2007) Hydrodynamic flow-mediated protein sorting on the cell surface of trypanosomes. Cell 131(3):505–515Google Scholar
  43. Field MC, Sergeenko T, Wang Y-N, Böhm S, Carrington M (2010) Chaperone requirements for biosynthesis of the trypanosome variant surface glycoprotein. PLoS One 5(1):e8468Google Scholar
  44. Folgueira C, Requena JM (2007) A postgenomic view of the heat shock proteins in kinetoplastids. FEMS Microbiol Rev 31(4):359–377Google Scholar
  45. Freeman BC, Morimoto RI (1996) The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-1 have distinct roles in recognition of a non-native protein and protein refolding. EMBO J 15(12):2969–2979Google Scholar
  46. Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD, Bairoch A (2005) Protein identification and analysis tools on the ExPASy server. In: Walker JM (ed) The proteomics protocols handbook. Humana Press, New York, pp 571–607Google Scholar
  47. Gazestani VH, Yip CW, Nikpour N, Berghuis N, Salavati R (2017) TrypsNetDB: an integrated framework for the functional characterization of trypanosomatid proteins. PLoS Negl Trop Dis 11(2):e0005368Google Scholar
  48. Gibson W (2012) The origins of the trypanosome genome strains Trypanosoma brucei brucei TREU 927, T. b. gambiense DAL 972, T. vivax Y486 and T. congolense IL3000. Parasit Vectors 5:71Google Scholar
  49. Girard M, McPherson PS (2008) RME-8 regulates trafficking of the epidermal growth factor receptor. FEBS Lett 582(6):961–966Google Scholar
  50. Girard M, Poupon V, Blondeau F, McPherson PS (2005) The DnaJ-domain protein RME-8 functions in endosomal trafficking. J Biol Chem 280:40135–40143Google Scholar
  51. Glass DJ, Polvere RI, Van der Ploeg LH (1986) Conserved sequences and transcription of the hsp70 gene family in Trypanosoma brucei. Mol Cell Biol 6(12):4657–4666Google Scholar
  52. Goldshmidt H, Sheiner L, Butikofer P, Roditi I, Uliel S, Gunzel M et al (2008) Role of protein translocation pathways across the endoplasmic reticulum in Trypanosoma brucei. J Biol Chem 283:32085–32098Google Scholar
  53. Goodman AG, Tanner BC, Chang ST, Esteban M, Katze MG (2011) Virus infection rapidly activates the P58(IPK) pathway, delaying peak kinase activation to enhance viral replication. Virology 417(1):27–36Google Scholar
  54. Goos C, Dejung M, Janzen CJ, Butter F, Kramer S (2017) The nuclear proteome of Trypanosoma brucei. PLoS One 12:e0181884. Google Scholar
  55. Grisard EC, Teixeira SMR, de Almeida LGP et al (2014) Trypanosoma cruzi clone Dm28c draft genome sequence. genome announcements. Genome Announc 2(1):e01114–e01113Google Scholar
  56. Gunasekera K, Wüthrich D, Braga-Lagache S, Heller M, Ochsenreiter T (2012) Proteome remodelling during development from blood to insect-form Trypanosoma brucei quantified by SILAC and mass spectrometry. BMC Genomics 13:556. Google Scholar
  57. Guo F, Snapp EL (2013) ERdj3 regulates BiP occupancy in living cells. J Cell Sci 126(6):1429–1439Google Scholar
  58. Gupta RS, Singh B (1994) Phylogenetic analysis of 70 kD heat shock protein sequences suggests a chimeric origin for the eukaryotic cell nucleus. Curr Biol 4:1104–1114Google Scholar
  59. Güther MLS, Urbaniak MD, Tavendale A, Prescott A, Ferguson MAJ (2014) High-confidence glycosome proteome for procyclic form Trypanosoma brucei by epitope-tag organelle enrichment and SILAC proteomics. J Proteome Res 13:2796–2806. Google Scholar
  60. Hartl FU (1996) Molecular chaperones in cellular protein folding. Nature 381(6583):571–579Google Scholar
  61. Hatle KM, Gummadidala P, Navasa N, Bernardo E, Dodge J, Silverstrim B, Fortner K, Burg E, Suratt BT, Hammer J, Radermacher M, Taatjes DJ, Thornton T, Anguita J, Rincon M (2013) MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations. Mol Cell Biol 33(11):2302–2314Google Scholar
  62. Höglund A, Dönnes P, Blum T, Adolph HW, Kohlbacher O (2006) MultiLoc: prediction of protein subcellular localization using N-terminal targeting sequences, sequence motifs and amino acid composition. Bioinformatics 22:1158–1165Google Scholar
  63. Horton P, Park KJ, Obayashi T, Fujita N, Harada H, Adams-Collier CJ, Nakai K (2007) WoLF PSORT: protein localization predictor. Nucleic Acids Res 35:W585–W587Google Scholar
  64. Huang J, van der Ploeg LH (1991) Maturation of polycistronic pre-mRNA in Trypanosoma brucei: analysis of trans splicing and poly(A) addition at nascent RNA transcripts from the hsp70 locus. Mol Cell Biol 11(6):3180–3190Google Scholar
  65. Hughes AL (1993) Nonlinear relationships among evolutionary rates identify regions of functional divergence in heat-shock protein-70 genes. Mol Biol Evol 10:243–255Google Scholar
  66. Iosefson O, Sharon S, Goloubinoff P, Azem A (2012) Reactivation of protein aggregates by mortalin and Tid1-the human mitochondrial Hsp70 chaperone system. Cell Stress Chaperones 17:57–66Google Scholar
  67. Jackson AP, Sanders M, Berry A, McQuillan J, Aslett MA, Quail MA, Chukualim B, Capewell P, MacLeod A, Melville SE, Gibson W, Barry JD, Berriman M, Hertz-Fowler C (2010) The genome sequence of Trypanosoma brucei gambiense, causative agent of chronic human African trypanosomiasis. PLoS Negl Trop Dis 4(4):e658Google Scholar
  68. Jin Y, Zhuang M, Hendershot LM (2009) ERdj3, a luminal ER DnaJ homologue, binds directly to unfolded proteins in the mammalian ER: identification of critical residues. Biochemistry 48:41–49Google Scholar
  69. Jones DT, Taylor WR, Thornton JM (1992) The rapid generation of mutation data matrices from protein sequences. CABIOS 8:275–282Google Scholar
  70. Jones KE, Patel NG, Levy MA, Storeygard A, Balk D, Gittleman JL (2008) Global trends in emerging infectious diseases. Nature 451:990–993Google Scholar
  71. Jung J, Kim J, Roh SH, Jun I, Sampson RD, Gee HY, Choi JY, Lee MG (2016) The HSP70 co-chaperone DNAJC14 targets misfolded pendrin for unconventional protein secretion. Nat Commun 7:11386Google Scholar
  72. Kabani M, Martineau CN (2008) Multiple hsp70 isoforms in the eukaryotic cytosol: mere redundancy or functional specificity? Curr Genomics 9(5):338–248Google Scholar
  73. Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11(8):579–592Google Scholar
  74. Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanquay RM, Bruford EA et al (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14(1):105–111Google Scholar
  75. Karpenahalli MR, Lupas AN, Söding J (2007) TPRpred: a tool for prediction of TPR-, PPR- and SEL1-like repeats from protein sequences. BMC Bioinformatics 8:2Google Scholar
  76. Kaschner LA, Sharma R, Shrestha OK, Meyer AE, Craig EA (2015) A conserved domain important for association of eukaryotic J-protein co-chaperones Jjj1 and Zuo1 with the ribosome. Biochim Biophys Acta 1853(5):1035–1045Google Scholar
  77. Klein KG, Olson CL, Engman DM (1995) Mitochondrial heat shock protein 70 is distributed throughout the mitochondrion in a dyskinetoplastic mutant of Trypanosoma brucei. Mol Biochem Parasitol 70:207–209Google Scholar
  78. Kominek J, Marszalek J, Neuveglise C, Craig EA, Williams BL (2013) The complex evolutionary dynamics of Hsp70s: a genomic and functional perspective. Genome Biol Evol 5:2460–2477Google Scholar
  79. Kumar S, Stecher G, Tamura K (2016) MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol 33:1870–1879Google Scholar
  80. Lamb JR, Tugendreich S, Hieter P (1995) Tetratrico peptide repeat interactions: to TPR or not to TPR? Trends Biochem Sci 20(7):257–259Google Scholar
  81. Larkin MA, Blackshield G, Brown NP, Chenna R, McGettigan PA, McWilliam H et al (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23(21):2947–2948Google Scholar
  82. Le SQ, Gascuel O (2008) An improved general amino acid replacement matrix. Mol Biol Evol 25(7):1307–1320Google Scholar
  83. Lee MG, Van der Ploeg LH (1990) Transcription of the heat shock 70 locus in Trypanosoma brucei. Mol Biochem Parasitol 41(2):221–231Google Scholar
  84. Letunic I, Doerks T, Bork P (2012) SMART 7: recent updates to the protein domain annotation resource. Nucleic Acids Res 40:D302–D305Google Scholar
  85. Liu S, Milne GT, Kuremsky JG, Fink GR, Leppla SH (2004) Identification of the proteins required for biosynthesis of diphthamide, the target of bacterial ADP-ribosylating toxins on translation elongation factor 2. Mol Cell Biol 24(21):9487–9497Google Scholar
  86. Louw CA, Ludewig ML, Mayer J, Blatch GL (2010a) The Hsp70 chaperones of the Tritryps are characterized by unusual features and novel members. Parasitol Int 59(4):497–505Google Scholar
  87. Louw CA, Ludewig MH, Blatch GL (2010b) Overproduction, purification and characterisation of Tbj1, a novel type III Hsp40 from Trypanosoma brucei, the African sleeping sickness parasite. Protein Expr Purif 69(2):168–177Google Scholar
  88. Ludewig MH, Boshoff A, Horn D, Blatch GL (2015) Trypanosoma brucei J protein 2 is a stress inducible and essential Hsp40. Int J Biochem Cell Biol 60:93–98Google Scholar
  89. Maharjan M, Madhubala R (2015) Heat shock protein 70 (HSP70) expression in antimony susceptible/resistant clinical isolates of Leishmania donovani. Nepal J Biotechnol 3(1):22–28Google Scholar
  90. Marcili A, Valente VC, Valente SA, Junqueira AC, da Silva FM, Pinto AY et al (2009) Trypanosoma cruzi in Brazilian Amazonia: lineages TCI and TCIIa in wild primates, Rhodnius spp. and in humans with Chagas disease associated with oral transmission. Int J Parasitol 39(5):615–623Google Scholar
  91. Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62(6):670–684Google Scholar
  92. Mizzen LA, Chang C, Garrels JI, Welch WJ (1989) Identification, characterization, and purification of two mammalian stress proteins present in mitochondria, grp 75, a member of the hsp 70 family and hsp 58, a homolog of the bacterial groEL protein. J Biol Chem 264:20664–20675Google Scholar
  93. Moffatt NS, Bruinsma E, Uhl C, Obermann WM, Toft D (2008) Role of the cochaperone Tpr2 in Hsp90 chaperoning. Biochemistry 47:8203–8213Google Scholar
  94. Mokranjac D, Paschen SA, Kozany C, Prokisch H, Hoppins SC, Nargang FE, Neupert W, Hell K (2003) Tim50, a novel component of the TIM23 preprotein translocase of mitochondria. EMBO J 22:816–825Google Scholar
  95. Muralidharan V, Oksman A, Pal P, Lindquist S, Goldberg DE (2012) Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeatrich parasite proteome during malarial fevers. Nat Commun 3:1310Google Scholar
  96. Murthy AE, Sohal SK, Carrington M, Bishop RP, Allsopp BA (1996) Identification and characterization of two novel tetratricopeptide repeat-containing genes. DNA Cell Biol 15:727–735Google Scholar
  97. Nett IRE, Martin DMA, Miranda-Saavedra D, Lamont D, Barber JD, Mehlert A, Ferguson MAJ (2009) The phosphoproteome of bloodstream form Trypanosoma brucei, causative agent of African sleeping sickness. Mol Cell Proteomics MCP 8:1527–1538. Google Scholar
  98. Niemann M, Wiese S, Mani J, Chanfon A, Jackson C, Meisinger C, Warscheid B, Schneider A (2013) Mitochondrial outer membrane proteome of Trypanosoma brucei reveals novel factors required to maintain mitochondrial morphology. Mol Cell Proteomics MCP 12:515–528. Google Scholar
  99. Ohno M, Kanayama T, Moore R, Ray M, Negishi M (2014) The roles of co-chaperone CCRP/DNAJC7 in Cyp2b10 gene activation and steatosis development in mouse livers. PLoS One 9(12):e115663Google Scholar
  100. Otto H, Conz C, Maier P, Wölfle T, Suzuki CK, Jenö P et al (2005) The chaperones MPP11 and Hsp70L1 form the mammalian ribosome-associated complex. Proc Natl Acad Sci U S A 102(29):10064–10069Google Scholar
  101. Panigrahi AK, Ogata Y, Zíková A, Anupama A, Dalley RA, Acestor N, Myler PJ, Stuart KD (2009) A comprehensive analysis of Trypanosoma brucei mitochondrial proteome. Proteomics 9:434–450. Google Scholar
  102. Peikert CD, Mani J, Morgenstern M, Käser S, Knapp B, Wenger C, Harsman A, Oeljeklaus S, Schneider A, Warscheid B (2017) Charting organellar importomes by quantitative mass spectrometry. Nat Commun 8:15272. Google Scholar
  103. Petersen TN, Brunak S, von Heijne G, Nielsen H (2011) SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods 8:785–786Google Scholar
  104. Petrova K, Oyadomari S, Hendershot LM, Ron D (2008) Regulated association of misfolded endoplasmic reticulum lumenal proteins with P58/DNAJc3. EMBO J 27:2862–2872Google Scholar
  105. Polier S, Dragovic Z, Hartl FU, Bracher A (2008) Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding. Cell 133:1068–1079Google Scholar
  106. Quieroz R, Benz C, Fellenberg K, Hoheisel J, Clayton C (2009) Transcriptome analysis of differentiating trypanosomes reveals the existence of multiple post-transcriptional regulons. BMC Genomics 10:495Google Scholar
  107. Raviol H, Sadlish H, Rodriguez F, Mayer MP, Bukau B (2006) Chaperone network in the yeast cytosol: Hsp110 is revealed as an Hsp70 nucleotide exchange factor. EMBO J 25(11):2510–2518Google Scholar
  108. Requena JM, Montalvo AM, Fraga J (2015) Molecular chaperones of Leishmania: central players in many stress-related and -unrelated physiological processes. Biomed Res Int 2015:301326Google Scholar
  109. Rowland AA, Voeltz GK (2012) Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol 13:607–625. Google Scholar
  110. Rutkowski DT, Kang SW, Goodman AG, Garrison JL, Taunton J, Katze MG, Kaufman RJ, Hegde RS (2007) The role of p58IPK in protecting the stressed endoplasmic reticulum. Mol Biol Cell 18(9):3681–3691Google Scholar
  111. Salmon D, Montero-Lomeli M, Goldenberg S (2001) A DnaJ-like protein homologous to the yeast cochaperone Sis1 (TcJ6p) is involved in initiation of translation in Trypanosoma cruzi. J Biol Chem 276:43970–43979Google Scholar
  112. Saxena A, Banasavadi-Siddegowda YK, Fan Y, Bhattacharya S, Roy G, Giovannucci DR, Frizzell RA, Wang X (2012) Human heat shock protein 105/110 kDa (Hsp105/110) regulates biogenesis and quality control of misfolded cystic fibrosis transmembrane conductance regulator at multiple levels. J Biol Chem 287:19158–19170Google Scholar
  113. Schlenstedt G, Harris S, Risse B, Lill R, Silver PA (1995) A yeast DnaJ homologue, Scj1p, can function in the endoplasmic reticulum with BiP/ Kar2p via a conserved domain that specifies interactions with Hsp70s. J Cell Biol 129:979–988Google Scholar
  114. Searle S, Smith DF (1993) Leishmania major: characterisation and expression of a cytoplasmic stress-related protein. Exp Parasitol 77(1):43–52Google Scholar
  115. Searle S, Campos AJ, Coulson RM, Spithill TW, Smith DF (1989) A family of heat shock protein 70-related genes are expressed in the promastigotes of Leishmania major. Nucleic Acids Res 17(13):5081–5095Google Scholar
  116. Shimogawa MM, Saada EA, Vashisht AA, Barshop WD, Wohlschlegel JA, Hill KL (2015) Cell surface proteomics provides insight into stage-specific remodeling of the host-parasite interface in Trypanosoma brucei. Mol Cell Proteomics MCP 14:1977–1988. Google Scholar
  117. Shonhai A, Maier AG, Przyborski JM, Blatch GL (2011) Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein Pept Lett 18:143–157Google Scholar
  118. Shrestha L, Bolaender A, Patel HJ, Taldone, T (2016) Heat shock protein (HSP) drug discovery and development: targeting heat shock proteins in disease. Curr Top Med Chem 16(25):2753-2764Google Scholar
  119. Sigrist CJ, Cerutti L, De Castro E, Langendijk-Genevaux PS, Bulliard V, Bairoch A et al (2009) PROSITE, a protein domain database for functional characterization and annotation. Nucleic Acids Res 38:161–166Google Scholar
  120. Simarro PP, Jannin J, Cattand P (2008) Eliminating human African trypanosomiasis: where do we stand and what comes next? PLoS Med 5:174–180Google Scholar
  121. Simpson AG, Stevens JR, Lukeš J (2006) The evolution and diversity of kinetoplastid flagellates. Trends Parasitol 22:168–174Google Scholar
  122. Subota I, Julkowska D, Vincensini L, Reeg N, Buisson J, Blisnick T, Huet D, Perrot S, Santi-Rocca J, Duchateau M, Hourdel V, Rousselle J-C, Cayet N, Namane A, Chamot-Rooke J, Bastin P (2014) Proteomic analysis of intact flagella of procyclic Trypanosoma brucei cells identifies novel flagellar proteins with unique sub-localization and dynamics. Mol Cell Proteomics MCP 13:1769–1786. Google Scholar
  123. Subramaniam C, Veazey P, Redmond S, Hayes-Sinclair J, Chambers E, Carrington M, Gull K, Matthews K, Horn D, Field MC (2006) Chromosome-wide analysis of gene function by RNA interference in the African trypanosome. Eukaryot Cell 5:1539–1549Google Scholar
  124. Terada K, Yomogida K, Imai T, Kiyonari H, Takeda N, Kadomatsu T, Yano M, Aizawa S, Mori M (2005) A type I DnaJ homolog, DjA1, regulates androgen receptor signaling and spermatogenesis. EMBO J 24(3):611–622Google Scholar
  125. Tibayrenc M (1998) Beyond strain typing and molecular epidemiology: integrated genetic epidemiology of infectious disease. Parasitol Today 14:323–329Google Scholar
  126. Tibayrenc M, Ayala FJ (2002) The clonal theory of parasitic protozoa: 12 years on. Trends Parasitol 18:405–410Google Scholar
  127. Tibayrenc M, Ward P, Moya A, Ayala FJ (1986) Natural populations of Trypanosoma cruzi, the agent of Chagas disease, have a complex multiclonal structure. Proc Natl Acad Sci U S A 83:1335–1339Google Scholar
  128. Tsigankov P, Gherardini PF, Helmer-Citterich M, Späth GF, Myler PJ, Zilberstein D (2014) Regulation dynamics of Leishmania differentiation: deconvoluting signals and identifying phosphorylation trends. Mol Cell Proteomics 13(7):1787–1799Google Scholar
  129. Týč J, Klingbeil MM, Lukeš J (2015) Mitochondrial heat shock protein machinery Hsp70/Hsp40 is indispensable for proper mitochondrial DNA maintenance and replication. MBio 6(1):e02425–e02414Google Scholar
  130. Uhrigshardt H, Singh A, Kovtunovych G, Ghosh M, Rouault TA (2010) Characterization of the human HSC20, an unusual DnaJ type III protein, involved in iron-sulfur cluster biogenesis. Hum Mol Genet 19(19):3816–3834Google Scholar
  131. Urbaniak MD, Guther MLS, Ferguson MAJ (2012) Comparative SILAC proteomic analysis of Trypanosoma brucei bloodstream and procyclic lifecycle stages. PLoS One 7:e36619. Google Scholar
  132. Urbaniak MD, Martin DMA, Ferguson MAJ (2013) Global quantitative SILAC phosphoproteomics reveals differential phosphorylation is widespread between the procyclic and bloodstream form lifecycle stages of Trypanosoma brucei. J Proteome Res 12:2233–2244. Google Scholar
  133. Urmenyi TP, Silva R, Rondinelli E (2014) The heat shock proteins of Trypanosoma cruzi. In: Santos A, Branquinha M, d’Avila-Levy C, Kneipp L, Sodré C (eds) Proteins and proteomics of Leishmania and Trypanosoma. Subcell Biochem, vol. Springer, Dordrecht, p 74Google Scholar
  134. Wallace FG (1966) The trypanosomatid parasites of insects and arachnids. Exp Parasitol 18:124–193Google Scholar
  135. Wang H, Pezeshki AM, Yu X, Guo C, Subjeck JR, Wang XY (2014) The endoplasmic reticulum chaperone GRP170: from immunobiology to cancer therapeutics. Front Oncol 4:377Google Scholar
  136. Wenzler Y, Schumann Burkard G, Schmidt RS, Mäser P, Bergner A, Roditi I, Brun R (2016) A new approach to chemotherapy: drug-induced differentiation kills African trypanosomes. Sci Rep 6(1)Google Scholar
  137. Wiesgigl M, Clos J (2001) The heat shock protein 90 of Leishmania donovani. Med Microbiol Immunol 190(1–2):27–31Google Scholar
  138. World Health Organization & WHO Expert Committee on the Control and Surveillance of Human African Trypanosomiasis (‎2013: Geneva, Switzerland)‎. (‎2013)‎. Control and surveillance of human African trypanosomiasis: report of a WHO expert committee. World Health Organization. Accessed 28 September 2018
  139. World Health Organization (2017) Report of the second WHO stakeholders meeting on rhodesiense human African trypanosomiasis, Geneva, 26–28 April 2017. World Health Organization, Geneva 2017 (WHO/HTM/NTD/IDM/2017.04). Licence: CC BY-NC-SA 3.0 IGOGoogle Scholar
  140. Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG (2002) Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc Natl Acad Sci U S A 99(25):15920–15925Google Scholar
  141. Yasuda K, Nakai A, Hatayama T, Nagata K (1995) Cloning and expression of murine high molecular mass heat shock proteins, HSP105. J Biol Chem 270(50):29718–29723Google Scholar
  142. Zíková A, Verner Z, Nenarokova A, Michels PAM, Lukeš J (2017) A paradigm shift: the mitoproteomes of procyclic and bloodstream Trypanosoma brucei are comparably complex. PLoS Pathog 13:e1006679. Google Scholar
  143. Zingales B, Miles MA, Campbell DA, Tibayrenc M, Macedo AM, Teixeira MM et al (2012) The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications. Infect Genet Evol 12(2):240–253Google Scholar

Copyright information

© Cell Stress Society International 2018

Authors and Affiliations

  1. 1.Biotechnology Innovation CentreRhodes UniversityGrahamstownSouth Africa

Personalised recommendations