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Plasmodial Hsp40 and Hsp70 chaperones: current and future perspectives

  • E.-R. PESCE (a1) and G. L. BLATCH (a1)

Plasmodium falciparum displays a large and remarkable variety of heat shock protein 40 family members (PfHsp40s). The majority of the PfHsp40s are poorly characterized, and although the functions of some of them have been suggested, their exact mechanism of action is still elusive and their interacting partners and client proteins are unknown. The P. falciparum heat shock protein 70 family members (PfHsp70s) have been more extensively characterized than the PfHsp40s, with certain members shown to function as molecular chaperones. However, little is known about the PfHsp70-PfHsp40 chaperone partnerships. There is mounting evidence that these chaperones are important not only in protein homoeostasis and cytoprotection, but also in protein trafficking across the parasitophorous vacuole (PV) and into the infected erythrocyte. We propose that certain members of these chaperone families work together to maintain exported proteins in an unfolded state until they reach their final destination. In this review, we critically evaluate what is known and not known about PfHsp40s and PfHsp70s.

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* Corresponding authors: College of Health and Biomedicine, Victoria University, Melbourne 8001, Victoria, Australia. E-mail: and
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Acharya, P., Pallavi, R., Chandran, S., Chakravarti, H., Middha, S., Acharya, J., Kochar, S., Kochar, D., Subudhi, A., Boopathi, A. P., Garg, S., Da, A. and Tatu, U. (2009). A glimpse into the clinical proteome of human malaria parasites Plasmodium falciparum and Plasmodium vivax . Proteomics. Clinical Applications 3, 13141325.
Acharya, P., Chaubey, S., Grover, M. and Tatu, U. (2012). An exported heat shock protein 40 associates with pathogenesis-related knobs in Plasmodium falciparum infected erythrocytes. PLoS ONE 7, e44605.
Aikawa, M., Torii, M., Sjölander, A., Berzins, K., Perlmann, P. and Miller, L. H. (1990). Pf155/RESA antigen is localized in dense granules of Plasmodium falciparum merozoites. Experimental Parasitology 71, 326329.
Akide-Ndunge, O. B., Tambini, E., Giribaldi, G., McMillan, P. J., Müller, S., Arese, P. and Turrini, F. (2009). Co-ordinated stage-dependent enhancement of Plasmodium falciparum antioxidant enzymes and heat shock protein expression in parasites growing in oxidatively stressed or G6PD-deficient red blood cells. Malaria Journal 8, 113.
Bell, S. L., Chiang, A. N. and Brodsky, J. L. (2011). Expression of a malarial Hsp70 improves defects in chaperone-dependent activities in ssa1 mutant yeast. PloS ONE 6, e20047.
Bennett, B. J., Mohandas, N. and Coppel, R. L. (1997). Defining the minimal domain of the Plasmodium falciparum protein MESA involved in the interaction with the red cell membrane skeletal protein 4.1. Journal of Biological Chemistry 272, 1529915306.
Bhattacharjee, S., van Ooij, C., Balu, B., Adams, J. H. and Haldar, K. (2008). Maurer's clefts of Plasmodium falciparum are secretory organelles that concentrate virulence protein reporters for delivery to the host erythrocyte. Blood 111, 24182426.
Boddey, J. A., Carvalho, T. G., Hodder, A. N., Sargeant, T. J., Sleebs, B. E., Marapana, D., Lopaticki, S., Nebl, T. and Cowman, A. F. (2013). Role of plasmepsin V in export of diverse protein families from the Plasmodium falciparum exportome. Traffic 14, 532550.
Botha, M., Pesce, E.-R. and Blatch, G. L. (2007). The Hsp40 proteins of Plasmodium falciparum and other apicomplexa: regulating chaperone power in the parasite and the host. International Journal of Biochemistry and Cell Biology 39, 17811803.
Botha, M., Chiang, A. N., Needham, P. G., Stephens, L. L., Hoppe, H. C., Külzer, S., Przyborski, J. M., Lingelbach, K., Wipf, P., Brodsky, J. L., Shonhai, A. and Blatch, G. L. (2011). Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock. Cell Stress and Chaperones 16, 389401.
Bullen, H. E., Crabb, B. S. and Gilson, P. R. (2012). Recent insights into the export of PEXEL/HTS-motif containing proteins in Plasmodium parasites. Current Opinion in Microbiology 15, 699704.
Charpian, S. and Przyborski, J. M. (2008). Protein transport across the parasitophorous vacuole of Plasmodium falciparum: into the great wide open. Traffic 9, 157165.
Culvenor, J. G., Day, K. P. and Anders, R. F. (1991). Plasmodium falciparum ring-infected erythrocyte surface antigen is released from merozoite dense granules after erythrocyte invasion. Infection and Immunity 59, 11831187.
de Koning-Ward, T. F., Gilson, P. R., Boddey, J. A., Rug, M., Smith, B. J., Papenfuss, A. T., Sanders, P. R., Lundie, R. J., Maier, A. G., Cowman, A. F. and Crabb, B. S. (2009). A newly discovered protein export machine in malaria parasites. Nature 459, 945949.
Deponte, M., Hoppe, H. C., Lee, M. C., Maier, A. G., Richard, D., Rug, M., Spielmann, T. and Przyborski, J. M. (2012). Wherever I may roam: protein and membrane trafficking in P. falciparum-infected red blood cells. Molecular and Biochemical Parasitology 186, 95116.
Diez-Silva, M., Park, Y., Huang, S., Bow, H., Mercereau-Puijalon, O., Deplaine, G., Lavazec, C., Perrot, S., Bonnefoy, S., Feld, M. S., Han, J., Dao, M. and Suresh, S. (2012). Pf155/RESA protein influences the dynamic microcirculatory behavior of ring-stage Plasmodium falciparum infected red blood cells. Scientific Reports 2, 614.
Durand, R., Migot-Nabias, F., Andriantsoanirina, V., Seringe, E., Viwami, F., Sagbo, G., Lalya, F., Deloron, P., Mercereau-Puijalon, O. and Bonnefoy, S. (2012). Possible association of the Plasmodium falciparum T1526C resa2 gene mutation with severe malaria. Malaria Journal 11, 128.
Foley, M., Murray, L. J. and Anders, R. F. (1990). The ring-infected erythrocyte surface antigen protein of Plasmodium falciparum is phosphorylated upon association with the host cell membrane. Molecular and Biochemical Parasitology 38, 6975.
Foley, M., Corcoran, L., Tilley, L. and Anders, R. (1994). Plasmodium falciparum: mapping the membrane-binding domain in the ring-infected erythrocyte surface antigen. Experimental Parasitology 79, 340350.
Foth, B. J., Ralph, S. A., Tonkin, C. J., Struck, N. S., Fraunholz, M., Roos, D. S., Cowman, A. F. and McFadden, G. I. (2003). Dissecting apicoplast targeting in the malaria parasite Plasmodium falciparum . Science 299, 705708.
Gitau, G. W., Mandal, P., Blatch, G. L., Przyborski, J. and Shonhai, A. (2012). Characterisation of the Plasmodium falciparum Hsp70-Hsp90 organising protein (PfHop). Cell Stress and Chaperones 17, 191202.
Gehde, N., Hinrichs, C., Montilla, I., Charpian, S., Lingelbach, K. and Przyborski, J. M. (2009). Protein unfolding is an essential requirement for transport across the parasitophorous vacuolar membrane of Plasmodium falciparum . Molecular Microbiology 71, 613628.
Goldshmidt, H., Sheiner, L., Bütikofer, P., Roditi, I., Uliel, S., Günzel, M., Engstler, M. and Michaeli, S. (2008). Role of protein translocation pathways across the endoplasmic reticulum in Trypanosoma brucei . Journal of Biological Chemistry 283, 3208532098.
Grover, M., Chaubey, S., Ranade, S. and Tatu, U. (2013). Identification of an exported heat shock protein 70 in Plasmodium falciparum . Parasite 20, 2.
Grüring, C., Heiber, A., Kruse, F., Flemming, S., Franci, G., Colombo, S. F., Fasana, E., Schoeler, H., Borgese, N., Stunnenberg, H. G., Przyborski, J. M., Gilberger, T. W. and Spielmann, T. (2012). Uncovering common principles in protein export of malaria parasites. Cell Host and Microbe 12, 717729.
Hagiwara, M. and Nagata, K. (2012). Redox-dependent protein quality control in the endoplasmic reticulum: folding to degradation. Antioxidants and Redox Signaling 16, 11191128.
Heiber, A., Kruse, F., Pick, C., Grüring, C., Flemming, S., Oberli, A., Schoeler, H., Retzlaff, S., Mesén-Ramírez, P., Hiss, J. A., Kadekoppala, M., Hecht, L., Holder, A. A., Gilberger, T. W. and Spielmann, T. (2013). Identification of new PNEPs indicates a substantial non-PEXEL exportome and underpins common features in Plasmodium falciparum protein export. PLoS Pathogens 9, e1003546.
Hiller, N. L., Bhattacharjee, S., van Ooij, C., Liolios, K., Harrison, T., Lopez-Estraño, C. and Haldar, K. (2004). A host-targeting signal in the virulence proteins reveals a secretome in malarial infection. Science 306, 19341937.
Joshi, B., Biswas, S. and Sharma, Y. D. (1992). Effect of heat-shock on Plasmodium falciparum viability, growth and expression of the heat-shock protein ‘PFHsp70-1’ gene. FEBS Letters 312, 9194.
Kampinga, H. H. and Craig, E. A. (2010). The Hsp70 chaperone machinery: J proteins as drivers of functional specificity. Nature Reviews. Molecular Cell Biology 11, 579592.
Külzer, S., Rug, M., Brinkmann, K., Cannon, P., Cowman, A., Lingelbach, K., Blatch, G. L., Maier, A. G. and Przyborski, J. M. (2010). Parasite-encoded Hsp40 proteins define novel mobile structures in the cytosol of the P. falciparum-infected erythrocyte. Cellular Microbiology 12, 13981420.
Külzer, S., Charnaud, S., Dagan, T., Riedel, J., Mandal, P., Pesce, E.-R., Blatch, G. L., Crabb, B. S., Gilson, P. R. and Przyborski, J. M. (2012). Plasmodium falciparum-encoded exported hsp70/hsp40 chaperone/co-chaperone complexes within the host erythrocyte. Cellular Microbiology 14, 17841795.
Kumar, A., Tanveer, A., Biswas, S., Ram, E. V., Gupta, A., Kumar, B. and Habib, S. (2010). Nuclear-encoded DnaJ homologue of Plasmodium falciparum interacts with replication ori of the apicoplast genome. Molecular Microbiology 75, 942956.
Kumar, N., Koski, G., Harada, M., Aikawa, M. and Zheng, H. (1991). Induction and localization of Plasmodium falciparum stress proteins related to the heat shock protein 70 family. Molecular and Biochemical Parasitology 48, 4758.
Lustigman, S., Anders, R. F., Brown, G. V., and Coppel, R. L. (1990). The mature-parasite-infected erythrocyte surface antigen (MESA) of Plasmodium falciparum associates with the erythrocyte membrane skeletal protein, band 4.1. Molecular and Biochemical Parasitology 38, 261270.
Magowan, C., Coppel, R. L., Lau, A. O., Moronne, M. M., Tchernia, G. and Mohandas, N. (1995). Role of the Plasmodium falciparum mature-parasite-infected erythrocyte surface antigen (MESA/PfEMP-2) in malarial infection of erythrocytes. Blood 86, 31963204.
Maier, A. G., Rug, M., O'Neill, M. T., Brown, M., Chakravorty, S., Szestak, T., Chesson, J., Wu, Y., Hughes, K., Coppel, R. L., Newbold, C., Beeson, J. G., Craig, A., Crabb, B. S. and Cowman, A. F. (2008). Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell 134, 4861.
Marti, M., Good, R. T., Rug, M., Knuepfer, E. and Cowman, A. F. (2004). Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 19301933.
Matambo, T. S., Odunuga, O. O., Boshoff, A. and Blatch, G. L. (2004). Overproduction, purification, and characterization of the Plasmodium falciparum heat shock protein 70. Protein Expression and Purification 33, 214222.
Mills, J. P., Diez-Silva, M., Quinn, D. J., Dao, M., Lang, M. J., Tan, K. S., Lim, C. T., Milon, G., David, P. H., Mercereau-Puijalon, O., Bonnefoy, S. and Suresh, S. (2007). Effect of plasmodial RESA protein on deformability of human red blood cells harboring Plasmodium falciparum . Proceedings of the National Academy of Sciences USA 104, 92139217.
Misra, G. and Ramachandran, R. (2009). Hsp70-1 from Plasmodium falciparum: protein stability, domain analysis and chaperone activity. Biophysical Chemistry 142, 5564.
Morahan, B. J., Strobel, C., Hasan, U., Czesny, B., Mantel, P. Y., Marti, M., Eksi, S. and Williamson, K. C. (2011). Functional analysis of the exported type IV Hsp40 protein PfGECO in Plasmodium falciparum gametocytes. Eukaryotic Cell 10, 1492–503.
Muralidharan, V., Oksman, A., Pal, P., Lindquist, S. and Goldberg, D. E. (2012). Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers. Nature Communications 3, 1310.
Njunge, J. M., Ludewig, M. H., Boshoff, A., Pesce, E.-R. and Blatch, G. L. (2013). Hsp70s and J proteins of Plasmodium parasites infecting rodents and primates: structure, function, clinical relevance, and drug targets. Current Pharmaceutical Design 19, 387403.
Nyalwidhe, J. and Lingelbach, K. (2006). Proteases and chaperones are the most abundant proteins in the parasitophorous vacuole of Plasmodium falciparum-infected erythrocytes. Proteomics 6, 15631573.
Pei, X., Guo, X., Coppel, R., Bhattacharjee, S., Haldar, K., Gratzer, W., Mohandas, N. and An, X. (2007). The ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum stabilizes spectrin tetramers and suppresses further invasion. Blood 110, 10361042.
Pesce, E.-R., Acharya, P., Tatu, U., Nicoll, W. S., Shonhai, A., Hoppe, H. C. and Blatch, G. L. (2008). The Plasmodium falciparum heat shock protein 40, Pfj4, associates with heat shock protein 70 and shows similar heat induction and localization patterns. International Journal of Biochemistry and Cell Biology 40, 29142926.
Ramya, T. N. C., Surolia, N. N. and Surolia, A. (2006). 15-Deoxyspergualin modulates Plasmodium falciparum heat shock protein function. Biochemical and Biophysical Research Communications 348, 585592.
Riglar, D. T., Rogers, K. L., Hanssen, E., Turnbull, L., Bullen, H. E., Charnaud, S. C., Przyborski, J., Gilson, P. R., Whitchurch, C. B., Crabb, B. S., Baum, J. and Cowman, A. F. (2013). Spatial association with PTEX complexes defines regions for effector export into Plasmodium falciparum-infected erythrocytes. Nature Communications 4, 1415.
Safeukui, I., Correas, J. M., Brousse, V., Hirt, D., Deplaine, G., Mulé, S., Lesurtel, M., Goasguen, N., Sauvanet, A., Couvelard, A., Kerneis, S., Khun, H., Vigan-Womas, I., Ottone, C., Molina, T. J., Tréluyer, J. M., Mercereau-Puijalon, O., Milon, G., David, P. H. and Buffet, P. A. (2008). Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen. Blood 112, 25202528.
Sargeant, T. J., Marti, M., Caler, E., Carlton, J. M., Simpson, K., Speed, T. P. and Cowman, A. F. (2006). Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biology 7, R12.
Shonhai, A., Boshoff, A. and Blatch, G. L. (2005). Plasmodium falciparum heat shock protein 70 is able to suppress the thermosensitivity of an Escherichia coli DnaK mutant strain. Molecular Genetics and Genomics 274, 7078.
Shonhai, A., Boshoff, A. and Blatch, G. L. (2007). The structural and functional diversity of Hsp70 proteins from Plasmodium falciparum . Protein Science 16, 18031818.
Shonhai, A., Botha, M., De Beer, T. J., Boshoff, A. and Blatch, G. L. (2008). Structure-function study of a Plasmodium falciparum Hsp70 using three dimensional modelling and in vitro analyses. Protein and Peptide Letters 15, 11171125.
Silva, M. D., Cooke, B. M., Guillotte, M., Buckingham, D. W., Sauzet, J.-P., Le Scanf, C., Contamin, H., David, P., Mercereau-Puijalon, O. and Bonnefoy, S. (2005). A role for the Plasmodium falciparum RESA protein in resistance against heat shock demonstrated using gene disruption. Molecular Microbiology 56, 9901003.
Spielmann, T. and Gilberger, T. W. (2010). Protein export in malaria parasites: do multiple export motifs add up to multiple export pathways? Trends in Parasitology 26, 610.
Tuteja, R. (2007). Unraveling the components of protein translocation pathway in human malaria parasite Plasmodium falciparum . Archives of Biochemistry and Biophysics 467, 249260.
Vincensini, L., Richert, S., Blisnick, T., Van Dorsselaer, A., Leize-Wagner, E., Rabilloud, T. and Braun Breton, C. (2005). Proteomic analysis identifies novel proteins of the Maurer's clefts, a secretory compartment delivering Plasmodium falciparum proteins to the surface of its host cell. Molecular and Cellular Proteomics 4, 582593.
Waller, K. L., Nunomura, W., An, X., Cooke, B. M., Mohandas, N. and Coppel, R. L. (2003). Mature parasite-infected erythrocyte surface antigen (MESA) of Plasmodium falciparum binds to the 30-kDa domain of protein 4.1 in malaria-infected red blood cells. Blood 102, 19111914.
Walsh, P., Bursać, D., Law, Y. C., Cyr, D. and Lithgow, T. (2004). The J-protein family: modulating protein assembly, disassembly and translocation. EMBO Reports 5, 567571.
Watanabe, J. (1997). Cloning and characterization of heat shock protein DnaJ homologues from Plasmodium falciparum and comparison with ring infected erythrocyte surface antigen. Molecular and Biochemical Parasitology 88, 253258.
Zimmermann, R. and Blatch, G. L. (2009). A novel twist to protein secretion in eukaryotes. Trends in Parasitology 25, 147150.
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