Hostname: page-component-586b7cd67f-tf8b9 Total loading time: 0 Render date: 2024-11-23T03:29:01.188Z Has data issue: false hasContentIssue false
  • English
  • Français

Immunophilin–protein interactions in Plasmodium falciparum

Published online by Cambridge University Press:  09 July 2015

DARREN LENEGHAN  and
ANGUS BELL
DARREN LENEGHAN
Affiliation:
Department of Microbiology, School of Genetics and Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin, Ireland
ANGUS BELL*
Affiliation:
Department of Microbiology, School of Genetics and Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin, Ireland
*
*Corresponding author. Department of Microbiology, School of Genetics and Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin, Ireland. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

Immunophilins comprise two protein families, cyclophilins (CYPs) and FK506-binding proteins (FKBPs), and are the major receptors for the immunosuppressive drugs cyclosporin A (CsA) and FK506 (tacrolimus), respectively. Most eukaryotic species have at least one immunophilin and some of them have been associated with pathogenesis of infectious or parasitic diseases or the action of antiparasitic drugs. The human malarial parasite Plasmodium falciparum has 13 immunophilin or immunophilin-like genes but the functions of their products are unknown. We set out to identify the parasite proteins that interact with the major CYPs, PfCYP19A and PfCYP19B, and the FKBP, PfFKBP35, using a combination of co-immunoprecipitation and yeast two-hybrid screening. We identified a cohort of putative interacting partners and further investigation of some of these revealed potentially novel roles in parasite biology. We demonstrated that (i) P. falciparum CYPs interacted with the heat shock protein 70, (ii) treatment of parasites with CYP ligands disrupted transport of the rhoptry-associated protein 1, and (iii) PfFKBP35 interacted with parasite histones in a way that might modulate gene expression. These findings begin to elucidate the functions of immunophilins in malaria. Furthermore, the known antimalarial effects of CsA, FK506 and non-immunosuppressive derivatives of these immunophilin ligands could be mediated through these partner proteins.

Keywords

Malariaimmunophilincyclosporin AFK506cyclophilinFK506-binding proteinhistonerhoptryHsp70protein–protein interaction
Type
Research Article
Information
Parasitology , Volume 142 , Issue 11 , September 2015 , pp. 1404 - 1414
Check for updates
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Acharya, P., Kumar, R. and Tatu, U. (2007). Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum . Molecular and Biochemical Parasitology 153, 85–94.CrossRefGoogle ScholarPubMed
Bell, A., Wernli, B. and Franklin, R. M. (1994). Roles of peptidyl-prolyl cis–trans isomerase and calcineurin in the mechanisms of antimalarial action of cyclosporin A, FK506, and rapamycin. Biochemical Pharmacology 48, 495–503.Google Scholar
Bell, A., Monaghan, P. and Page, A. P. (2006). Peptidyl-prolyl cis–trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action. International Journal for Parasitology 36, 261–276.CrossRefGoogle ScholarPubMed
Brandts, J. F., Halvorson, H. R. and Brennan, M. (1975). Consideration of the possibility that the slow step in protein denaturation reactions is due to cis–trans isomerism of proline residues. Biochemistry 14, 4953–4963.Google Scholar
Braun, P. D., Barglow, K. T., Lin, Y. M., Akompong, T., Briesewitz, R., Ray, G. T., Haldar, K. and Wandless, T. J. (2003). A bifunctional molecule that displays context-dependent cellular activity. Journal of the American Chemical Society 125, 7575–7580.Google Scholar
Cowman, A. F., Berry, D. and Baum, J. (2012). The cellular and molecular basis for malaria parasite invasion of the human red blood cell. Journal of Cell Biology 198, 961–971.CrossRefGoogle ScholarPubMed
Dolinski, K., Muir, S., Cardenas, M. and Heitman, J. (1997). All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae . Proceedings of the National Academy of Sciences of the United States of America 94, 13093–13098.CrossRefGoogle ScholarPubMed
Fennell, B. J., Naughton, J. A., Dempsey, E. and Bell, A. (2006). Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: tubulin as a specific antimalarial target. Molecular and Biochemical Parasitology 145, 226–238.Google Scholar
Fischer, G. and Schmid, F. X. (1990). The mechanism of protein folding. Implications of in vitro refolding models for de novo protein folding and translocation in the cell. Biochemistry 29, 2205–2212.Google Scholar
Fischer, G., Gallay, P. and Hopkins, S. (2010). Cyclophilin inhibitors for the treatment of HCV infection. Current Opinion in Investigational Drugs 11, 911–918.Google Scholar
Frausto, S. D., Lee, E. and Tang, H. (2013). Cyclophilins as modulators of viral replication. Viruses 5, 1684–1701.Google Scholar
Galat, A. (2003). Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity–targets–functions. Current Topics in Medicinal Chemistry 3, 1315–1347.CrossRefGoogle ScholarPubMed
Galat, A. and Bua, J. (2010). Molecular aspects of cyclophilins mediating therapeutic actions of their ligands. Cellular and Molecular Life Sciences 67, 3467–3488.Google Scholar
Gavigan, C. S., Kiely, S. P., Hirtzlin, J. and Bell, A. (2003). Cyclosporin-binding proteins of Plasmodium falciparum . International Journal for Parasitology 33, 987–996.CrossRefGoogle ScholarPubMed
Gothel, S. F., Scholz, C., Schmid, F. X. and Marahiel, M. A. (1998). Cyclophilin and trigger factor from Bacillus subtilis catalyze in vitro protein folding and are necessary for viability under starvation conditions. Biochemistry 37, 13392–13399.CrossRefGoogle ScholarPubMed
Hanes, S. D., Shank, P. R. and Bostian, K. A. (1989). Sequence and mutational analysis of ESS1, a gene essential for growth in Saccharomyces cerevisiae . Yeast 5, 55–72.Google Scholar
Harikishore, A., Leow, M. L., Niang, M., Rajan, S., Pasunooti, K. K., Preiser, P. R., Liu, X. and Yoon, H. S. (2013 a). Adamantyl derivative as a potent inhibitor of Plasmodium FK506 binding protein 35. ACS Medicinal Chemistry Letters 4, 1097–1101.CrossRefGoogle ScholarPubMed
Harikishore, A., Niang, M., Rajan, S., Preiser, P. R. and Yoon, H. S. (2013 b). Small molecule Plasmodium FKBP35 inhibitor as a potential antimalaria agent. Scientific Reports 3, 2501.CrossRefGoogle ScholarPubMed
Ho, S., Clipstone, N., Timmermann, L., Northrop, J., Graef, I., Fiorentino, D., Nourse, J. and Crabtree, G. R. (1996). The mechanism of action of cyclosporin A and FK506. Clinical Immunology and Immunopathology 80, S40–S45.CrossRefGoogle ScholarPubMed
Jiang, L., Mu, J., Zhang, Q., Ni, T., Srinivasan, P., Rayavara, K., Yang, W., Turner, L., Lavstsen, T., Theander, T. G., Peng, W., Wei, G., Jing, Q., Wakabayashi, Y., Bansal, A., Luo, Y., Ribeiro, J. M., Scherf, A., Aravind, L., Zhu, J., Zhao, K. and Miller, L. H. (2013). PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum . Nature 499, 223–227.Google Scholar
Justice, S. S., Hunstad, D. A., Harper, J. R., Duguay, A. R., Pinkner, J. S., Bann, J., Frieden, C., Silhavy, T. J. and Hultgren, S. J. (2005). Periplasmic peptidyl prolyl cis–trans isomerases are not essential for viability, but SurA is required for pilus biogenesis in Escherichia coli . Journal of Bacteriology 187, 7680–7686.CrossRefGoogle Scholar
Kamath, R. S., Fraser, A. G., Dong, Y., Poulin, G., Durbin, R., Gotta, M., Kanapin, A., Le Bot, N., Moreno, S., Sohrmann, M., Welchman, D. P., Zipperlen, P. and Ahringer, J. (2003). Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature, 421, 231–237.CrossRefGoogle ScholarPubMed
Kang, C. B., Ye, H., Dhe-Paganon, S. and Yoon, H. S. (2008). FKBP family proteins: immunophilins with versatile biological functions. Neurosignals 16, 318–325.Google Scholar
Krucken, J., Greif, G. and von Samson-Himmelstjerna, G. (2009). In silico analysis of the cyclophilin repertoire of apicomplexan parasites. Parasit Vectors 2, 27.Google Scholar
Kumar, R., Adams, B., Musiyenko, A., Shulyayeva, O. and Barik, S. (2005). The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity. Molecular and Biochemical Parasitology 141, 163–173.CrossRefGoogle ScholarPubMed
Kuzuhara, T. and Horikoshi, M. (2004). A nuclear FK506-binding protein is a histone chaperone regulating rDNA silencing. Nature Structural & Molecular Biology 11, 275–283.Google Scholar
LaCount, D. J., Vignali, M., Chettier, R., Phansalkar, A., Bell, R., Hesselberth, J. R., Schoenfeld, L. W., Ota, I., Sahasrabudhe, S., Kurschner, C., Fields, S. and Hughes, R. E. (2005). A protein interaction network of the malaria parasite Plasmodium falciparum . Nature 438, 103–107.CrossRefGoogle ScholarPubMed
Longhurst, H. J. and Holder, A. A. (1997). The histones of Plasmodium falciparum: identification, purification and a possible role in the pathology of malaria. Parasitology 114(Pt 5), 413–419.CrossRefGoogle Scholar
Maniatis, T. F. E. and Sambrook, J. (1982). Molecular Cloning: A Laboratory Manual. Cold Spring Harbour, New York, USA.Google Scholar
Marin-Menendez, A. and Bell, A. (2011). Overexpression, purification and assessment of cyclosporin binding of a family of cyclophilins and cyclophilin-like proteins of the human malarial parasite Plasmodium falciparum . Protein Expression and Purification 78, 225–234.Google Scholar
Marin-Menendez, A., Monaghan, P. and Bell, A. (2012). A family of cyclophilin-like molecular chaperones in Plasmodium falciparum . Molecular and Biochemical Parasitology 184, 44–47.Google Scholar
Monaghan, P. and Bell, A. (2005). A Plasmodium falciparum FK506-binding protein (FKBP) with peptidyl-prolyl cis–trans isomerase and chaperone activities. Molecular and Biochemical Parasitology 139, 185–195.Google Scholar
Monaghan, P., Fardis, M., Revill, W. P. and Bell, A. (2005). Antimalarial effects of macrolactones related to FK520 (ascomycin) are independent of the immunosuppressive properties of the compounds. Journal of Infectious Diseases 191, 1342–1349.Google Scholar
Moreno, R., Poltl-Frank, F., Stuber, D., Matile, H., Mutz, M., Weiss, N. A. and Pluschke, G. (2001). Rhoptry-associated protein 1-binding monoclonal antibody raised against a heterologous peptide sequence inhibits Plasmodium falciparum growth in vitro . Infection and Immunity 69, 2558–2568.Google Scholar
Nelson, C. J., Santos-Rosa, H. and Kouzarides, T. (2006). Proline isomerization of histone H3 regulates lysine methylation and gene expression. Cell 126, 905–916.Google Scholar
Phizicky, E. M. and Fields, S. (1995). Protein–protein interactions: methods for detection and analysis. Microbiology Reviews 59, 94–123.CrossRefGoogle ScholarPubMed
Ratajczak, T., Ward, B. K. and Minchin, R. F. (2003). Immunophilin chaperones in steroid receptor signalling. Current Topics in Medicinal Chemistry 3, 1348–1357.CrossRefGoogle ScholarPubMed
Wu, Y. and Craig, A. (2006). Comparative proteomic analysis of metabolically labelled proteins from Plasmodium falciparum isolates with different adhesion properties. Malaria Journal 5, 67.Google Scholar
Wu, Y., Li, Q. and Chen, X. Z. (2007). Detecting protein–protein interactions by far western blotting. Nature Protocols 2, 3278–3284.CrossRefGoogle ScholarPubMed
Zuckerman, A., Spira, D. and Hamburger, J. (1967). A procedure for the harvesting of mammalian plasmodia. Bulletin of the World Health Organization 37, 431–436.Google ScholarPubMed
Supplementary material: File

Leneghan and Bell supplementary material

Figure S1

Download Leneghan and Bell supplementary material(File)
File 324.8 KB
Supplementary material: File

Leneghan and Bell supplementary material

Leneghan and Bell supplementary material 2

Download Leneghan and Bell supplementary material(File)
File 18.9 KB
Supplementary material: File

Leneghan and Bell supplementary material

Leneghan and Bell supplementary material 3

Download Leneghan and Bell supplementary material(File)
File 95.7 KB