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PreprintCited by 21Malaria Research and ControlToxoplasma gondii Research StudiesErythrocyte Function and Pathophysiology

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Plasmepsin X activates function of the PCRCR complex in P. falciparum by processing PfRh5 for binding to basigin and invasion of human erythrocytes

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Triglia, Tony, Scally, Stephen, Seager, Benjamin, Pasternak, Michal, Dagley, Laura, Cowman, Alan·2023·Nature Communications
DOI 10.21203/rs.3.rs-2410384/v1PMC PMC10113190

Preprint — published as 10.1038/s41467-023-37890-2

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Abstract

Plasmodium falciparum causes the most severe form of malaria in humans. The protozoan parasite develops within erythrocytes to mature schizonts, that contain more than 16 merozoites, which egress and invade fresh erythrocytes. The aspartic protease plasmepsin X (PMX), processes proteins and proteases essential for merozoite egress from the schizont and invasion of the host erythrocyte, including the leading vaccine candidate PfRh5. PfRh5 is anchored to the merozoite surface through a 5-membered complex (PCRCR), consisting of Plasmodium thrombospondin-related apical merozoite protein (PTRAMP), cysteine-rich small secreted protein (CSS), Rh5-interacting protein (PfRipr) and cysteine-rich protective antigen (CyRPA). We show that PCRCR is processed by PMX in micronemes to remove the N-terminal prodomain of PhRh5 and this activates the function of the complex unmasking a form that can bind basigin on the erythrocyte membrane and mediate merozoite invasion. The ability to activate PCRCR at a specific time in merozoite invasion most likely masks potential deleterious effects of its function until they are required. These results provide an important understanding of the essential role of PMX and the fine regulation of PCRCR function in P. falciparum biology.

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Research works printed but not linked: 44

  1. Cowman AF, Healer J, Marapana D, Marsh K. Malaria: Biology and Disease. Cell 167, 610–624 (2016). · DOI
  2. Cowman AF, Tonkin CJ, Tham WH, Duraisingh MT. The molecular basis of erythrocyte invasion by malaria parasites. Cell Host Microbe 22, 232–245 (2017). · DOI
  3. Dasgupta S, et al. Membrane-wrapping contributions to malaria parasite invasion of the human erythrocyte. Biophys J 107, 43–54 (2014). · DOI
  4. Gilson PR, Crabb BS. Morphology and kinetics of the three distinct phases of red blood cell invasion by Plasmodium falciparum merozoites. Int J Parasitol 39, 91–96 (2009). · DOI
  5. Weiss GE, et al. Revealing the Sequence and Resulting Cellular Morphology of Receptor-Ligand Interactions during Plasmodium falciparum Invasion of Erythrocytes. PLoS Pathog 11, e1004670 (2015). · DOI
  6. Glushakova S, et al. Rounding precedes rupture and breakdown of vacuolar membranes minutes before malaria parasite egress from erythrocytes. Cell Microbiol 20, e12868 (2018). · DOI
  7. Hale VL, et al. Parasitophorous vacuole poration precedes its rupture and rapid host erythrocyte cytoskeleton collapse in Plasmodium falciparum egress. Proc Natl Acad Sci U S A 114, 3439–3444 (2017). · DOI
  8. Nasamu AS, et al. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science 358, 518–522 (2017). · DOI
  9. Pino P, et al. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science 358, 522–528 (2017). · DOI
  10. Favuzza P, et al. Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle. Cell Host Microbe 27, 642–658 e612 (2020). · DOI
  11. de Lera Ruiz M, et al. The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria. ACS Med Chem Lett 13, 1745–1754 (2022). · DOI
  12. Taylor HM, et al. The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony. Eukaryot Cell 9, 37–45 (2010). · DOI
  13. Collins CR, et al. Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress. PLoS Pathog 9, e1003344 (2013). · DOI
  14. Yeoh S, et al. Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes. Cell 131, 1072–1083 (2007). · DOI
  15. Ruecker A, et al. Proteolytic activation of the essential parasitophorous vacuole cysteine protease SERA6 accompanies malaria parasite egress from its host erythrocyte. J Biol Chem 287, 37949–37963 (2012). · DOI
  16. Wickham M, Culvenor J, Cowman A. Selective inhibition of a two-step egress of malaria parasites from the host erythrocyte. J Biol Chem 278, 37658–37663 (2003). · DOI
  17. Glushakova S, Yin D, Li T, Zimmerberg J. Membrane transformation during malaria parasite release from human red blood cells. Curr Biol 15, 1645–1650 (2005). · DOI
  18. Abkarian M, Massiera G, Berry L, Roques M, Braun-Breton C. A novel mechanism for egress of malarial parasites from red blood cells. Blood 117, 4118–4124 (2011). · DOI
  19. Tham WH, et al. Plasmodium falciparum Adhesins Play an Essential Role in Signalling and Activation of Invasion into Human Erythrocytes. PLoS Pathog 11, e1005343 (2015). · DOI
  20. Crosnier C, et al. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature 480, 534–537 (2011). · DOI
  21. Scally SW, et al. PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum. Nat Microbiol 7, 2039–2053 (2022). · DOI
  22. Baum J, et al. Reticulocyte-binding protein homologue 5 - an essential adhesin involved in invasion of human erythrocytes by Plasmodium falciparum. Int J Parasitol 39, 371–373 (2009). · DOI
  23. Galaway F, et al. P113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5. Nat Commun 8, 14333 (2017). · DOI
  24. Bullen HE, et al. The Plasmodium falciparum parasitophorous vacuole protein P113 interacts with the parasite protein export machinery and maintains normal vacuole architecture. Mol Microbiol 117, 1245–1262 (2022). · DOI
  25. Kudyba HM, et al. The endoplasmic reticulum chaperone PfGRP170 is essential for asexual development and is linked to stress response in malaria parasites. Cell Microbiol 21, e13042 (2019). · DOI
  26. Volz JC, et al. Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plasmodium falciparum Invasion of Erythrocytes. Cell Host Microbe 20, 60–71 (2016). · DOI
  27. Triglia T, et al. Plasmodium falciparum merozoite invasion is inhibited by antibodies that target the PfRh2a and b binding domains. PLoS Pathog 7, e1002075 (2011). · DOI
  28. Wong W, et al. Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion complex. Nature 565, 118–121 (2019). · DOI
  29. Healer J, Crawford S, Ralph S, McFadden G, Cowman A. Independent translocation of two micronemal proteins in developing Plasmodium falciparum merozoites. Infect Immun 70, 5751–5758 (2002). · DOI
  30. Ebrahimzadeh Z, et al. A pan-apicomplexan phosphoinositide-binding protein acts in malarial microneme exocytosis. EMBO Rep 20, (2019). · DOI
  31. Singh S, Plassmeyer M, Gaur D, Miller LH. Mononeme: a new secretory organelle in Plasmodium falciparum merozoites identified by localization of rhomboid-1 protease. Proc Natl Acad Sci U S A 104, 20043–20048 (2007). · DOI
  32. Mukherjee S, Nguyen S, Sharma E, Goldberg DE. Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X. Nat Commun 13, 4537 (2022). · DOI
  33. Wright KE, et al. Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Nature 515, 427–430 (2014). · DOI
  34. Bannister LH, et al. Plasmodium falciparum apical membrane antigen 1 (PfAMA-1) is translocated within micronemes along subpellicular microtubules during merozoite development. J Cell Sci 116, 3825–3834 (2003). · DOI
  35. Hallee S, Counihan NA, Matthews K, de Koning-Ward TF, Richard D. The malaria parasite Plasmodium falciparum Sortilin is essential for merozoite formation and apical complex biogenesis. Cell Microbiol 20, e12844 (2018). · DOI
  36. Knuepfer E, Napiorkowska M, van Ooij C, Holder AA. Generating conditional gene knockouts in Plasmodium - a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR/Cas9. Scientific reports 7, 3881 (2017). · DOI
  37. Xu J, et al. A fixation method for the optimisation of western blotting. Sci Rep 9, 6649 (2019). · DOI
  38. Wisniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods 6, 359–362 (2009). · DOI · Paper page
  39. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res 10, 1794–1805 (2011). · DOI
  40. Fairlie WD, et al. Inhibition of malaria parasite development by a cyclic peptide that targets the vital parasite protein SERA5. Infect Immun 76, 4332–4344 (2008). · DOI
  41. Coley AM, et al. Rapid and precise epitope mapping of monoclonal antibodies against Plasmodium falciparum AMA1 by combined phage display of fragments and random peptides. Protein Eng 14, 691–698 (2001). · DOI
  42. Fairhead M, Howarth M. Site-specific biotinylation of purified proteins using BirA. Methods Mol Biol 1266, 171–184 (2015). · DOI
  43. Perez-Riverol Y, et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res 47, D442-D450 (2019). · DOI
  44. Schechter I, Berger A. On the size of the active site in proteases. I. Papain. Biochemical and Biophysical Research Communications 27, 157–162 (1967). · DOI

Metadata

Authors
Triglia, T., Scally, S., Seager, B., Pasternak, M., Dagley, L., & Cowman, A.
Affiliations
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • The University of Melbourne (AU)
  • Walter and Eliza Hall Institute of Medical Research
Corresponding author
Cowman, Alan
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-01-12
Volume
14
Issue
1
Pages
2219-2219
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-2410384/v1
PMC
PMC10113190
OpenAlex
W4366352789
Cited by
21
References
1
Citations by year
2026: 8 · 2025: 5 · 2024: 5 · 2023: 3
FWCI
5.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Wellcome Trust (206515/Z/17/Z, /Z/15/Z, 202749/Z/16/Z, 109662/Z/15/Z)
  • Medical Research Council
  • National Health and Medical Research Council (1194535, 1173049, 637406, 1057960, 1011453)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Immunology and Microbiology › Parasitology › Toxoplasma gondii Research Studies
  • Health Sciences › Medicine › Physiology (medical) › Erythrocyte Function and Pathophysiology
Keywords
Plasmodium falciparum, PfRH5, merozoite invasion, erythrocyte invasion, aspartic protease, micronemes, CD147, merozoite egress, schizonts
MeSH terms
Animals, Antigens, Protozoan, Cysteine, Erythrocytes, Humans, Plasmodium falciparum, Protozoan Proteins, Aspartic Acid Endopeptidases, Malaria, Falciparum, Merozoites

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