Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites

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Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. / Sleebs, Brad E; Lopaticki, Sash; Marapana, Danushka S; O'Neill, Matthew T; Rajasekaran, Pravin; Gazdik, Michelle; Günther, Svenja; Whitehead, Lachlan W; Lowes, Kym N; Barfod, Lea; Hviid, Lars; Shaw, Philip J; Hodder, Anthony N; Smith, Brian J; Cowman, Alan F; Boddey, Justin A.

In: P L o S Biology, Vol. 12, No. 7, 2014, p. e1001897.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Sleebs, BE, Lopaticki, S, Marapana, DS, O'Neill, MT, Rajasekaran, P, Gazdik, M, Günther, S, Whitehead, LW, Lowes, KN, Barfod, L, Hviid, L, Shaw, PJ, Hodder, AN, Smith, BJ, Cowman, AF & Boddey, JA 2014, 'Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites', P L o S Biology, vol. 12, no. 7, pp. e1001897. https://doi.org/10.1371/journal.pbio.1001897

APA

Sleebs, B. E., Lopaticki, S., Marapana, D. S., O'Neill, M. T., Rajasekaran, P., Gazdik, M., Günther, S., Whitehead, L. W., Lowes, K. N., Barfod, L., Hviid, L., Shaw, P. J., Hodder, A. N., Smith, B. J., Cowman, A. F., & Boddey, J. A. (2014). Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. P L o S Biology, 12(7), e1001897. https://doi.org/10.1371/journal.pbio.1001897

Vancouver

Sleebs BE, Lopaticki S, Marapana DS, O'Neill MT, Rajasekaran P, Gazdik M et al. Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. P L o S Biology. 2014;12(7):e1001897. https://doi.org/10.1371/journal.pbio.1001897

Author

Sleebs, Brad E ; Lopaticki, Sash ; Marapana, Danushka S ; O'Neill, Matthew T ; Rajasekaran, Pravin ; Gazdik, Michelle ; Günther, Svenja ; Whitehead, Lachlan W ; Lowes, Kym N ; Barfod, Lea ; Hviid, Lars ; Shaw, Philip J ; Hodder, Anthony N ; Smith, Brian J ; Cowman, Alan F ; Boddey, Justin A. / Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. In: P L o S Biology. 2014 ; Vol. 12, No. 7. pp. e1001897.

Bibtex

@article{46a1cf5f1e134fb3a6de065e714dd1ce,
title = "Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites",
abstract = "The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target.",
author = "Sleebs, {Brad E} and Sash Lopaticki and Marapana, {Danushka S} and O'Neill, {Matthew T} and Pravin Rajasekaran and Michelle Gazdik and Svenja G{\"u}nther and Whitehead, {Lachlan W} and Lowes, {Kym N} and Lea Barfod and Lars Hviid and Shaw, {Philip J} and Hodder, {Anthony N} and Smith, {Brian J} and Cowman, {Alan F} and Boddey, {Justin A}",
year = "2014",
doi = "10.1371/journal.pbio.1001897",
language = "English",
volume = "12",
pages = "e1001897",
journal = "PLoS Biology",
issn = "1544-9173",
publisher = "Public Library of Science",
number = "7",

}

RIS

TY - JOUR

T1 - Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites

AU - Sleebs, Brad E

AU - Lopaticki, Sash

AU - Marapana, Danushka S

AU - O'Neill, Matthew T

AU - Rajasekaran, Pravin

AU - Gazdik, Michelle

AU - Günther, Svenja

AU - Whitehead, Lachlan W

AU - Lowes, Kym N

AU - Barfod, Lea

AU - Hviid, Lars

AU - Shaw, Philip J

AU - Hodder, Anthony N

AU - Smith, Brian J

AU - Cowman, Alan F

AU - Boddey, Justin A

PY - 2014

Y1 - 2014

N2 - The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target.

AB - The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target.

U2 - 10.1371/journal.pbio.1001897

DO - 10.1371/journal.pbio.1001897

M3 - Journal article

C2 - 24983235

VL - 12

SP - e1001897

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 7

ER -

ID: 118048037