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Plasmepsin V cleaves malaria effector proteins in a distinct endoplasmic reticulum translocation interactome for export to the erythrocyte

Nature Microbiology volume 3, pages 1010–1022 (2018)Cite this article

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Abstract

Plasmodium falciparum exports hundreds of virulence proteins within infected erythrocytes, a process that requires cleavage of a pentameric motif called Plasmodium export element or vacuolar transport signal by the endoplasmic reticulum (ER)-resident protease plasmepsin V. We identified plasmepsin V-binding proteins that form a unique interactome required for the translocation of effector cargo into the parasite ER. These interactions are functionally distinct from the Sec61–signal peptidase complex required for the translocation of proteins destined for the classical secretory pathway. This interactome does not involve the signal peptidase (SPC21) and consists of PfSec61, PfSPC25, plasmepsin V and PfSec62, which is an essential component of the post-translational ER translocon. Together, they form a distinct portal for the recognition and translocation of a large subset of Plasmodium export element effector proteins into the ER, thereby remodelling the infected erythrocyte that is required for parasite survival and pathogenesis.

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Fig. 1: Identifying PfSPC25 as an interacting partner of PMV.
Fig. 2: PfSPC25 is required for parasite growth and export of PEXEL proteins.
Fig. 3: Dissecting the PMV–PfSPC25 interaction.
Fig. 4: Characterization of the signal peptidase catalytic subunit PfSPC21.
Fig. 5: A mutant PfEMP3 PEXEL protein causes an accumulation of co-expressed PEXEL proteins.
Fig. 6: PfSec62 regulates the ER import of distinct PEXEL proteins.

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Acknowledgements

We thank the Red Cross Blood Service (Melbourne, Victoria, Australia) for the supply of donor blood for our cell culture. This work was supported by the NHMRC of Australia and the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIISS. A.F.C. is a Howard Hughes International Scholar. M.P. was supported by the EMBO Long-Term Fellowship ALTF 793-2016.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Danushka S. Marapana, Laura F. Dagley, Jarrod J. Sandow, Thomas Nebl, Tony Triglia, Michał Pasternak, Andrew I. Webb, Justin A. Boddey & Alan F. Cowman

  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

    Danushka S. Marapana, Laura F. Dagley, Jarrod J. Sandow, Thomas Nebl, Michał Pasternak, Andrew I. Webb, Justin A. Boddey & Alan F. Cowman

  3. Burnet Institute, Melbourne, Victoria, Australia

    Benjamin K. Dickerman, Brendan S. Crabb & Paul R. Gilson

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Contributions

D.S.M. conceived and performed the experiments, acquired and analysed the data and wrote the manuscript. L.F.D. conceived and performed the experiments, acquired and analysed the data and edited the manuscript. J.J.S. conceived and performed the experiments, acquired and analysed the data and edited the manuscript. T.N. conceived and performed the experiments, acquired and analysed the data and edited the manuscript. T.T. performed the experiments, acquired and analysed the data and edited the manuscript. M.P. performed the experiments, acquired and analysed the data and edited the manuscript. B.K.D. conceived and performed the experiments, acquired and analysed the data and edited the manuscript. B.S.C. conceived the experiments, analysed the data and edited the manuscript. P.R.G. conceived the experiments, analysed the data and edited the manuscript. A.I.W. conceived and performed the experiments, acquired and analysed the data and edited the manuscript. J.A.B. conceived the experiments, analysed the data and edited the manuscript. A.F.C. conceived the experiments, analysed the data and wrote the manuscript.

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Correspondence to Alan F. Cowman.

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Marapana, D.S., Dagley, L.F., Sandow, J.J. et al. Plasmepsin V cleaves malaria effector proteins in a distinct endoplasmic reticulum translocation interactome for export to the erythrocyte. Nat Microbiol 3, 1010–1022 (2018). https://doi.org/10.1038/s41564-018-0219-2

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