Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding

Justin A. Boddey; Matthew T.  O'Neill; Sash Lopaticki; Teresa G. Carvalho; Anthony N. Hodder; Thomas  Nebl; Stephan Wawra; Pieter Van West; Zeinab Ebrahimzadeh; Dave Richard; Sven Flemming; Tobias Spielmann; Jude Pryzborski; Jeff J. Babon; Alan F.  Cowman

doi:10.1038/ncomms10470

Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding

Justin A. Boddey^* (Corresponding Author), Matthew T. O'Neill, Sash Lopaticki, Teresa G. Carvalho, Anthony N. Hodder, Thomas Nebl, Stephan Wawra, Pieter Van West, Zeinab Ebrahimzadeh, Dave Richard, Sven Flemming, Tobias Spielmann, Jude Pryzborski, Jeff J. Babon, Alan F. Cowman^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV). A recent study reported that phosphatidylinositol-3-phosphate (PI(3)P) concentrated in the ER binds to PEXEL motifs and is required for export independent of PMV, and that PEXEL motifs are functionally interchangeable with RxLR motifs of oomycete effectors. Here we show that the PEXEL does not bind PI(3)P, and that this lipid is not concentrated in the ER. We find that RxLR motifs cannot mediate export in P. falciparum. Parasites expressing a mutated version of KAHRP, with the PEXEL motif repositioned near the signal sequence, prevented PMV cleavage. This mutant possessed the putative PI(3)P-binding residues but is not exported. Reinstatement of PEXEL to its original location restores processing by PMV and export. These results challenge the PI(3)P hypothesis and provide evidence that PEXEL position is conserved for co-translational processing and export.

Original language	English
Article number	10470
Pages (from-to)	1-14
Number of pages	14
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10470
Publication status	Published - 1 Feb 2016

Bibliographical note

Acknowledgements
We thank the Red Cross blood bank in Melbourne for human erythrocytes. We thank Svenja Gunther for expression of GBP130 66–196 proteins; Michelle Gazdik and Chris Burns for help in preparing lipids; Lachlan Whitehead (Centre for Dynamic Imaging, Walter and Eliza Hall Institute) for assistance with quantification of export; and David Bocher for help with generation of STEVOR constructs. This work was supported by the National Health and Medical Research Council of Australia (grants 637406, 1010326, 1049811 and 1057960), a Ramaciotti Foundation Establishment Grant (3197/2010), a Victorian State Government Operational Infrastructure Support and Australian
Government NHMRC IRIISS, and the Canadian Institutes for Health Research
(MOP#130359). J.A.B is an Australian Research Council QEII Fellow, SF was supported by the Research Training Group GRK1459 of the German Research Foundation, and AFC is a Howard Hughes International Scholar.

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Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding
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Boddey, J. A., O'Neill, M. T., Lopaticki, S., Carvalho, T. G., Hodder, A. N., Nebl, T., Wawra, S., Van West, P., Ebrahimzadeh, Z., Richard, D., Flemming, S., Spielmann, T., Pryzborski, J., Babon, J. J., & Cowman, A. F. (2016). Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding. Nature Communications, 7, 1-14. Article 10470. https://doi.org/10.1038/ncomms10470

Boddey, JA, O'Neill, MT, Lopaticki, S, Carvalho, TG, Hodder, AN, Nebl, T, Wawra, S, Van West, P, Ebrahimzadeh, Z, Richard, D, Flemming, S, Spielmann, T, Pryzborski, J, Babon, JJ & Cowman, AF 2016, 'Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding', Nature Communications, vol. 7, 10470, pp. 1-14. https://doi.org/10.1038/ncomms10470

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title = "Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding",

abstract = "Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV). A recent study reported that phosphatidylinositol-3-phosphate (PI(3)P) concentrated in the ER binds to PEXEL motifs and is required for export independent of PMV, and that PEXEL motifs are functionally interchangeable with RxLR motifs of oomycete effectors. Here we show that the PEXEL does not bind PI(3)P, and that this lipid is not concentrated in the ER. We find that RxLR motifs cannot mediate export in P. falciparum. Parasites expressing a mutated version of KAHRP, with the PEXEL motif repositioned near the signal sequence, prevented PMV cleavage. This mutant possessed the putative PI(3)P-binding residues but is not exported. Reinstatement of PEXEL to its original location restores processing by PMV and export. These results challenge the PI(3)P hypothesis and provide evidence that PEXEL position is conserved for co-translational processing and export.",

author = "Boddey, {Justin A.} and O'Neill, {Matthew T.} and Sash Lopaticki and Carvalho, {Teresa G.} and Hodder, {Anthony N.} and Thomas Nebl and Stephan Wawra and {Van West}, Pieter and Zeinab Ebrahimzadeh and Dave Richard and Sven Flemming and Tobias Spielmann and Jude Pryzborski and Babon, {Jeff J.} and Cowman, {Alan F.}",

note = "Acknowledgements We thank the Red Cross blood bank in Melbourne for human erythrocytes. We thank Svenja Gunther for expression of GBP130 66–196 proteins; Michelle Gazdik and Chris Burns for help in preparing lipids; Lachlan Whitehead (Centre for Dynamic Imaging, Walter and Eliza Hall Institute) for assistance with quantification of export; and David Bocher for help with generation of STEVOR constructs. This work was supported by the National Health and Medical Research Council of Australia (grants 637406, 1010326, 1049811 and 1057960), a Ramaciotti Foundation Establishment Grant (3197/2010), a Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS, and the Canadian Institutes for Health Research (MOP#130359). J.A.B is an Australian Research Council QEII Fellow, SF was supported by the Research Training Group GRK1459 of the German Research Foundation, and AFC is a Howard Hughes International Scholar.",

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AU - O'Neill, Matthew T.

AU - Lopaticki, Sash

AU - Carvalho, Teresa G.

AU - Hodder, Anthony N.

AU - Nebl, Thomas

AU - Wawra, Stephan

AU - Van West, Pieter

AU - Ebrahimzadeh, Zeinab

AU - Richard, Dave

AU - Flemming, Sven

AU - Spielmann, Tobias

AU - Pryzborski, Jude

AU - Babon, Jeff J.

AU - Cowman, Alan F.

N1 - Acknowledgements We thank the Red Cross blood bank in Melbourne for human erythrocytes. We thank Svenja Gunther for expression of GBP130 66–196 proteins; Michelle Gazdik and Chris Burns for help in preparing lipids; Lachlan Whitehead (Centre for Dynamic Imaging, Walter and Eliza Hall Institute) for assistance with quantification of export; and David Bocher for help with generation of STEVOR constructs. This work was supported by the National Health and Medical Research Council of Australia (grants 637406, 1010326, 1049811 and 1057960), a Ramaciotti Foundation Establishment Grant (3197/2010), a Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS, and the Canadian Institutes for Health Research (MOP#130359). J.A.B is an Australian Research Council QEII Fellow, SF was supported by the Research Training Group GRK1459 of the German Research Foundation, and AFC is a Howard Hughes International Scholar.

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N2 - Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV). A recent study reported that phosphatidylinositol-3-phosphate (PI(3)P) concentrated in the ER binds to PEXEL motifs and is required for export independent of PMV, and that PEXEL motifs are functionally interchangeable with RxLR motifs of oomycete effectors. Here we show that the PEXEL does not bind PI(3)P, and that this lipid is not concentrated in the ER. We find that RxLR motifs cannot mediate export in P. falciparum. Parasites expressing a mutated version of KAHRP, with the PEXEL motif repositioned near the signal sequence, prevented PMV cleavage. This mutant possessed the putative PI(3)P-binding residues but is not exported. Reinstatement of PEXEL to its original location restores processing by PMV and export. These results challenge the PI(3)P hypothesis and provide evidence that PEXEL position is conserved for co-translational processing and export.

AB - Plasmodium falciparum exports proteins into erythrocytes using the Plasmodium export element (PEXEL) motif, which is cleaved in the endoplasmic reticulum (ER) by plasmepsin V (PMV). A recent study reported that phosphatidylinositol-3-phosphate (PI(3)P) concentrated in the ER binds to PEXEL motifs and is required for export independent of PMV, and that PEXEL motifs are functionally interchangeable with RxLR motifs of oomycete effectors. Here we show that the PEXEL does not bind PI(3)P, and that this lipid is not concentrated in the ER. We find that RxLR motifs cannot mediate export in P. falciparum. Parasites expressing a mutated version of KAHRP, with the PEXEL motif repositioned near the signal sequence, prevented PMV cleavage. This mutant possessed the putative PI(3)P-binding residues but is not exported. Reinstatement of PEXEL to its original location restores processing by PMV and export. These results challenge the PI(3)P hypothesis and provide evidence that PEXEL position is conserved for co-translational processing and export.

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DO - 10.1038/ncomms10470

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JF - Nature Communications

M1 - 10470

ER -

Export of malaria proteins requires co-translational processing of the PEXEL motif independent of phosphatidylinositol-3-phosphate binding

Abstract

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