20S proteasomes secreted by the malaria parasite promote its growth

Elya Dekel; Dana Yaffe; Irit Rosenhek-Goldian; Gili Ben-Nissan; Yifat Ofir-Birin; Mattia I. Morandi; Tamar Ziv; Xavier Sisquella; Matthew A. Pimentel; Thomas Nebl; Eugene Kapp; Yael Ohana Daniel; Paula Abou Karam; Daniel Alfandari; Ron Rotkopf; Shimrit Malihi; Tal Block Temin; Debakshi Mullick; Or Yam Revach; Ariel Rudik; Nir S. Gov; Ido Azuri; Ziv Porat; Giulia Bergamaschi; Raya Sorkin; Gijs J.L. Wuite; Ori Avinoam; Teresa G. Carvalho; Sidney R. Cohen; Michal Sharon; Neta Regev-Rudzki

doi:10.1038/s41467-021-21344-8

20S proteasomes secreted by the malaria parasite promote its growth

Elya Dekel, Dana Yaffe, Irit Rosenhek-Goldian, Gili Ben-Nissan, Yifat Ofir-Birin, Mattia I. Morandi, Tamar Ziv, Xavier Sisquella, Matthew A. Pimentel, Thomas Nebl, Eugene Kapp, Yael Ohana Daniel, Paula Abou Karam, Daniel Alfandari, Ron Rotkopf, Shimrit Malihi, Tal Block Temin, Debakshi Mullick, Or Yam Revach, Ariel RudikNir S. Gov, Ido Azuri, Ziv Porat, Giulia Bergamaschi, Raya Sorkin, Gijs J.L. Wuite, Ori Avinoam, Teresa G. Carvalho, Sidney R. Cohen, Michal Sharon^*, Neta Regev-Rudzki

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Mature red blood cells (RBCs) lack internal organelles and canonical defense mechanisms, making them both a fascinating host cell, in general, and an intriguing choice for the deadly malaria parasite Plasmodium falciparum (Pf), in particular. Pf, while growing inside its natural host, the human RBC, secretes multipurpose extracellular vesicles (EVs), yet their influence on this essential host cell remains unknown. Here we demonstrate that Pf parasites, cultured in fresh human donor blood, secrete within such EVs assembled and functional 20S proteasome complexes (EV-20S). The EV-20S proteasomes modulate the mechanical properties of naïve human RBCs by remodeling their cytoskeletal network. Furthermore, we identify four degradation targets of the secreted 20S proteasome, the phosphorylated cytoskeletal proteins β-adducin, ankyrin-1, dematin and Epb4.1. Overall, our findings reveal a previously unknown 20S proteasome secretion mechanism employed by the human malaria parasite, which primes RBCs for parasite invasion by altering membrane stiffness, to facilitate malaria parasite growth.

Original language	English
Article number	1172
Pages (from-to)	1-19
Number of pages	19
Journal	Nature Communications
Volume	12
Issue number	1
Early online date	19 Feb 2021
DOIs	https://doi.org/10.1038/s41467-021-21344-8
Publication status	Published - Dec 2021

Bibliographical note

Funding Information:
We thank the Malaria Research Reference Reagent Resource Center (MR4) for their generous supply of parasite strains. We thank the laboratory of Alan Cowman and the proteomics unit from the Walter and Eliza Institute, Melbourne for the scientific work on EV proteomic analysis. We thank Dr. Adi Naamati from the University of Cambridge for scientific discussions. We thank the laboratory of Prof. Georg Fantner from EPFL Lausanne for design and assistance with implementation of the fast-scanning AFM. We thank Moran Shalev, Ari Elson, and Haim Barr from the Weizmann Institute for assistance with the kinase assays. This research was supported by a Weizmann Institute Staff Scientist Grant for ZP. The research of OA is supported by the David Barton Center for Research on the Chemistry of Life and the Jeanne and Joseph Nissim Center for Life Sciences Research. OA is the incumbent of the Miriam Berman Presidential Development Chair. We thank Timo Betz for useful discussions. The research of N.R.-R. is supported by the Benoziyo Endowment Fund for the Advancement of Science, the Jeanne and Joseph Nissim Foundation for Life Sciences Research and the Samuel M. Soref and Helene K. Soref Foundation. N.R.-R. is supported by a research grant from David E. and Sheri Stone and by a research grant from Richard and Mica Hadar. N.R.-R. is the incumbent of the Enid Barden and Aaron J. Jade President’s Development Chair for New Scientists in Memory of Cantor John Y. Jade. N.R.-R. is grateful for the support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 757743), and the Israel Science Foundation (ISF) (619/16 and 2235/16). M.S. is grateful for the support of a Starting Grant from the ERC (Horizon 2020/ERC grant agreement No. 636752), and for an Israel Science Foundation grant (300/17). M.S. is the incumbent of the Aharon and Ephraim Katzir Memorial Professorial Chair. N.S.G. is the incumbent of the Lee and William Abramowitz Professorial Chair of Biophysics.

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

We thank the Malaria Research Reference Reagent Resource Center (MR4) for their generous supply of parasite strains. We thank the laboratory of Alan Cowman and the proteomics unit from the Walter and Eliza Institute, Melbourne for the scientific work on EV proteomic analysis. We thank Dr. Adi Naamati from the University of Cambridge for scientific discussions. We thank the laboratory of Prof. Georg Fantner from EPFL Lausanne for design and assistance with implementation of the fast-scanning AFM. We thank Moran Shalev, Ari Elson, and Haim Barr from the Weizmann Institute for assistance with the kinase assays. This research was supported by a Weizmann Institute Staff Scientist Grant for ZP. The research of OA is supported by the David Barton Center for Research on the Chemistry of Life and the Jeanne and Joseph Nissim Center for Life Sciences Research. OA is the incumbent of the Miriam Berman Presidential Development Chair. We thank Timo Betz for useful discussions. The research of N.R.-R. is supported by the Benoziyo Endowment Fund for the Advancement of Science, the Jeanne and Joseph Nissim Foundation for Life Sciences Research and the Samuel M. Soref and Helene K. Soref Foundation. N.R.-R. is supported by a research grant from David E. and Sheri Stone and by a research grant from Richard and Mica Hadar. N.R.-R. is the incumbent of the Enid Barden and Aaron J. Jade President’s Development Chair for New Scientists in Memory of Cantor John Y. Jade. N.R.-R. is grateful for the support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 757743), and the Israel Science Foundation (ISF) (619/16 and 2235/16). M.S. is grateful for the support of a Starting Grant from the ERC (Horizon 2020/ERC grant agreement No. 636752), and for an Israel Science Foundation grant (300/17). M.S. is the incumbent of the Aharon and Ephraim Katzir Memorial Professorial Chair. N.S.G. is the incumbent of the Lee and William Abramowitz Professorial Chair of Biophysics.

Funders	Funder number
Benoziyo Endowment Fund for the Advancement of Science
Jeanne and Joseph Nissim Center for Life Sciences Research
Jeanne and Joseph Nissim Foundation for Life Sciences Research
Horizon 2020 Framework Programme
H2020 European Research Council	757743
H2020 European Research Council
European Research Council
Israel Science Foundation	2235/16, 619/16
Israel Science Foundation
Horizon 2020	300/17, 636752
Horizon 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-21344-8

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Dekel, E., Yaffe, D., Rosenhek-Goldian, I., Ben-Nissan, G., Ofir-Birin, Y., Morandi, M. I., Ziv, T., Sisquella, X., Pimentel, M. A., Nebl, T., Kapp, E., Ohana Daniel, Y., Karam, P. A., Alfandari, D., Rotkopf, R., Malihi, S., Temin, T. B., Mullick, D., Revach, O. Y., ... Regev-Rudzki, N. (2021). 20S proteasomes secreted by the malaria parasite promote its growth. Nature Communications, 12(1), 1-19. Article 1172. https://doi.org/10.1038/s41467-021-21344-8

@article{f69535b2c2f0430d844ba43446ffb796,

title = "20S proteasomes secreted by the malaria parasite promote its growth",

abstract = "Mature red blood cells (RBCs) lack internal organelles and canonical defense mechanisms, making them both a fascinating host cell, in general, and an intriguing choice for the deadly malaria parasite Plasmodium falciparum (Pf), in particular. Pf, while growing inside its natural host, the human RBC, secretes multipurpose extracellular vesicles (EVs), yet their influence on this essential host cell remains unknown. Here we demonstrate that Pf parasites, cultured in fresh human donor blood, secrete within such EVs assembled and functional 20S proteasome complexes (EV-20S). The EV-20S proteasomes modulate the mechanical properties of na{\"i}ve human RBCs by remodeling their cytoskeletal network. Furthermore, we identify four degradation targets of the secreted 20S proteasome, the phosphorylated cytoskeletal proteins β-adducin, ankyrin-1, dematin and Epb4.1. Overall, our findings reveal a previously unknown 20S proteasome secretion mechanism employed by the human malaria parasite, which primes RBCs for parasite invasion by altering membrane stiffness, to facilitate malaria parasite growth.",

author = "Elya Dekel and Dana Yaffe and Irit Rosenhek-Goldian and Gili Ben-Nissan and Yifat Ofir-Birin and Morandi, {Mattia I.} and Tamar Ziv and Xavier Sisquella and Pimentel, {Matthew A.} and Thomas Nebl and Eugene Kapp and {Ohana Daniel}, Yael and Karam, {Paula Abou} and Daniel Alfandari and Ron Rotkopf and Shimrit Malihi and Temin, {Tal Block} and Debakshi Mullick and Revach, {Or Yam} and Ariel Rudik and Gov, {Nir S.} and Ido Azuri and Ziv Porat and Giulia Bergamaschi and Raya Sorkin and Wuite, {Gijs J.L.} and Ori Avinoam and Carvalho, {Teresa G.} and Cohen, {Sidney R.} and Michal Sharon and Neta Regev-Rudzki",

note = "Funding Information: We thank the Malaria Research Reference Reagent Resource Center (MR4) for their generous supply of parasite strains. We thank the laboratory of Alan Cowman and the proteomics unit from the Walter and Eliza Institute, Melbourne for the scientific work on EV proteomic analysis. We thank Dr. Adi Naamati from the University of Cambridge for scientific discussions. We thank the laboratory of Prof. Georg Fantner from EPFL Lausanne for design and assistance with implementation of the fast-scanning AFM. We thank Moran Shalev, Ari Elson, and Haim Barr from the Weizmann Institute for assistance with the kinase assays. This research was supported by a Weizmann Institute Staff Scientist Grant for ZP. The research of OA is supported by the David Barton Center for Research on the Chemistry of Life and the Jeanne and Joseph Nissim Center for Life Sciences Research. OA is the incumbent of the Miriam Berman Presidential Development Chair. We thank Timo Betz for useful discussions. The research of N.R.-R. is supported by the Benoziyo Endowment Fund for the Advancement of Science, the Jeanne and Joseph Nissim Foundation for Life Sciences Research and the Samuel M. Soref and Helene K. Soref Foundation. N.R.-R. is supported by a research grant from David E. and Sheri Stone and by a research grant from Richard and Mica Hadar. N.R.-R. is the incumbent of the Enid Barden and Aaron J. Jade President{\textquoteright}s Development Chair for New Scientists in Memory of Cantor John Y. Jade. N.R.-R. is grateful for the support from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement No. 757743), and the Israel Science Foundation (ISF) (619/16 and 2235/16). M.S. is grateful for the support of a Starting Grant from the ERC (Horizon 2020/ERC grant agreement No. 636752), and for an Israel Science Foundation grant (300/17). M.S. is the incumbent of the Aharon and Ephraim Katzir Memorial Professorial Chair. N.S.G. is the incumbent of the Lee and William Abramowitz Professorial Chair of Biophysics. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-21344-8",

language = "English",

volume = "12",

pages = "1--19",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Dekel, E, Yaffe, D, Rosenhek-Goldian, I, Ben-Nissan, G, Ofir-Birin, Y, Morandi, MI, Ziv, T, Sisquella, X, Pimentel, MA, Nebl, T, Kapp, E, Ohana Daniel, Y, Karam, PA, Alfandari, D, Rotkopf, R, Malihi, S, Temin, TB, Mullick, D, Revach, OY, Rudik, A, Gov, NS, Azuri, I, Porat, Z, Bergamaschi, G, Sorkin, R, Wuite, GJL, Avinoam, O, Carvalho, TG, Cohen, SR, Sharon, M & Regev-Rudzki, N 2021, '20S proteasomes secreted by the malaria parasite promote its growth', Nature Communications, vol. 12, no. 1, 1172, pp. 1-19. https://doi.org/10.1038/s41467-021-21344-8

TY - JOUR

T1 - 20S proteasomes secreted by the malaria parasite promote its growth

AU - Dekel, Elya

AU - Yaffe, Dana

AU - Rosenhek-Goldian, Irit

AU - Ben-Nissan, Gili

AU - Ofir-Birin, Yifat

AU - Morandi, Mattia I.

AU - Ziv, Tamar

AU - Sisquella, Xavier

AU - Pimentel, Matthew A.

AU - Nebl, Thomas

AU - Kapp, Eugene

AU - Ohana Daniel, Yael

AU - Karam, Paula Abou

AU - Alfandari, Daniel

AU - Rotkopf, Ron

AU - Malihi, Shimrit

AU - Temin, Tal Block

AU - Mullick, Debakshi

AU - Revach, Or Yam

AU - Rudik, Ariel

AU - Gov, Nir S.

AU - Azuri, Ido

AU - Porat, Ziv

AU - Bergamaschi, Giulia

AU - Sorkin, Raya

AU - Wuite, Gijs J.L.

AU - Avinoam, Ori

AU - Carvalho, Teresa G.

AU - Cohen, Sidney R.

AU - Sharon, Michal

AU - Regev-Rudzki, Neta

N1 - Funding Information: We thank the Malaria Research Reference Reagent Resource Center (MR4) for their generous supply of parasite strains. We thank the laboratory of Alan Cowman and the proteomics unit from the Walter and Eliza Institute, Melbourne for the scientific work on EV proteomic analysis. We thank Dr. Adi Naamati from the University of Cambridge for scientific discussions. We thank the laboratory of Prof. Georg Fantner from EPFL Lausanne for design and assistance with implementation of the fast-scanning AFM. We thank Moran Shalev, Ari Elson, and Haim Barr from the Weizmann Institute for assistance with the kinase assays. This research was supported by a Weizmann Institute Staff Scientist Grant for ZP. The research of OA is supported by the David Barton Center for Research on the Chemistry of Life and the Jeanne and Joseph Nissim Center for Life Sciences Research. OA is the incumbent of the Miriam Berman Presidential Development Chair. We thank Timo Betz for useful discussions. The research of N.R.-R. is supported by the Benoziyo Endowment Fund for the Advancement of Science, the Jeanne and Joseph Nissim Foundation for Life Sciences Research and the Samuel M. Soref and Helene K. Soref Foundation. N.R.-R. is supported by a research grant from David E. and Sheri Stone and by a research grant from Richard and Mica Hadar. N.R.-R. is the incumbent of the Enid Barden and Aaron J. Jade President’s Development Chair for New Scientists in Memory of Cantor John Y. Jade. N.R.-R. is grateful for the support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 757743), and the Israel Science Foundation (ISF) (619/16 and 2235/16). M.S. is grateful for the support of a Starting Grant from the ERC (Horizon 2020/ERC grant agreement No. 636752), and for an Israel Science Foundation grant (300/17). M.S. is the incumbent of the Aharon and Ephraim Katzir Memorial Professorial Chair. N.S.G. is the incumbent of the Lee and William Abramowitz Professorial Chair of Biophysics. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - Mature red blood cells (RBCs) lack internal organelles and canonical defense mechanisms, making them both a fascinating host cell, in general, and an intriguing choice for the deadly malaria parasite Plasmodium falciparum (Pf), in particular. Pf, while growing inside its natural host, the human RBC, secretes multipurpose extracellular vesicles (EVs), yet their influence on this essential host cell remains unknown. Here we demonstrate that Pf parasites, cultured in fresh human donor blood, secrete within such EVs assembled and functional 20S proteasome complexes (EV-20S). The EV-20S proteasomes modulate the mechanical properties of naïve human RBCs by remodeling their cytoskeletal network. Furthermore, we identify four degradation targets of the secreted 20S proteasome, the phosphorylated cytoskeletal proteins β-adducin, ankyrin-1, dematin and Epb4.1. Overall, our findings reveal a previously unknown 20S proteasome secretion mechanism employed by the human malaria parasite, which primes RBCs for parasite invasion by altering membrane stiffness, to facilitate malaria parasite growth.

AB - Mature red blood cells (RBCs) lack internal organelles and canonical defense mechanisms, making them both a fascinating host cell, in general, and an intriguing choice for the deadly malaria parasite Plasmodium falciparum (Pf), in particular. Pf, while growing inside its natural host, the human RBC, secretes multipurpose extracellular vesicles (EVs), yet their influence on this essential host cell remains unknown. Here we demonstrate that Pf parasites, cultured in fresh human donor blood, secrete within such EVs assembled and functional 20S proteasome complexes (EV-20S). The EV-20S proteasomes modulate the mechanical properties of naïve human RBCs by remodeling their cytoskeletal network. Furthermore, we identify four degradation targets of the secreted 20S proteasome, the phosphorylated cytoskeletal proteins β-adducin, ankyrin-1, dematin and Epb4.1. Overall, our findings reveal a previously unknown 20S proteasome secretion mechanism employed by the human malaria parasite, which primes RBCs for parasite invasion by altering membrane stiffness, to facilitate malaria parasite growth.

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JO - Nature Communications

JF - Nature Communications

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ER -

20S proteasomes secreted by the malaria parasite promote its growth

Abstract

Bibliographical note

Funding

UN SDGs

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