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

School of Chemistry

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

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
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21344-8
State	Published - 1 Dec 2021

Funding

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
European Research Council
Israel Science Foundation	2235/16, 619/16
Horizon 2020	300/17, 636752

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), Article 1172. https://doi.org/10.1038/s41467-021-21344-8

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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 = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

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

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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. https://doi.org/10.1038/s41467-021-21344-8

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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

PY - 2021/12/1

Y1 - 2021/12/1

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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20S proteasomes secreted by the malaria parasite promote its growth

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