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 JournalArticleAcademicpeer-review


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 languageEnglish
Article number1172
Pages (from-to)1-19
Number of pages19
JournalNature Communications
Issue number1
Early online date19 Feb 2021
Publication statusPublished - 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 2021 Elsevier B.V., All rights reserved.


Dive into the research topics of '20S proteasomes secreted by the malaria parasite promote its growth'. Together they form a unique fingerprint.

Cite this