The ESCRT-III machinery participates in the production of extracellular vesicles and protein export during Plasmodium falciparum infection

Author:

Avalos-Padilla YunuenORCID,Georgiev Vasil N.,Lantero ElenaORCID,Pujals SilviaORCID,Verhoef René,N. Borgheti-Cardoso LiviaORCID,Albertazzi Lorenzo,Dimova RumianaORCID,Fernàndez-Busquets XavierORCID

Abstract

Infection with Plasmodium falciparum enhances extracellular vesicle (EV) production in parasitized red blood cells (pRBCs), an important mechanism for parasite-to-parasite communication during the asexual intraerythrocytic life cycle. The endosomal sorting complex required for transport (ESCRT), and in particular the ESCRT-III sub-complex, participates in the formation of EVs in higher eukaryotes. However, RBCs have lost the majority of their organelles through the maturation process, including an important reduction in their vesicular network. Therefore, the mechanism of EV production in P. falciparum-infected RBCs remains to be elucidated. Here we demonstrate that P. falciparum possesses a functional ESCRT-III machinery activated by an alternative recruitment pathway involving the action of PfBro1 and PfVps32/PfVps60 proteins. Additionally, multivesicular body formation and membrane shedding, both reported mechanisms of EV production, were reconstituted in the membrane model of giant unilamellar vesicles using the purified recombinant proteins. Moreover, the presence of PfVps32, PfVps60 and PfBro1 in EVs purified from a pRBC culture was confirmed by super-resolution microscopy and dot blot assays. Finally, disruption of the PfVps60 gene led to a reduction in the number of the produced EVs in the KO strain and affected the distribution of other ESCRT-III components. Overall, our results increase the knowledge on the underlying molecular mechanisms during malaria pathogenesis and demonstrate that ESCRT-III P. falciparum proteins participate in EV production.

Funder

H2020 Marie Skłodowska-Curie Actions

Severo Ochoa programme of the Spanish Ministry of Science and Competitiveness

Spanish Ministry of Science and Innovation

European Research Council/Horizon 2020

“la Caixa” Foundation

Generalitat de Catalunya through the CERCA program

Ministerio de Ciencia Tecnología y Telecomunicaciones

Federal Ministry of Education and Research of Germany

Max Planck Society

Fundación Ramón Areces

Spanish Ministry of Science, Innovation and Universities

Publisher

Public Library of Science (PLoS)

Subject

Virology,Genetics,Molecular Biology,Immunology,Microbiology,Parasitology

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