A revised mechanism for how Plasmodium falciparum recruits and exports proteins into its erythrocytic host cell

PLoS Pathog. 2022 Feb 22;18(2):e1009977. doi: 10.1371/journal.ppat.1009977. eCollection 2022 Feb.

Abstract

Plasmodium falciparum exports ~10% of its proteome into its host erythrocyte to modify the host cell's physiology. The Plasmodium export element (PEXEL) motif contained within the N-terminus of most exported proteins directs the trafficking of those proteins into the erythrocyte. To reach the host cell, the PEXEL motif of exported proteins is processed by the endoplasmic reticulum (ER) resident aspartyl protease plasmepsin V. Then, following secretion into the parasite-encasing parasitophorous vacuole, the mature exported protein must be unfolded and translocated across the parasitophorous vacuole membrane by the Plasmodium translocon of exported proteins (PTEX). PTEX is a protein-conducting channel consisting of the pore-forming protein EXP2, the protein unfoldase HSP101, and structural component PTEX150. The mechanism of how exported proteins are specifically trafficked from the parasite's ER following PEXEL cleavage to PTEX complexes on the parasitophorous vacuole membrane is currently not understood. Here, we present evidence that EXP2 and PTEX150 form a stable subcomplex that facilitates HSP101 docking. We also demonstrate that HSP101 localises both within the parasitophorous vacuole and within the parasite's ER throughout the ring and trophozoite stage of the parasite, coinciding with the timeframe of protein export. Interestingly, we found that HSP101 can form specific interactions with model PEXEL proteins in the parasite's ER, irrespective of their PEXEL processing status. Collectively, our data suggest that HSP101 recognises and chaperones PEXEL proteins from the ER to the parasitophorous vacuole and given HSP101's specificity for the EXP2-PTEX150 subcomplex, this provides a mechanism for how exported proteins are specifically targeted to PTEX for translocation into the erythrocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Erythrocytes / parasitology
  • Parasites* / metabolism
  • Plasmodium falciparum* / metabolism
  • Protein Transport / physiology
  • Protozoan Proteins / metabolism

Substances

  • Protozoan Proteins

Grants and funding

T.K.J. is a recipient of the Melbourne Research Scholarship and M.G. a recipient of a Deakin University Postgraduate Research Scholarship. T.F.dK-W is an NHMRC Senior Research Fellow. B.E.S. is an Ellen Corin Fellow. We thank the Nora Baart Foundation for travel support for CB. This work was supported by the Victorian Operational Infrastructure Support Program received by the Burnet Institute and National Health and Research Council grants 1092789, 1128198 and 1197805 (https://www.nhmrc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.