Identification of a non-exported Plasmepsin V substrate that functions in the parasitophorous vacuole of malaria parasites

Fréville, Aline; Ressurreição, Margarida; van Ooij, Christiaan

Abstract

Malaria parasites alter multiple properties of the host erythrocyte by exporting proteins into the host cell. Many exported proteins contain a five-amino acid motif called the Plasmodium export element (PEXEL) that is cleaved by the parasite protease Plasmepsin V (PM V). The presence of a PEXEL is considered a signature of protein export and has been used to identify a large number of exported proteins. The export of proteins becomes essential midway through the intraerythrocytic cycle—preventing protein export blocks parasite development 18–24 h after invasion. However, a genetic investigation revealed that the absence of the PEXEL protein PFA0210c (PF3D7_0104200) causes parasite development to arrest immediately after invasion. We now show that this protein is cleaved by PM V but not exported into the host erythrocyte and instead functions in the parasitophorous vacuole; hence, the protein was renamed PV6. We additionally show that the lysine residue that becomes the N-terminus of PV6 after processing by PM V prevents export. This is the first example of a native Plasmodium falciparum PM V substrate that remains in the parasitophorous vacuole. We also provide evidence suggesting that the parasite may produce at least one additional essential, non-exported PM V substrate. Therefore, the presence of a PEXEL and, hence, processing of a protein by PM V do not always target a protein for export, and PM V likely has a broader function in parasite growth beyond processing exported proteins. Furthermore, we utilized this finding to investigate possible requirements for protein export further.

Citation

Fréville, A., Ressurreição, M., & van Ooij, C. (2024). Identification of a non-exported Plasmepsin V substrate that functions in the parasitophorous vacuole of malaria parasites. mBio, 15(1), https://doi.org/10.1128/mbio.01223-23

• Journal Article Type: Article
• Acceptance Date: Oct 26, 2023
• Publication Date: Jan 16, 2024
• Deposit Date: Feb 25, 2025
• Journal: mBio
• Print ISSN: 2150-7511
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 1
• DOI: https://doi.org/10.1128/mbio.01223-23
• Keywords: malaria, proteolysis, plasmodium, protein export, host-parasite relationship
• Public URL: https://keele-repository.worktribe.com/output/1079120
• Publisher URL: https://journals.asm.org/doi/10.1128/mbio.01223-23
• Additional Information: Received: 2023-05-12; Accepted: 2023-10-26; Published: 2023-12-11