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Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum
Shirin Arastu-Kapur1, Elizabeth L Ponder, Ursa Pecar Fonović
1Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, USA.
Abstract:
Newly replicated Plasmodium falciparum parasites escape from host erythrocytes through a tightly regulated process that is mediated by multiple classes of proteolytic enzymes. However, the identification of specific proteases has been challenging. We describe here a forward chemical genetic screen using a highly focused library of more than 1,200 covalent serine and cysteine protease inhibitors to identify compounds that block host cell rupture by P. falciparum. Using hits from the library screen, we identified the subtilisin-family serine protease PfSU B1 and the cysteine protease dipeptidyl peptidase 3 (DPAP3) as primary regulators of this process. Inhibition of both DPAP3 and PfSUB1 caused a block in proteolytic processing of the serine repeat antigen (SERA) protein SERA5 that correlated with the observed block in rupture. Furthermore, DPAP3 inhibition reduced the levels of mature PfSUB1. These results suggest that two mechanistically distinct proteases function to regulate processing of downstream substrates required for efficient release of parasites from host red blood cells.
Insights
Researchers identified two key proteases, PfSUB1 and dipeptidyl peptidase 3 (DPAP3), that regulate Plasmodium falciparum parasite release from red blood cells. Inhibiting these proteases blocks parasite escape by preventing essential protein processing.
Area of Science:
- Biochemistry
- Parasitology
- Molecular Biology
Background:
- Plasmodium falciparum parasite release from host erythrocytes is crucial for malaria transmission.
- This egress process is regulated by proteolytic enzymes, but specific proteases remain largely unidentified.
- Identifying these proteases is essential for developing novel antimalarial strategies.
Purpose of the Study:
- To identify specific proteases involved in Plasmodium falciparum host cell rupture using a chemical genetic screen.
- To elucidate the roles of identified proteases in the parasite egress pathway.
Main Methods:
- Conducted a forward chemical genetic screen using a library of over 1,200 covalent serine and cysteine protease inhibitors.
- Identified inhibitors that block host cell rupture by P. falciparum.
- Investigated the function of identified proteases, PfSUB1 and DPAP3, in parasite egress and substrate processing.
Main Results:
- Identified subtilisin-family serine protease PfSUB1 and cysteine protease dipeptidyl peptidase 3 (DPAP3) as key regulators of parasite egress.
- Inhibition of both DPAP3 and PfSUB1 blocked the proteolytic processing of SERA5, a substrate essential for rupture.
- DPAP3 inhibition led to reduced levels of mature PfSUB1, indicating a regulatory relationship.
Conclusions:
- PfSUB1 and DPAP3 are critical proteases regulating Plasmodium falciparum parasite release.
- These proteases act through distinct mechanisms to process downstream substrates required for efficient parasite egress.
- Targeting DPAP3 and PfSUB1 represents a promising strategy for developing new antimalarial drugs.
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