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bioRxiv · 10.1101/2025.06.02.657352

A Plasmodium lipase is critical for the disruption of the parasitophorous vacuole membrane and egress of hepatic merozoites.

Devi, R.·Mehra, P.·Ali, S.·Mishra, S.
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Abstract

Malaria parasites develop within a specialized vacuole delimited by the parasitophorous vacuolar membrane (PVM). The exit of Plasmodium from host cells is a well-regulated process involving several molecules that disrupt the PVM to continue the life cycle. While several protein classes play a role in Plasmodium PVM rupture and merozoite egress, the first class of enzymes one would consider to act on membranes is lipases. However, the role of a lipase in PVM disruption remains unknown. Here, we characterized the role of UIS28 (upregulated in infective sporozoite gene 28) in Plasmodium berghei. Bioinformatic studies indicated that UIS28 is a class 3 lipase containing a fungal lipase-like domain. We found that UIS28 localizes to the PVM in infected hepatocytes. To understand the role of UIS28 in PVM disruption, we validated its lipase activity and found that it breaks down lipids into glycerol. Parasites lacking UIS28 develop normally in the blood and mosquito stages and mature fully into hepatic merozoites but show a defect in egress from host hepatocytes. We quantified the PVM rupture and reported that mutant parasites exhibit delayed egress due to impaired PVM disruption. Together, our results demonstrate that UIS28 is a lipase involved in the disruption of the PVM and the successful egress of hepatic merozoites. Author SummaryAn essential step in the life cycle of malaria parasites is their egress from hepatocytes, allowing them to transition from the liver stage to the blood stage. Liver stage parasites reside in a PV, which is surrounded by a PVM. Parasites must breakdown the PVM before they can infect other cells. This complex, multistep process is orchestrated by the parasite and involves several molecules to disrupt the PVM. However, little is known about these molecules. Here, we validated that UIS28 is indeed a lipase. We show that UIS28 is expressed in sporozoites and in the liver stage, and that it localizes to the PVM of parasites within hepatocytes. Disruption of UIS28 gene does not affect blood and mosquito stage development. However, mutant parasites show a defect in the disruption of the PVM and egress of hepatic merozoites. For the first time, we demonstrate the role of a lipase in PVM rupture during the release of liver-stage merozoites.

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Devi, R., Mehra, P., Ali, S., Mishra, S.. 2025-06-02. A Plasmodium lipase is critical for the disruption of the parasitophorous vacuole membrane and egress of hepatic merozoites.. https://doi.org/10.1101/2025.06.02.657352

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