# PI3-kinase has multiple functions in asexual blood stages of Plasmodium falciparum

## TL;DR

This study shows that a specific enzyme in the malaria parasite is crucial for digestion, survival, and drug resistance.

## Contribution

The paper identifies PfPI3-kinase as essential for parasite survival and links it to digestion, apicoplast biology, and artemisinin resistance.

## Key findings

- PfPI3-kinase is essential for parasite survival and hemoglobin digestion.
- Reduced PI3P levels correlate with lower artemisinin resistance in mutant parasites.
- PI3P-dependent processes are important for apicoplast inheritance in P. falciparum.

## Abstract

All symptoms of malaria are caused during the replication of the parasite Plasmodium falciparum in human red blood cells. The parasite digests the host cell cytoplasm in its food vacuole, a pathway of particular interest as drug target. The Vps34-type PI3-kinase in P. falciparum produces PI3-monophophate (PI3P) and has been linked to haemoglobin digestion, to resistance to the current first line antimalarial artemisinin and to biology of the apicoplast. Here we dissect the functions of PfPI3-kinase by inducible deletion of its gene using the loxP-DiCre system and find that PfPI3-kinase is essential for parasite survival. Mutant parasites accumulate undigested haemoglobin (Hb) confirming a defect in the pathway of Hb uptake and digestion, the most likely reason for parasite death. Some parasites are affected in apicoplast inheritance demonstrating that PI3P-dependent processes are important for apicoplast biology in P. falciparum. Finally, we discover that in PI3-kinase mutant parasites carrying a mutation conferring resistance to artemisinin, the lower amounts of PI3P correlate with lower levels of artemisinin resistance. We suggest that the reduced levels of PI3P in the PI3-kinase mutant dampen repair mechanisms like the autophagic processes normally associated with Kelch13 mutations, leading to a proteotoxic stress and to an increase in susceptibility to artemisinin.

The online version contains supplementary material available at 10.1038/s41598-025-01397-1.