FKBP35 secures ribosome homeostasis in Plasmodium falciparum

Plasmodium falciparum is the most virulent malaria parasite and accounts for the majority of over 600’000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged, posing a serious threat to disease control efforts. The need for drugs with alternative modes of action is thus undoubted. The parasite’s FKBP protein (PfFKBP35) has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506. Whilst there is considerable interest in targeting PfFKBP35 with small molecules, a genetic validation of this factor as a drug target is missing. As a consequence, the function of PfFKBP35 in live parasites remains elusive. Here, we report the generation of inducible knock-out, knock-down and over-expression cell lines and show that blood stage parasites require PfFKBP35 for maintaining ribosome function. Limiting PfFKBP35 levels are lethal to P. falciparum and result in a delayed-death phenotype that is characterized by defective ribosome homeostasis and protein translation. We furthermore show that, while FK506 is indeed binding to PfFKBP35, the drug exerts it parasiticidal activity in a PfFKBP35-independent manner and, using cellular thermal shift assays, we identify FK506-targets beyond PfFKBP35. In addition to revealing first functional insights on the role of PfFKBP35 in P. falciparum parasites, our results show that current efforts to develop PfFKBP35-targeting drugs need to be reconsidered urgently.