Identification of essential exported Plasmodium falciparum protein kinases in malaria‐infected red blood cells

Abstract

Summary FIKK kinases in the human malaria parasite Plasmodium falciparum are attractive targets for new anti‐malaria drugs, as they have no orthologues in humans and have been linked to disease severity. Six FIKKs are known to be exported into red blood cells (RBCs) where they mediate dramatic structural and functional changes to RBCs that are central to pathogenesis. Eleven members of this family, which are predicted to be exported into infected RBCs (iRBCs), remain uncharacterised. Using a targeted gene‐knockout approach, we have characterised these FIKKs and discovered that five are essential for parasite survival. Three of these five FIKKs (FIKK9.1, FIKK10.1, FIKK10.2) were exported from the parasite into iRBCs and for two of these (FIKK9.1 and FIKK10.1), export was via Maurer’s clefts (parasite‐derived structures involved in protein trafficking and pathognomonic of falciparum malaria). Of the remaining two essential kinases, FIKK3 was associated with rhoptries (specialised protein secretory organelles in the parasite) and FIKK9.5 was localised in the parasite nucleus. The diverse localisation and essentiality of these FIKKs demonstrate that they play different but essential roles in the survival of P. falciparum in RBCs and therefore are attractive new drug targets for the prevention or treatment of falciparum malaria.

An exported kinase family mediates species-specific erythrocyte remodelling and virulence in human malaria

“…Species-specific RBC phosphosites are observed on proteins predicted to play a role in cytoskeletal connections, nutrient permeability, and the ubiquitination system, all of which have been previously reported to be modulated during P. falciparum infection 23 , 25 , 56 – 66 and our analysis indicates that FIKKs may regulate these pathways, either directly or by co-opting host kinases 24 , 67 , 68 . Although no consistent growth defect was observed upon deletion of any exported FIKK kinase after 120 hours under optimal cell culture conditions, a recent genetic screen indicated that disruption of some FIKKs may have a fitness defect over a longer time scale 69 , and some FIKKs were refractory to non-conditional gene deletion 70 . Additionally, FIKK9.3 has been implicated in providing some protection against elevated temperatures, suggesting it may be important during fever 71 .…”

Plasmodium kinase disruption: new hopes for anti‐malarial drug discovery

“…In conclusion, the study reported by Siddiqui et al (2019) in this issue of the British Journal of Haematology should encourage further studies to identify more essential parasite kinases for the development of new anti-malarial drug compounds in the context of anti-malarial drug resistance.…”

“…Several previous studies have showed that Plasmodium kinases have many essential functions during the Plasmodium life cycle and not only in the blood stage (Zhang, et al , ). The importance of the targeting methodology used by Siddiqui et al () showed that global mutagenesis approaches can miss essential genes and the fact that the parasite fitness cost for some targeting genes can be different between different P. falciparum strains and obviously for other Plasmodium species.…”

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors

“…Although the biological functions of this group of kinases are still unclear, evidence suggests that most FIKK kinases are involved in erythrocyte remodelling during infection [169,170]. Studies have identified nine FIKK kinases that are exported via the Maurer's clefts to the erythrocytic membrane, where remodelling occurs [169,171]. Disruption of individual genes encoding for Pf FIKK4.2, Pf FIKK7.1 or Pf FIKK12 significantly altered erythrocytic membrane rigidity and phosphorylation of certain cytoskeletal membrane proteins [170,172].…”

“…To date, five P. falciparum FIKK kinase members have been identified as essential for parasite survival, three of which are exported to the erythrocytic membrane (Pf FIKK9.1, Pf FIKK10.1 and Pf FIKK10.2) and two of which are localised within the parasite (Pf FIKK3 and Pf FIKK9.5) [171]. The non-exported FIKK8 kinase was also demonstrated to be essential to P. berghei erythrocytic parasites [180].…”