FIKK1, a member of the FIKK kinase family, phosphorylates VAR2CSA and regulates adhesion of Plasmodium falciparum-infected erythrocytes to the placental receptor CSA
Abstract
lasmodium falciparum promotes the adhesion of infected erythrocytes (IEs) to host cells by extensively remodeling their surface. For this process, the parasite exports a large number of proteins to its host erythrocyte, including members of the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) adhesin family and members of the FIKK family. Several FIKK have been shown to play a role in P. falciparum virulence, notably affecting IEs cell surface remodeling, rigidity and cytoadhesion. VAR2CSA, a member of the PfEMP1 adhesin family, is associated with IEs sequestration in the placenta and has been shown to be phosphorylated. In view of the previously described importance of VAR2CSA phosphorylation, we investigated the role of FIKK1. We show that FIKK1 is capable of phosphorylating VAR2CSA in vitro, and that this phosphorylation increases the binding of recombinant VAR2CSA to the placental receptor chondroitin sulphate A (CSA). In an inducible transgenic cell line expressing HA-tagged FIKK1, immunofluorescence assays indicate that the kinase localizes to punctuated foci within Maurer’s Cleft, similarly to VAR2CSA. Rapamycin-induced knock-out of FIKK1 reduces IEs cytoadhesion to CSA, even though levels of VAR2CSA are not affected. In vitro phosphorylation assays show that FIKK1 can phosphorylate recombinant DBL1–3 domains on several residues, including S429 and T934, previously implicated in in vitro binding and IEs cytoadhesion to CSA. Taken together, these data support a model whereby FIKK1 contributes to placental malaria virulence through IEs sequestration mediated by VAR2CSA phosphorylation. Having no orthologs in mammals, this orphan kinase therefore represents an attractive target for the development of drugs against placental malaria.
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BibTeX
@article{gamain2026fikk1,
title = {{FIKK1, a member of the FIKK kinase family, phosphorylates VAR2CSA and regulates adhesion of Plasmodium falciparum-infected erythrocytes to the placental receptor CSA}},
author = {Benoît Gamain and Jean-Philippe Semblat and Heledd Eavis and Hugo Belda and Romain Hamelin and Christian Doerig and Moritz Treeck and Dominique Dorin-Semblat and Clara-Eva Paquereau},
journal = {PLoS Pathogens},
year = {2026},
month = jul,
doi = {10.1371/journal.ppat.1014108},
url = {https://hal.science/hal-05749053v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - FIKK1, a member of the FIKK kinase family, phosphorylates VAR2CSA and regulates adhesion of Plasmodium falciparum-infected erythrocytes to the placental receptor CSA
AU - Benoît Gamain
AU - Jean-Philippe Semblat
AU - Heledd Eavis
AU - Hugo Belda
AU - Romain Hamelin
AU - Christian Doerig
AU - Moritz Treeck
AU - Dominique Dorin-Semblat
AU - Clara-Eva Paquereau
PY - 2026
DA - 2026/07/29
JO - PLoS Pathogens
DO - 10.1371/journal.ppat.1014108
UR - https://hal.science/hal-05749053v1
AB - lasmodium falciparum promotes the adhesion of infected erythrocytes (IEs) to host cells by extensively remodeling their surface. For this process, the parasite exports a large number of proteins to its host erythrocyte, including members of the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) adhesin family and members of the FIKK family. Several FIKK have been shown to play a role in P. falciparum virulence, notably affecting IEs cell surface remodeling, rigidity and cytoadhesion. VAR2CSA, a member of the PfEMP1 adhesin family, is associated with IEs sequestration in the placenta and has been shown to be phosphorylated. In view of the previously described importance of VAR2CSA phosphorylation, we investigated the role of FIKK1. We show that FIKK1 is capable of phosphorylating VAR2CSA in vitro, and that this phosphorylation increases the binding of recombinant VAR2CSA to the placental receptor chondroitin sulphate A (CSA). In an inducible transgenic cell line expressing HA-tagged FIKK1, immunofluorescence assays indicate that the kinase localizes to punctuated foci within Maurer’s Cleft, similarly to VAR2CSA. Rapamycin-induced knock-out of FIKK1 reduces IEs cytoadhesion to CSA, even though levels of VAR2CSA are not affected. In vitro phosphorylation assays show that FIKK1 can phosphorylate recombinant DBL1–3 domains on several residues, including S429 and T934, previously implicated in in vitro binding and IEs cytoadhesion to CSA. Taken together, these data support a model whereby FIKK1 contributes to placental malaria virulence through IEs sequestration mediated by VAR2CSA phosphorylation. Having no orthologs in mammals, this orphan kinase therefore represents an attractive target for the development of drugs against placental malaria.
SN - 1553-7366
SN - 1553-7374
ER -