Journal article

Publication year: 2022

Journal: Parasitology International

Volume number: 87

ISSN: 1383-5769

eISSN: 1873-0329

DOI Link: https://doi.org/10.1016/j.parint.2021.102513

Publisher: Elsevier

Abstract: 
Plasmodium falciparum macrophage migration inhibitory factor (PfMIF) is a homologue of the multifunctional human host cytokine MIF (HsMIF). Upon schizont rupture it is released into the human blood stream where it acts as a virulence factor, modulating the host immune system. Whereas for HsMIF a tautomerase, an oxidoreductase, and a nuclease activity have been identified, the latter has not yet been studied for PfMIF. Furthermore, previous studies identified PfMIF as a target for several redox post-translational modifications. Therefore, we analysed the impact of S-glutathionylation and S-nitmsation on the protein's functions. To determine the impact of the four cysteines of PfMIF we produced His-tagged cysteine to alanine mutants of PfMIF via site-directed mutagenesis. Recombinant proteins were analysed via mass spectrometry, and enzymatic assays.Here we show for the first time that PfMIF acts as a DNase of human genomic DNA and that this activity is greater than that shown by HsMIF. Moreover, we observed a significant decrease in the maximum velocity of the DCME tautomerase activity of PfMIF upon alanine replacement of Cys3, and Cys3/Cys4 double mutant. Lastly, using a yeast reporter system, we were able to verify binding of PfMIF to the human chemokine receptors CXCR4, and demonstrate a so-far overlooked binding to CXCR2, both of which function as non-cognate receptors for HsMIF. While S-glutathionylation and S-nitrosation of PfMIF did not impair the tautomerase activity of PfMIF, activation of these receptors was significantly decreased.

Harvard Citation style: Schipper, S., Springer, E., Hahn, J., Rahlfs, S., Bourilhon, P., Bernhagen, J., et al. (2022) Characterization of Plasmodium falciparum macrophage migration inhibitory factor homologue and its cysteine deficient mutants, Parasitology International, 87, Article 102513. https://doi.org/10.1016/j.parint.2021.102513

APA Citation style: Schipper, S., Springer, E., Hahn, J., Rahlfs, S., Bourilhon, P., Bernhagen, J., Becker, K., & Przyborski, J. (2022). Characterization of Plasmodium falciparum macrophage migration inhibitory factor homologue and its cysteine deficient mutants. Parasitology International. 87, Article 102513. https://doi.org/10.1016/j.parint.2021.102513