Plasmodium early transcribed membrane proteins appear tailored to the host range of malaria parasites.
Brandsma, A. M., Hilmer, C., Rauch, M., Matuschewski, K. and Montagna, G. N.
Parasitology Unit, Max Planck Institute for Infection Biology, 10117 Berlin, Germany; Princess Maxima Center for Pediatric Oncology, Heidelberg 25, 3584 CS Utrecht, The Netherlands.
Parasitology Unit, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
Parasitology Unit, Max Planck Institute for Infection Biology, 10117 Berlin, Germany; Dept. of Molecular Parasitology, Institute of Biology, Humboldt University, 10115 Berlin, Germany.
Parasitology Unit, Max Planck Institute for Infection Biology, 10117 Berlin, Germany; Instituto de Investigaciones Biotecnologicas Dr Rodolfo Ugalde' (IIBio), UNSAM-CONICET 1650 San Martin, Buenos Aires, Argentina. Electronic address: gmontagna@iib.unsam.edu.ar.
Early transcribed membrane proteins form a unique protein family in malaria parasites. These molecules are expressed during Plasmodium intracellular phases and inserted at the parasite parasitophorus vacuole membrane, which constitutes the host-parasite interface. Upregulated in infectious sporozoites 4 (UIS4) is an essential early transcribed membrane protein of liver stages of the murine malaria model parasite Plasmodium berghei. Despite its relevance for liver stage maturation, the molecular functions of UIS4 remain elusive, and UIS4 orthologs in human malaria parasites have not yet been identified. In order to characterise functional domains of UIS4, we generated P. berghei parasites carrying a carboxy-terminally truncated version of UIS4. We observed that uis4Deltac parasites are severely impaired in liver stage development, similar to uis4(-) parasites, indicating an important role of the C-terminal domain for UIS4 function. To test whether members of the P. falciparum early transcribed membrane protein family are potential UIS4 orthologs, we selected candidates based on structural homology and parasitophorous vacuole membrane localization. We generated transgenic P. berghei parasites where UIS4 was replaced by Plasmodium falciparum ETRAMP8 or ETRAMP10.3. Both early transcribed membrane proteins were expressed in transgenic parasite lines, but liver stage maturation was impaired, indicating that the selected early transcribed membrane proteins failed to substitute the function of UIS4. As a control, we included the UIS4 ortholog from the murine parasite Plasmodium chaubaudi. We observed that PcUIS4 successfully restores UIS4 function in P. berghei. Together, these results suggest that Plasmodium parasites express tailor-made parasitophorous vacuole membrane proteins that might at least partially explain the narrow host range of malaria parasites.
International Journal for Parasitology 52(2-3): 135-143 (2022)