Abstract
O-glycosylation of the Plasmodium sporozoite surface proteins CSP and TRAP was recently identified, but the role of this modification in the parasite life cycle and its relevance to vaccine design remain unclear. Here, we identify the Plasmodium protein O-fucosyltransferase (POFUT2) responsible for O-glycosylating CSP and TRAP. Genetic disruption of POFUT2 in Plasmodium falciparum results in ookinetes that are attenuated for colonizing the mosquito midgut, an essential step in malaria transmission. Some POFUT2-deficient parasites mature into salivary gland sporozoites although they are impaired for gliding motility, cell traversal, hepatocyte invasion, and production of exoerythrocytic forms in humanized chimeric liver mice. These defects can be attributed to destabilization and incorrect trafficking of proteins bearing thrombospondin repeats (TSRs). Therefore, POFUT2 plays a similar role in malaria parasites to that in metazoans: it ensures the trafficking of Plasmodium TSR proteins as part of a non-canonical glycosylation-dependent endoplasmic reticulum protein quality control mechanism.
Highlights
O-glycosylation of the Plasmodium sporozoite surface proteins circumsporozoite protein (CSP) and thrombospondin-related anonymous protein (TRAP) was recently identified, but the role of this modification in the parasite life cycle and its relevance to vaccine design remain unclear
The identification of glycosylated thrombospondin repeats (TSRs) proteins in P. falciparum suggests a similar protein quality control mechanism is present in the malaria parasite, an idea supported by the observation that heterologous expression of CSP24 and TRAP25 TSR domains in mammalian cell lines yield proteins modified with the same β-D-glucosyl-1,3-α-L-fucose disaccharide
We proceeded to inspect the sequence of every P. falciparum protein with a TSR domain for this O-fucosylation sequon (Fig. 1d) to and found that, in addition to CSP and TRAP, potential protein O-fucosyltransferase 2 (POFUT2) substrates include: circumsporozoite- and TRAP-related protein (CTRP), expressed in ookinetes[28, 29], as well as TRAP-like protein (TLP)[30], thrombospondin-related sporozoite protein (TRSP)[31] and thrombospondin-related protein 1 (TRP1)[32] from the sporozoite stages
Summary
O-glycosylation of the Plasmodium sporozoite surface proteins CSP and TRAP was recently identified, but the role of this modification in the parasite life cycle and its relevance to vaccine design remain unclear. The identification of glycosylated TSR proteins in P. falciparum suggests a similar protein quality control mechanism is present in the malaria parasite, an idea supported by the observation that heterologous expression of CSP24 and TRAP25 TSR domains in mammalian cell lines yield proteins modified with the same β-D-glucosyl-1,3-α-L-fucose disaccharide.
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