Erythrocytes are extensively remodelled by the malaria parasite following invasion of the cell. Plasmodium falciparum encodes numerous virulence-associated and host-cell remodelling proteins that are trafficked to the cytoplasm, the cell membrane and the surface of the infected erythrocyte. The export of soluble proteins relies on a sequence directing entry into the secretory pathways in addition to an export signal. The export signal consisting of five amino acids is termed the Plasmodium export element (PEXEL) or the vacuole transport signal (VTS). Genome mining studies have revealed that PEXEL/VTS carrying protein families have expanded dramatically in P. falciparum compared with other malaria parasite species, possibly due to lineage-specific expansion linked to the unique requirements of P. falciparum for host-cell remodelling. The functional characterization of such genes and gene families may reveal potential drug targets that could inhibit protein trafficking in infected erythrocytes. This review highlights some of the recent advances and key knowledge gaps in protein trafficking pathways in P. falciparum-infected red cells and speculates on the impact of exported gene families in the trafficking pathway.

Glycosylphosphatidylinositol (GPI) anchors are critical for the membrane attachment of a wide variety of essential signaling and cell adhesion proteins. The GPI anchor is a complex glycolipid structure that utilizes glycosylphosphatidylinositol-mannosyltransferases (GPI-MTs) for the addition of three core mannose residues during its biosynthesis. Here, we demonstrate that Drosophila GPI-MT2 is required for the GPI-mediated membrane attachment of several GPI-anchored proteins, including the photoreceptor-specific cell adhesion molecule, chaoptin. Mutations in gpi-mt2 lead to defects in chaoptin trafficking to the plasma membrane in Drosophila photoreceptor cells. In gpi-mt2 mutants, loss of sufficient chaoptin in the membrane leads to microvillar instability, photoreceptor cell pathology, and retinal degeneration. Finally, using site-directed mutagenesis, we have identified key amino acids that are essential for GPI-MT2 function and cell viability in Drosophila. Our findings on GPI-MT2 provide a mechanistic link between GPI anchor biosynthesis and protein trafficking in Drosophila and shed light on a novel mechanism for inherited retinal degeneration.

The human malarial parasite Plasmodium falciparum extensively modifies its host erythrocyte, and to this end, is faced with an interesting challenge. It must not only sort proteins to common organelles such as endoplasmic reticulum, Golgi and mitochondria, but also target proteins across the ‘extracellular’ cytosol of its host cell. Furthermore, as a member of the phylum Apicomplexa, the parasite has to sort proteins to novel organelles such as the apicoplast, micronemes and rhoptries. In order to overcome these difficulties, the parasite has created a novel secretory system, which has been characterized in ever-increasing detail in the past decade. Along with the ‘hardware’ for a secretory system, the parasite also needs to ‘program’ proteins to enable high fidelity sorting to their correct subcellular location. The nature of these sorting signals has remained until relatively recently, enigmatic. Experimental work has now begun to dissect the sorting signals responsible for correct subcellular targeting of parasite-encoded proteins. In this review we summarize the current understanding of such signals, and comment on their role in protein sorting in this organism, which may become a model for the study of novel protein trafficking mechanisms.