The long and winding road: protein trafficking mechanisms in the Plasmodium falciparum infected erythrocyte.

Mature human erythrocytes infected with the human malarial parasite Plasmodium falciparum are extensively modified to provide a more comfortable "home" for their intracellular guests. This process is mediated by parasite-encoded factors that are exported into, and through the host erythrocyte. This intra- yet simultaneously extra-cellular protein trafficking and sorting system has, in the past decades received much attention, also due to its unusual nature. Recent reports have highlighted the importance of a short peptide sequence, referred to individually as Plasmodium export element (PEXEL), vacuolar translocation signal (VTS) or generally as host cell targeting signal (HCT) in the export of both soluble and membrane bound proteins, allowing the partial definition of the parasite's "exportome". Mechanistically however, the discovery of this sequence raises as many questions as it answers. In this article, we comment on current models of protein transport to the host cell, discuss the mechanistic problems highlighted by these signals, and suggest what might be the next important steps in studying the protein export mechanisms of an obligate intracellular parasite that chooses to inhabit a de-nucleated host cell.