Protein export in malaria parasites: many membranes to cross

Abstract

The continuous multiplication of Plasmodium parasites in red blood cells leads to a rapid increase in parasite numbers and is responsible for the disease symptoms of malaria. Survival and virulence of the parasite are linked to parasite-induced changes of the host red blood cells. These alterations require export of a large number of parasite proteins that are trafficked across multiple membranes to reach the host cell. Two classes of exported proteins are known, those with a conserved Plasmodium export element (PEXEL/HT) or those without this motif (PNEPs). Recent work has revealed new aspects of the determinants required for export of these 2 protein classes, shedding new light on the mode of trafficking during the different transport steps en route to the host cell.

Figure 1

Export motifs in context. (a) Types of exported proteins with PfEMP1 representing a potential subtype of PNEPs. (b) Strategies to uncouple export from plasmepsin V (PM5) cleavage. Top, PEXEL proteins; middle, construct with a PNEP TM containing the mature PEXEL N-terminus only; bottom, insertion of a self-cleaving protease domain similarly exposes a mature PEXEL N-terminus. Blue lines labeled 1–4 represent signals influencing export. (c) Export determinants in the mature N-terminus. The consensus from the strategies used in (b) to test export without the full PEXEL [14,15] suggests multiple determinants influencing export. Green circles with a plus indicate export signals, squares with a minus export inhibitory signals. The column labeled ‘export’ indicates whether the combination of signals leads to export of a reporter (+) or not (−). The primary (1°) signal consists of the PEXEL residues remaining in the exposed mature N-terminus.

Figure 2

General transport pathway into the host cell. (a) Overview of an infected RBC. Modes of transport for particular steps are indicated with labeled arrows. EPM, erythrocyte plasma membrane; ER, endoplasmic reticulum; G, Golgi, MC, Maurer’s clefts; V, secretory vesicle. Squares indicate particular steps shown in (a) and (c). (b) Possible arrangements for translocons. A soluble (green) and a TM protein (red, with dark blue TM) are shown. The soluble protein can reach the host cell through PTEX (green). TM proteins either pass through a translocon spanning both the PPM and PVM (yellow), or get extracted into the PV (pink) to translocate through PTEX or a different PNEP-specific translocon (blue). (c) Development of Maurer’s clefts. Shown are the different states of Maurer’s clefts in rings (or in RBCs with mutated hemoglobin) and trophozoites (or wild type RBCs); the latter are more permissive for vesicular transport of virulence factors to the host cell surface.