Protein trafficking in malaria-infected erythrocytes

Abstract

The malaria parasite invades the human erythrocyte and converts this simple sack of haemoglobin back into a functional eukaryotic cell. Parasite-encoded proteins are trafficked to the red blood cell membrane where they modify its properties to meet the needs of the intracellular parasite. Trafficking of proteins within the parasite probably occurs via a classical vesicle-mediated secretory pathway; however, the transit of proteins from the parasite plasma membrane to the erythrocyte membrane appears to involve both a novel vesicle-mediated pathway and a direct protein-translocation system. The polypeptide signals that direct parasite proteins into these novel export pathways may include an unusual internal hydrophobic sequence, as well as a series of basic motifs.

Introduction

The classical protein secretory pathway in eukaryotic cells involves the transport of proteins between intracellular organelles by the budding and fusion of small vesicles. Exported proteins transit through the endoplasmic reticulum (ER) and the Golgi apparatus, prior to release, by exocytosis, at the cell surface. The polypeptide signal which directs proteins to the secretory pathway is a hydrophobic segment near the N-terminus of the protein sequence [1]. Additional targeting signals are used to divert proteins to other compartments (e.g., to the lysosome or to a regulated secretory compartment; see [2], for review). Protein trafficking in malaria-infected erythrocytes has an added level of complexity in that the parasite exports proteins beyond the confines of its own plasma membrane, to achieve extensive modifications of both the cytoplasm and the plasma membrane of the host r.b.c. (Fig. 1) 3, 4.

In the mature stages of the intra-erythrocytic cycle, the membrane of the erythrocyte becomes distorted with knobby protrusions. These knobs are involved in cytoadherence of infected erythrocytes to the vascular endothelium [5]. The adhesive structures are formed by deposition of parasite proteins underneath the erythrocyte membrane and insertion of proteins into the erythrocyte membrane bilayer (Fig. 2). Two major components of these knobs are a peripheral membrane protein, the knob-associated histidine-rich protein (KAHRP), which forms the major structural element of the knob [6]and an integral membrane protein, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1), which is inserted into the erythrocyte membrane and acts as the ligand for binding to endothelial cell receptors 7, 8, 9. To target proteins to the r.b.c. membrane, the parasite has to transport them past its own plasma membrane (PM) across the parasitophorous vacuolar membrane (PVM) and then out to the r.b.c. membrane (Fig. 1). Although the molecular machinery involved in the external part of this transport system is largely uncharacterised, it presumably involves unusual, parasite-specific components.