Trends in Parasitology
Volume 20, Issue 12, December 2004, Pages 581-589
Journal home page for Trends in Parasitology

Protein trafficking in Plasmodium falciparum-infected red blood cells

https://doi.org/10.1016/j.pt.2004.09.008Get rights and content

Plasmodium falciparum inhabits a niche within the most highly terminally differentiated cell in the human body – the mature red blood cell. Life inside this normally quiescent cell offers the parasite protection from the host's immune system, but provides little in the way of cellular infrastructure. To survive and replicate in the red blood cell, the parasite exports proteins that interact with and dramatically modify the properties of the host red blood cell. As part of this process, the parasite appears to establish a system within the red blood cell cytosol that allows the correct trafficking of parasite proteins to their final cellular destinations. In this review, we examine recent developments in our understanding of the pathways and components involved in the delivery of important parasite-encoded proteins to their final destination in the host red blood cell. These complex processes are not only fundamental to the survival of malaria parasites in vivo, but are also major determinants of the unique pathogenicity of this parasite.

Section snippets

Trafficking of proteins to the parasitophorous vacuole

Trafficking of proteins within the confines of the parasite appears to involve most of the elements of a classical vesicle-mediated secretory pathway. Brefeldin A (BFA) is a drug that specifically blocks classical vesicle-mediated trafficking by interfering with the Plasmodium ADP ribosylation factor GDP–GTP exchange protein [a key molecule required for the assembly of coat protein (COP), which coats the transport vesicles] [6] and prevents secretion of most exported proteins examined so far.

Trafficking of proteins across the PVM

Attempts to analyze the signal sequences of exported parasite proteins have revealed some rather unusual motifs. Proteins destined for sites in the ER, parasite PM, PV, PVM and apical organelles appear to have classical hydrophobic N-terminal signal sequences (i.e. a stretch of ∼15 hydrophobic amino acids commencing three to 17 amino acids from the N-terminus) 24, 25, 26. By contrast, several proteins that are directed past the PVM to the RBC cytosol have a longer (up to 30 amino acids)

Exported membrane structures in the host RBC cytosol

The mature human RBC has no architecture of intracellular membranes; thus the parasite needs to set up its own transport system. Proteins, such as KAHRP, HRP-2 and MESA, have been observed in large membrane-free aggregates in the RBC cytosol 30, 39, 40. These proteins could transit the PV as unfolded polypeptides, then refold and form complexes that diffuse across the host RBC compartment, and spontaneously assemble at the appropriate destinations as a result of interactions with RBC proteins.

Trafficking machinery in the host RBC cytosol

The membranous structures in the RBC cytosol are assumed to be involved in trafficking of membrane-associated proteins. However, the mechanics of the trafficking process still need to be defined. Given that the RBC lacks the endogenous coat proteins needed for vesicle-mediated transport, the parasite must set up its own budding and fusion machinery. In this context, it is of some interest that components of the Plasmodium COPII complex have been reported to be exported to the host cell cytosol.

The role of Maurer's clefts in protein trafficking

MCs are thought to be an important transit depot for PfEMP-1 en route to the RBC membrane. Transit of newly synthesized protein to the pRBC surface requires about nine hours, and a significant proportion of the PfEMP-1 population appears to remain in an as yet poorly identified intracellular pool (most likely associated with MCs) [45]. PfEMP-1 is inserted into the MC membrane with the C-terminal domain exposed to the RBC cytoplasm and the N-terminal domain buried inside the cleft [45]. The

Future directions

Over the past few years, our understanding of the cell biological processes underlying host RBC modification by P. falciparum has advanced considerably. This is largely because of the complete sequencing and annotation of the P. falciparum genome, the development of transfection systems for asexual-stage parasites, highly sophisticated morphological analyses, and the identification of new parasite proteins exported into the RBC and their interactions with other RBC and parasite proteins.

Acknowledgements

We acknowledge funding from the National Health and Medical Research Council of Australia (B.M.C. and L.T.), The National Institutes of Health (B.M.C.), The Wellcome Trust (L.H.B.) and the Deutsche Forschungsgemeinschaft (K.L.). We thank John Hopkins for electron micrographic assistance.

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