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Divide and Conquer: How malaria parasites use divergent means to modify its host cell

Human malaria parasites are able to pull off a stunning trick inside our bodies. At the point at which the major disease symptoms are observed, the parasites hide inside red blood cells (RBCs); cells that are terminally differentiated and contain no nuclei or organelles that the parasite could subvert to its own ends. In addition, during the course of circulation the spleen routinely investigates RBCs and destroys those that show signs of structural damage. The trick the parasite pulls off is the ability to survive, and indeed thrive, within a cell that for all intents and purposes appears to be overtly inhospitable. Once within the cell, the parasite also establishes multiple membrane barriers (the inner parasite membrane and the outer parasitophorous vacuole membrane (PVM)) between itself and the host cell cytoplasm, therefore rendering intraerythrocytic survival even more problematic. The parasite overcomes these biological obstacles by means of a simple barcode. This signal, reported by two independent groups in 2004, is termed the Plasmodium Export Element or PEXEL. At its core, the PEXEL is a substrate for an export-licensing enzyme with the parasite endoplasmic reticulum known as Plasmepsin V or PMV. The PEXEL is found at the N-terminus of a protein following a predicted hydrophobic region (predominantly the signal sequence). Its cleavage by PMV results in the now-matured protein being exported beyond the parasitophorous vacuole and into the host cell cytoplasm. These exported proteins dramatically modify the environment of the host erythrocyte to create a niche suitable for parasite survival. We attempted to answer a critical question in disease pathogenesis involving the very beginning of this pathway. How are PEXEL-containing proteins recognised by Plasmepsin V? Using a proteomics based approach; we identified specific ER proteins that interact with PMV. The first of these, SPC25, provided the link between PMV and the protein entry site at the ER, the Sec61 translocon. Interestingly, this translocon was supplemented with an auxiliary partner protein Sec62, which converts the co-translational translocon to a post-translational form. This addition, as we identified, creates a new requirement for a distinct subset of PEXEL proteins to be fully translated in the parasite cytoplasm before being imported into the ER for PEXEL cleavage. We also discovered that the catalytic signal peptidase, which removes signal sequences, is not involved in this process and is also not associated with PMV in any form. This paper can be found here at Nature MIcrobiology: https://doi.org/10.1038/s41564-018-0219-2 In trying to answer a single question, we ended up answering several queries that had been nagging the malaria field. It also opened up exciting new avenues for exploration. What is the molecular mechanism by which Sec62 interacts with PEXEL proteins? Does it act as a direct PEXEL detector or is there an intermediary in this process? Does the translocon that imports PEXEL proteins contain novel components that could give us new insight into post-translational protein translocation? What happens to the mature PEXEL protein post-PMV cleavage? We believe that answering these questions will provide valuable information about the mechanism by which the most deadly human parasite causes disease.

Go to the profile of Danushka Marapana
Aug 26, 2018
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At the point at which the major disease symptoms are observed, the parasites hide inside red blood cells (RBCs); cells that are terminally differentiated and contain no nuclei or organelles that the parasite could subvert to its own ends. In addition, during the course of circulation the spleen routinely investigates RBCs and destroys those that show signs of structural damage. 

The trick the parasite pulls off is the ability to survive, and indeed thrive, within a cell that for all intents and purposes appears to be overtly inhospitable. Once within the cell, the parasite also establishes multiple membrane barriers (the inner parasite membrane and the outer parasitophorous vacuole membrane (PVM)) between itself and the host cell cytoplasm, therefore rendering intraerythrocytic survival even more problematic. 

The parasite overcomes these biological obstacles by means of a simple barcode. This signal, reported by two independent groups in 2004, is termed the Plasmodium Export Element or PEXEL. At its core, the PEXEL is a substrate for an export-licensing enzyme with the parasite endoplasmic reticulum known as Plasmepsin V or PMV. The PEXEL is found at the N-terminus of a protein following a predicted hydrophobic region (predominantly the signal sequence). Its cleavage by PMV results in the now-matured protein being exported beyond the parasitophorous vacuole and into the host cell cytoplasm. These exported proteins dramatically modify the environment of the host erythrocyte to create a niche suitable for parasite survival. 

We attempted to answer a critical question in disease pathogenesis involving the very beginning of this pathway. 

How are PEXEL-containing proteins recognised by Plasmepsin V? 

Using a proteomics based approach; we identified specific ER proteins that interact with PMV. The first of these, SPC25, provided the link between PMV and the protein entry site at the ER, the Sec61 translocon. Interestingly, this translocon was supplemented with an auxiliary partner protein Sec62, which converts the co-translational translocon to a post-translational form. This addition, as we identified, creates a new requirement for a distinct subset of PEXEL proteins to be fully translated in the parasite cytoplasm before being imported into the ER for PEXEL cleavage. We also discovered that the catalytic signal peptidase, which removes signal sequences, is not involved in this process and is also not associated with PMV in any form. 

This paper can be found here at Nature MIcrobiology: go.nature.com/2LvRKn5

In trying to answer a single question, we ended up answering several queries that had been nagging the malaria field. It also opened up exciting new avenues for exploration. 

What is the molecular mechanism by which Sec62 interacts with PEXEL proteins? Does it act as a direct PEXEL detector or is there an intermediary in this process? Does the translocon that imports PEXEL proteins contain novel components that could give us new insight into post-translational protein translocation? What happens to the mature PEXEL protein post-PMV cleavage? 

We believe that answering these questions will provide valuable information about the mechanism by which the most deadly human parasite causes disease. 

Go to the profile of Danushka Marapana

Danushka Marapana

Postdoctoral Fellow, The Walter and Eliza Hall Institute of Medical Research

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