Poster Presentation First Malaria World Congress 2018

Malaria effector proteins traffic via a distinct ER interactome that licenses parasite virulence (#335)

Danushka S Marapana 1 , Laura F Dagley 1 , Jarrod J Sandow 1 , Thomas Nebl 1 , Tony Triglia 1 , Michał Pasternak 1 , Benjamin K Dickerman 2 , Brendan S Crabb 2 , Paul R Gilson 2 , Andrew I Webb 2 , Justin A Boddey 1 , Alan F Cowman 1
  1. Walter and Eliza Hall Institute, Parkville, Melbourne, VIC, Australia
  2. Burnet Institute, Melbourne, Victoria, Australia

The most lethal human malaria is caused by Plasmodium falciparum with over 450,000 deaths each year. All disease symptoms occur due to parasite infection of human erythrocytes.

Following erythrocyte invasion, the parasite induces remarkable changes to the host cell’s biochemical and biophysical properties, a process termed remodeling. Remodeling is mediated by the trafficking of 10% of the parasite proteome into the host cytoplasm and membrane.

During erythrocyte infection the parasite resides in a membrane-bound parasitophorous vacuole (PV), separating it from the erythrocyte cytosol. Presence of the PV requires the parasite to overcome an extra membrane barrier in order to export proteins into the host cell.

Majority of exported parasite proteins contain unusual ER entry signal sequences followed by a distinct N-terminal motif known as the Plasmodium Export Element (PEXEL). Current evidence suggests that exported proteins are co-translationally translocated into the parasite ER, where the signal sequence is removed by catalytic signal peptidase and the PEXEL is subsequently cleaved by an ER protease termed Plasmepsin V (PMV). PMV is an excellent antimalarial drug target as PEXEL cleavage by PMV is essential for protein export and inhibition of PMV is lethal to parasite survival.

Contrary to current knowledge, we discovered that PMV-dependent exported proteins are translocated to the ER by the ER protein Sec62 and that this occurs at ER translocons dedicated to translocating exported proteins. PMV is linked to this translocation site by a non-catalytic subunit of the signal peptidase complex. This site houses PMV but not catalytic signal peptidase, which implies that exported proteins divert away from classical protein secretion and toward an export pathway at the point of protein translocation into the ER.

To date, this is the first report in a eukaryotic human pathogen where dedicated ER translocons function in translocation and maturation of distinct cargo.