An ER CREC family protein regulates the egress proteolytic cascade in malaria parasites

The endoplasmic reticulum is thought to play an essential role during egress of malaria parasites because the ER is assumed to be the calcium (Ca2+) signaling hub and required for biogenesis of egress organelles. However, no proteins localized to the parasite ER have been shown to play a role in egress of malaria parasites. In this study, we generated conditional mutants of the Plasmodium falciparum Endoplasmic Reticulum-resident Calcium-binding protein (PfERC), a member of the CREC family. Knockdown of PfERC shows that this gene is essential for asexual growth of P. falciparum. Analysis of the intraerythocytic lifecycle revealed that PfERC is required for parasite egress and invasion. We found that PfERC knockdown prevents the rupture of the parasitophorous vacuole membrane. This is because PfERC knockdown inhibited the proteolytic maturation of the subtilisin-like serine protease, SUB1, and the essential SUB1 substrate, the merozoite surface protein 1. PfERC knockdown further inhibited the proteolytic maturation of the essential invasion ligand, Apical Membrane Antigen 1 (AMA1), which occurs during egress. These data establish the ER-resident CREC family protein, PfERC, as a key early regulator of the egress proteolytic cascade of malaria parasites.