RT Journal Article SR Electronic T1 An ER CREC family protein is a novel regulator of the egress proteolytic cascade in malaria parasites JF bioRxiv FD Cold Spring Harbor Laboratory SP 457481 DO 10.1101/457481 A1 Manuel A. Fierro A1 Miryam A. HortuaTriana A1 Carrie F. Brooks A1 Beejan Asady A1 Catherine Li A1 Silvia N.J. Moreno A1 Vasant Muralidharan YR 2018 UL http://biorxiv.org/content/early/2018/12/05/457481.abstract AB The role of the endoplasmic reticulum (ER) during egress of malaria parasites from erythrocytes is undefined. The parasite ER is thought to enable egress by acting as the main calcium (Ca2+) signaling hub in these divergent eukaryotic parasites. However, no proteins involved in Ca2+-signaling have been identified in the ER of these deadly human parasites. In this study, we explored the role of the Endoplasmic Reticulum-resident Calcium-binding protein (ERC), a member of the CREC family, in the lifecycle of two apicomplexan parasites, Toxoplasma gondii and Plasmodium falciparum. We find that the Toxoplasma ortholog (TgERC) plays a role in the storage of Ca2+ in the ER but is dispensable for the asexual lytic cycle. On the other hand, the Plasmodium ortholog (PfERC) is essential for asexual growth but not required for Ca2+ storage, organelle biogenesis, or protein trafficking. Instead, knockdown of PfERC inhibits parasite egress and invasion. Our results show that PfERC is critical for the rupture of the parasitophorous vacuole membrane, which is the first step in the egress of malaria parasites from erythrocytes. Surprisingly, PfERC knockdown does not affect the Ca2+-dependent autoprocessing of the key egress protease, SUB1, but knockdown inhibits the second proteolytic maturation of SUB1 that occurs during its secretion from exoneme vesicles. We have therefore identified the first ER protein in Plasmodium that regulates egress of malaria parasites.