PT  - JOURNAL ARTICLE
AU  - Fierro, Manuel A.
AU  - HortuaTriana, Miryam A.
AU  - Brooks, Carrie F.
AU  - Asady, Beejan
AU  - Li, Catherine
AU  - Moreno, Silvia N.J.
AU  - Muralidharan, Vasant
TI  - An ER-resident calcium binding protein modulates egress of malaria parasites from erythrocytes
AID  - 10.1101/457481
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 457481
4099  - http://biorxiv.org/content/early/2018/11/01/457481.short
4100  - http://biorxiv.org/content/early/2018/11/01/457481.full
AB  - Calcium signaling pathways coordinate the lifecycle progression of apicomplexan parasites, specifically playing a key role in egress from host cells. The main Ca2+-signaling hub in these divergent eukaryotic parasites is presumed to be the endoplasmic reticulum (ER); 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) 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-resident protein in Plasmodium that modulates egress of malaria parasites.