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Ca2+ signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.

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posted on 30.03.2021, 10:41 by Aurélia C Balestra, Konstantinos Koussis, Natacha Klages, Steven A Howell, Helen R Flynn, Marcus Bantscheff, Carla Pasquarello, Abigail J Perrin, Lorenzo Brusini, Patrizia Arboit, Olalla Sanz, Laura Peces-Barba Castaño, Chrislaine Withers-Martinez, Alexandre Hainard, Sonja Ghidelli-Disse, Ambrosius P Snijders, David A Baker, Michael J Blackman, Mathieu Brochet
Calcium signaling regulated by the cGMP-dependent protein kinase (PKG) controls key life cycle transitions in the malaria parasite. However, how calcium is mobilized from intracellular stores in the absence of canonical calcium channels in Plasmodium is unknown. Here, we identify a multipass membrane protein, ICM1, with homology to transporters and calcium channels that is tightly associated with PKG in both asexual blood stages and transmission stages. Phosphoproteomic analyses reveal multiple ICM1 phosphorylation events dependent on PKG activity. Stage-specific depletion of Plasmodium berghei ICM1 prevents gametogenesis due to a block in intracellular calcium mobilization, while conditional loss of Plasmodium falciparum ICM1 is detrimental for the parasite resulting in severely reduced calcium mobilization, defective egress, and lack of invasion. Our findings suggest that ICM1 is a key missing link in transducing PKG-dependent signals and provide previously unknown insights into atypical calcium homeostasis in malaria parasites essential for pathology and disease transmission.

Funding

Crick (Grant ID: 10043, Grant title: Blackman FC001043) Crick (Grant ID: 10011, Grant title: STP Proteomics) Wellcome Trust (Grant ID: 106239/Z/14/A, Grant title: WT 106239/Z/14/A)

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