A multipass membrane protein interacts with the cGMP-dependent protein kinase to regulate critical calcium signals in malaria parasites

In malaria parasites, all cGMP-dependent signalling is mediated through a single cGMP-dependent protein kinase (PKG), a major function of which is to control essential calcium signals. However, how PKG transmits these signals in the absence of known second messenger-dependent calcium channels or sca...

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Published inbioRxiv
Main Authors Balestra, Aurelia C, Koussis, Konstantinos, Klages, Natacha, Howell, Steven A, Flynn, Helen R, Bantscheff, Marcus, Pasquarello, Carla, Perrin, Abigail J, Brusini, Lorenzo, Arboit, Patrizia, Sanz, Olalla, Laura Peces-Barba Castano, Withers-Martinez, Chrislaine, Hainard, Alexandre, Ghidelli-Disse, Sonja, Snijders, Ambrosius P, Baker, David A, Blackman, Michael J, Brochet, Mathieu
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 18.07.2020
Subjects
Calcium (intracellular)
Calcium channels
Calcium homeostasis
Calcium signalling
Cyclic GMP
Disease transmission
Gametocytes
Gametogenesis
Homeostasis
Homology
Kinases
Malaria
Membrane proteins
Parasites
Phosphorylation
Plasmodium falciparum
Protein kinase
Protein kinase G
Proteins
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Summary:In malaria parasites, all cGMP-dependent signalling is mediated through a single cGMP-dependent protein kinase (PKG), a major function of which is to control essential calcium signals. However, how PKG transmits these signals in the absence of known second messenger-dependent calcium channels or scaffolding proteins is unknown. Here we identify a polytopic membrane protein, ICM1, with homology to transporters and calcium channels that is tightly-associated with PKG in both Plasmodium falciparum asexual blood stages and P. berghei gametocytes. Phosphoproteomic analyses in both Plasmodium species reveal multiple ICM1 phosphorylation events dependent upon PKG activity. Stage-specific depletion of P. berghei ICM1 blocks gametogenesis due to the inability of mutant parasites to mobilise intracellular calcium upon PKG activation, whilst conditional loss of P. falciparum ICM1 results in reduced calcium mobilisation, defective egress and lack of invasion. Our findings provide new insights into atypical calcium homeostasis in malaria parasites essential for pathology and disease transmission. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.07.18.209973