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

ABSTRACT: 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.

SUBMITTER: Balestra AC

PROVIDER: S-EPMC7990342 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Ca<sup>2+</sup> signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.

Balestra Aurélia C AC Koussis Konstantinos K Klages Natacha N Howell Steven A SA Flynn Helen R HR Bantscheff Marcus M Pasquarello Carla C Perrin Abigail J AJ Brusini Lorenzo L Arboit Patrizia P Sanz Olalla O Castaño Laura Peces-Barba LP Withers-Martinez Chrislaine C Hainard Alexandre A Ghidelli-Disse Sonja S Snijders Ambrosius P AP Baker David A DA Blackman Michael J MJ Brochet Mathieu M

Science advances 20210324 13

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 <i>Plasmodium</i> 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 mu ...[more]

PMID: 33762339

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Project description:BackgroundEgress of Plasmodium falciparum, from erythrocytes at the end of its asexual cycle and subsequent parasite invasion into new host cells, is responsible for parasite dissemination in the human body. The egress pathway is emerging as a coordinated multistep programme that extends in time for tens of minutes, ending with rapid parasite extrusion from erythrocytes. While the Ca2+ regulation of the invasion of P. falciparum in erythrocytes is well established, the role of Ca2+ in parasite egress is poorly understood. This study analysed the involvement of cytoplasmic free Ca2+ in infected erythrocytes during the multistep egress programme of malaria parasites.MethodsLive-cell fluorescence microscopy was used to image parasite egress from infected erythrocytes, assessing the effect of drugs modulating Ca2+ homeostasis on the egress programme.ResultsA steady increase in cytoplasmic free Ca2+ is found to precede parasite egress. This increase is independent of extracellular Ca2+ for at least the last two hours of the cycle, but is dependent upon Ca2+ release from internal stores. Intracellular BAPTA chelation of Ca2+ within the last 45 minutes of the cycle inhibits egress prior to parasitophorous vacuole swelling and erythrocyte membrane poration, two characteristic morphological transformations preceding parasite egress. Inhibitors of the parasite endoplasmic reticulum (ER) Ca2+-ATPase accelerate parasite egress, indicating that Ca2+ stores within the ER are sufficient in supporting egress. Markedly accelerated egress of apparently viable parasites was achieved in mature schizonts using Ca2+ ionophore A23187. Ionophore treatment overcomes the BAPTA-induced block of parasite egress, confirming that free Ca2+ is essential in egress initiation. Ionophore treatment of immature schizonts had an adverse effect inducing parasitophorous vacuole swelling and killing the parasites within the host cell.ConclusionsThe parasite egress programme requires intracellular free Ca2+ for egress initiation, vacuole swelling, and host cell cytoskeleton digestion. The evidence that parasitophorous vacuole swelling, a stage of unaffected egress, is dependent upon a rise in intracellular Ca2+ suggests a mechanism for ionophore-inducible egress and a new target for Ca2+ in the programme liberating parasites from the host cell. A regulatory pathway for egress that depends upon increases in intracellular free Ca2+ is proposed.

Dataset Information

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

Publications

Ca<sup>2+</sup> signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

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

Publications

Ca&lt;sup&gt;2+&lt;/sup&gt; signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Ca<sup>2+</sup> signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.