Dataset Information

Phosphorylation Dependent Assembly of a 14-3-3 Anchored Signaling Complex During Erythrocyte Invasion by Plasmodium falciparum Merozoites

ABSTRACT: Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signalling pathways. However, the signalling pathways in merozoites that regulate microneme secretion and RBC invasion are not completely understood. Exposure of P. falciparum merozoites to a low potassium (K+) ionic environment as found in blood plasma has been shown to lead to a rise in cytosolic calcium (Ca2+), which triggers microneme secretion. Here, we present a phosphoproteome analysis of extracellular merozoites revealing 3700 phosphorylation sites of which 1705 were not previously known. Upon investigation of phosphorylation changes in merozoites subjected to different ionic environments (high K+/ low K+) we identified 394 protein phosphorylation sites out of which changes in 143 were Ca2+-dependent. We observed that the catalytic and regulatory subunits of protein kinase A (PfPKAc and PfPKAr), calcium-dependent protein kinase 1 (PfCDPK1) and scaffold protein Pf14-3-3I form a phosphorylation-dependent multiprotein complex when merozoites are exposed to the low K+ signal. Moreover, disruption of this complex using phospho-peptides, or small molecule inhibitors blocks microneme secretion and RBC invasion. This study sheds light on the regulatory mechanisms used by merozoites to invade RBCs and identifies new targets for development of drugs against malaria.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Plasmodium Falciparum (isolate 3d7)

DISEASE(S): Plasmodium Falciparum Malaria

SUBMITTER: Thibaut Douché

LAB HEAD: Chetan Chitnis

PROVIDER: PXD015093 | Pride | 2021-03-05

REPOSITORIES: Pride

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Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by Plasmodium falciparum Merozoites.

More Kunal R KR Kaur Inderjeet I Giai Gianetto Quentin Q Invergo Brandon M BM Chaze Thibault T Jain Ravi R Huon Christéle C Gutenbrunner Petra P Weisser Hendrik H Matondo Mariette M Choudhary Jyoti S JS Langsley Gordon G Singh Shailja S Chitnis Chetan E CE

mBio 20200818 4

Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signaling pathways. Exposure of P. falciparum merozoites to the physiological signal of low K+, as found in blood plasma, leads to a rise in cytosolic Ca2+, which mediates microneme secretion, motility, and invasion. We have used global phosphoproteomic analysis of merozoites to identify signaling pathways that are activated during invasion. Using quantitative ...[more]

PMID: 32817103

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Project description:Gene expression in malaria parasites is subject to various layers of regulation, including histone post-translational modifications (PTMs). Gene regulatory mechanisms have been extensively studied during the main developmental stages of Plasmodium parasites inside erythrocytes, from the ring stage following invasion to the schizont stage leading up to egress. However, gene regulation in merozoites that mediate the transition from one host cell to the next is an understudied area of parasite biology. Here, we sought to characterize gene expression and the corresponding histone PTM landscape during this stage of the parasite lifecycle through RNA-seq and ChIP-seq on P. falciparum blood stage schizonts, merozoites, and rings, as well as P. berghei liver stage merozoites. In both hepatic and erythrocytic merozoites, we identified a subset of genes with a unique histone PTM profile characterized by depletion of H3K4me3 in their promoter regions. These genes were upregulated in merozoites and rings, had roles in protein export, translation, and host cell remodeling, and shared a DNA motif. These results indicate that similar regulatory mechanisms may underlie merozoite formation in the liver and blood stages. We also observed that H3K4me2 was deposited in gene bodies of gene families encoding variant surface antigens in erythrocytic merozoites, which may facilitate switching of gene expression between different members of these families. Finally, H3K18me and H2K27me were uncoupled from gene expression and were enriched around the centromeres in erythrocytic merozoites, suggesting roles in the maintenance of chromosomal organization during schizogony. Together, our results demonstrate that extensive changes in gene expression and histone landscape occur during the schizont-to-ring transition to facilitate productive erythrocyte infection. The dynamic remodeling of the transcriptional program in hepatic and erythrocytic merozoites makes this stage attractive as a target for novel anti-malarial approaches that may have activity against both the liver and blood stages.

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