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Plasmodium falciparum S-adenosylmethionine synthetase is essential for parasite survival through a complex interaction network with cytoplasmic and nuclear proteins

ABSTRACT: Life-cycle progression of the human malaria parasite Plasmodium falciparum in the human and mosquito hosts requires epigenetic mechanisms to regulate the stage-dependency of gene expression, including DNA and histone methylation. Methylation reactions require S-adenosylmethionine (SAM), a universal biological methyl donor whose synthesis is catalyzed by the enzyme S-adenosylmethionine synthetase (SAMS). In P. falciparum, PfSAMS is encoded by a single gene and has been suggested to be crucial for malaria pathogenesis and transmission; however, to date PfSAMS has not been fully characterized. To gain deeper insight into the function of PfSAMS, we generated a conditional gene knockdown (KD) using the pSLI-glmS system. We show that PfSAMS is expressed in the cytosol and nucleus of blood stage parasites. PfSAMS-KD results in reduced histone methylation marks and leads to impaired intraerythrocytic growth and gametocyte development. To further determine the interaction network of PfSAMS we performed BioID analyses. We identified 664 nuclear and 213 cytosolic interactors linked to biological processes like transcriptional and cell cycle regulation. Our interaction data further unveil PfSAMS-specific interaction clusters of proteins involved in DNA replication, transcription and translation as well as proteostasis. Our findings emphasize the key roles of PfSAMS during intraerythrocytic growth and sexual stage development.

ORGANISM(S): Cellular Organisms

SUBMITTER: Gabriele Pradel

PROVIDER: PXD034111 | JPOST Repository | Wed Jul 13 00:00:00 BST 2022

REPOSITORIES: jPOST

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Project description:Plasmodium falciparum is the main causative agent of human malaria. During the intraerythrocytic development cycle, P. falciparum morphology changes dramatically from circulating young rings to sequestered mature trophozoites and schizonts. Sequestered forms contribute to the pathophysiology of severe malaria as the infected erythrocytes obstruct the microvascular flow in deep organs and induce local inflammation. However, the sequestration mechanism limits the access to the corresponding parasitic form in clinical samples from patients infected with P. falciparum. To complement this deficiency, we aimed to evaluate the relevance of mRNA study as a proxy of protein expression in sequestered parasites. To do so, we conducted a proteotranscriptomic analysis using five independent P. falciparum laboratory strains samples. RNA sequencing was performed on circulating ring stage parasites and LC-MS/MS on the corresponding sequestered mature forms. All analyzes were performed within the same development cycle for direct individual correlation. mRNA expression level was assessed at the circulating ring stage and the corresponding protein expression level was measured after 18h-24h of maturation to reach the mature trophozoite stage. Overall, our results showed a strong transcriptome/transcriptome and proteome/proteome correlation between samples. Moreover, strong correlations of mRNA and proteins expressions levels were found between ring stage transcriptomes and mature forms proteomes. However, twice more transcripts were identified at ring stage than proteins at mature trophozoite stage. A high level of transcript expression did not guarantee the detection of the corresponding protein. Finally, we pointed out discrepancies at the individual gene level. Taken together, our results show that transcripts and proteins expression are overall correlated. However, mRNA abundance is not a perfect proxy of protein expression at the individual level. Importantly, our study shows limitations of the “blind” use of RNA-seq and the importance of multi-omics approaches for P. falciparum blood stage study in clinical samples.

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Plasmodium falciparum S-adenosylmethionine synthetase is essential for parasite survival through a complex interaction network with cytoplasmic and nuclear proteins

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