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Metabolic dependency of ribosome heterogeneity in the human malaria parasite

ABSTRACT: To infect new hosts, the human malaria parasite Plasmodium falciparum needs to transmit to a mosquito vector. One of the most compelling adaptations to the two different host environments is the transcription of divergent ribosomal RNA genes that are transcribed from distinct genomic loci. Here we show that the silencing of mosquito-stage specific rRNA transcription is coupled to the level of aerobic glycolysis, the parasites premier metabolic pathway in the human host. We show that NAD+ levels originating from lactate fermentation are translated on a molecular level by the histone deacetylase Sir2a. By comprehensively characterizing histone epigenetic modifications in Sir2a-KO and wild-type cells coupled with quantitative chromatin immunoprecipitation, we show that the parasite metabolic state is linked to a functional transcriptional output.

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ORGANISM(S): Plasmodium Falciparum

SUBMITTER: Vanessa Masson

LAB HEAD: Damarys Loew

PROVIDER: PXD060142 | Pride | 2025-11-25

REPOSITORIES: Pride

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Project description:Chromatin structure and function is maintained by dynamic protein-protein and protein-nucleic acid interactions. Histones are a family of proteins that are abundant chromatin constituents and that carry numerous post-translational modifications (PTMs). Histone PTMs mediate a variety of biological activities, including recruitment of enzymatic readers, writers and erasers that modulate protein activities, DNA replication, transcription and repair. Individual histone molecules contain multiple co-existing PTMs some of which exhibit crosstalk, i.e. coordinated or mutually exclusive activities. We here present an integrated experimental and computational approach for systems level molecular characterization of PTMs and PTM crosstalk. Using wildtype and engineered mouse embryonic stem cells with perturbations in the Polycomb Repressive Complex 1 (PRC1, suz12-/-), PRC2 (Ring1A/b-/-) and DNA methyltransferases (Dnmt1/3a/3b-/-) we performed comprehensive PTM analysis of histone H3 tails. We identified unique histone H3 PTM features of each of the four cell lines and we detected common combinatorial PTM features across cell lines. Using quantitative middle-down proteomics combined with probabilistic and statistical data analysis we extracted histone H3 PTM profiles for all four mESC systems. PTM crosstalk emerged as mutually exclusive histone PTMs or coordinately regulated PTMs independent of histone peptide abundance in the four model systems. We detected positive crosstalk between adjacent mono-methylated marks but strong negative crosstalk among most of the seven characterized di- and tri-methylations on lysines. We report novel features of PTM interplay involving hitherto poorly characterized arginine methylation and lysine methylation sites in histone H3, including H3R2me, H3R8me and H3K37me, which exhibited specific PTM codes suggesting a particular role in chromatin. All histone H3 PTM data is available in our publicly available CrossTalkDB repository at http://crosstalkdb.bmb.sdu.dk

			Action	DRS
	DesignPRIDE.xlsx	Xlsx
	F036348.dat	Other
	F036349.dat	Other
	F036350.dat	Other
	F036351.dat	Other

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Metabolic dependency of ribosome heterogeneity in the human malaria parasite

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