PXD043747

PXD043747 is an original dataset announced via ProteomeXchange.

Title	tRNA modification reprogramming of Plasmodium falciparum as a feature of artemisinin resistance
Description	Artemisinin (ART)-resistant Plasmodium falciparum (Pf) threatens global malaria control. Resistance, driven by mutations in Pfk13, is multifaceted but quiescence plays a central role. Epigenetic regulation may contribute, given that only a percentage of parasites survive a pulse of the active drug metabolite dihydroartemisinin (DHA). The identities or roles of these epigenetic factors, however, have yet to be identified. tRNA modifications are a conserved epigenetic translational control mechanism, whereby cellular stress leads to modification reprogramming and codon-biased translation. Here we use liquid chromatography-mass spectrometry to profile tRNA modifications in ring-stage ART-sensitive (ART-S) Dd2 and ART-resistant (ART-R) Dd2PfK13_R539T before and after drug pulse. ART-R parasites differentially reprogram their tRNA modification profiles in response to DHA, specifically by mcm5s2U hypomodification of tRNAs. Proteomic and subsequent codon usage analysis revealed that the ART-R parasite proteome displays codon bias, uncovering a new layer of proteomic regulation in drug-resistant parasites. A subset of these proteins were not transcriptionally regulated, suggesting codon-bias translation. Upregulated proteins were enriched for LysAAA, HisCAT and AspGAT and downregulated proteins were enriched for their cognate codons (LysAAG, HisCAC and AspGAC). PfK13 and its interacting partner BIP were among the codon-controlled upregulated proteins. Interestingly, mcm5s2U occurs on the U34 of LysAAA/AAG codons to regulate translational fidelity, providing a mechanistic link between tRNA modification and proteomic data. Transcriptomics revealed enrichment of wobble-base tRNA modification in ART-R parasites post-ART treatment. An anhydrotetracycline-regulated conditional knockdown (cKD) of the terminal s2U methyltransferase, PfMnmA, displayed increased ART survival, signifying that hypomodification plays a critical role in the ART-R parasite response to DHA. cKD parasites also had altered responses to proteotoxic and mitochondrial antimalarials, uncovering overlaps between epigenetic stress response pathways. This work describes a novel epigenetic pathway via tRNA s2U reprogramming that ART-R parasites may use to help survive ART-induced stress.
HostingRepository	PRIDE
AnnounceDate	2024-06-22
AnnouncementXML	Submission_2024-06-22_08:43:11.267.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD043747
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	AMEYA SINHA
SpeciesList	scientific name: Plasmodium falciparum; NCBI TaxID: 5833;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-13 02:08:36	ID requested
⏵ 1	2024-06-22 08:43:12	announced

10.6019/PXD043747;

10.1038/s41564-024-01664-3;

Small-Saunders JL, Sinha A, Bloxham TS, Hagenah LM, Sun G, Preiser PR, Dedon PC, Fidock DA, tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum. Nat Microbiol, 9(6):1483-1498(2024) [pubmed]

submitter keyword: Plasmodium, Artemisinin, RNA modification

Peter Preiser
contact affiliation	School of Biological Sciences
contact email	prpreiser@ntu.edu.sg
lab head
AMEYA SINHA
contact affiliation	NTU
contact email	ameya.sinha@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043747
     1. Label: PRIDE project
     2. Name: tRNA modification reprogramming of Plasmodium falciparum as a feature of artemisinin resistance