Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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TCR alpha sequencing of CD4+ Tcells infiltrating melanoma B16 control or depleted of Elp3

ABSTRACT: The tRNA epitranscriptome is composed of a wide variety of base modifications in tRNAs and is emerging as a potential key vulnerability of cancer. Wobble tRNA modifications are required for specific codon decoding during translation and maintenance of protein homeostasis and support cancer metastasis and resistance to therapy. Here we show that ablation of enzymes catalyzing wobble uridine (U34) tRNA modification (U34 enzymes) remodels the MHC-II-associated antigen repertoire of melanoma by perturbing codon-specific mRNA translation. This perturbation in translation triggers the formation of aggregates that are subsequently degraded through the autophagy-lysosomal pathway and presented on MHC-II. The remodeled MHC-II repertoire in turn induces a CD4+ effector T cell-mediated anti-tumor response displaying specific clonal selection and immunodominance in melanoma. Our results identify a novel, potentially tractable, vulnerability of melanoma, in which codon-specific mRNA translation through wobble uridine tRNA modification, optimizes proteome homeostasis, prevents excessive antigen presentation, and limits T cell activity in melanoma.

INSTRUMENT(S): Illumina MiSeq

ORGANISM(S): Mus musculus

SUBMITTER: Francesca Rapino

PROVIDER: E-MTAB-13867 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project 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.

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TCR alpha sequencing of CD4+ Tcells infiltrating melanoma B16 control or depleted of Elp3

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