Unveiling novel conserved HIV-1 open reading frames encoding T-cell antigens using ribosome profiling.
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ABSTRACT:
PROVIDER: PRJNA1001014 | ENA |
REPOSITORIES: ENA
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Project description:Protein-coding small open reading frames (smORFs) are emerging as an important class of genes, however, the coding capacity of smORFs in the human genome is unclear. By integrating de novo transcriptome assembly and Ribo-Seq, we confidently annotate thousands of novel translated smORFs in three human cell lines. We find that smORF translation prediction is noisier than for annotated coding sequences, underscoring the importance of analyzing multiple experiments and footprinting conditions. These smORFs are located within non-coding and antisense transcripts, the UTRs of mRNAs, and unannotated transcripts. Analysis of RNA levels and translation efficiency during cellular stress identifies regulated smORFs and provides an approach for identifying smORFs for further investigation. Sequence conservation and signatures of positive selection indicate that encoded microproteins are likely functional. Additionally, proteomics data from enriched human leukocyte antigen complexes validates the translation of hundreds of smORFs and positions them as a source of novel antigens. Thus, smORFs represent a significant number of important, yet unexplored human genes.
2019-07-03 | GSE125218 | GEO
Project description:Upstream open reading frames (uORFs) represent translational control elements within eukaryotic transcript leader sequences. Recent data showed that uORFs can encode for biologically active proteins and human leucocyte antigen (HLA)-presented peptides and suggest their potential role in cancer cell development and survival. However, it is so far unclear if uORF-encoded peptides could serve as tumor-associated antigen targets and thus also play a role in cancer immune surveillance. Combining mass spectrometry-based immunopeptidome analysis in primary tumor and healthy tissues and evaluation of proto-oncogene-associated uORF-mediated translational control we here identified a panel of HLA-presented tumor-associated uORF-derived antigens. These uORF-derived tumor antigens were further shown to induce multifunctional antigen-specific T cells, validating their suitability as antigen targets for T cell-based cancer immunotherapy. Our data further unravel the role of uORF-encoded peptides in malignant disease, suggesting uORF-derived tumor-associated antigens as targets for anti-cancer immune surveillance and immunotherapy development.
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Project description:We present a genome-wide assessment of small open reading frames (smORF) translation by ribosomal profiling of polysomal fractions in Drosophila S2 cell. In this way, mRNAs bound by multiple ribosomes and hence actively translated can be isolated and distinguished from mRNAs bound by sporadic, putatively non-productive single ribosomes or ribosomal subunits. Ribosomal profiling of large and small polysomal fractions in Drosophila S2 cells to assess translation of smORFs
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Project description:Ribosome profiling has revealed pervasive but largely uncharacterized translation outside of canonical coding sequences (CDSs). Here, we exploit a systematic CRISPR-based screening strategy to identify hundreds of non-canonical CDSs that are essential for cellular growth and whose disruption elicit specific, robust transcriptomic and phenotypic changes in human cells. Functional characterization of the encoded microproteins reveals distinct cellular localizations, specific protein binding partners, and hundreds that are presented by the HLA system. Interestingly, we find multiple microproteins encoded in upstream open reading frames, which form stable complexes with the main, canonical protein encoded on the same mRNA, thus revealing the diverse use of functional bicistronic operons in mammals. Together, our results point to a family of functional human microproteins that play critical and diverse cellular roles.
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